Open Access

The dual roles of cytokines in Alzheimer’s disease: update on interleukins, TNF-α, TGF-β and IFN-γ

Translational Neurodegeneration20165:7

https://doi.org/10.1186/s40035-016-0054-4

Received: 1 January 2016

Accepted: 29 March 2016

Published: 5 April 2016

Abstract

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders in the elderly. Although the mechanisms underlying AD neurodegeneration are not fully understood, it is well recognized that inflammation plays a crucial role in the initiation and/or deterioration of AD neurodegeneration. Increasing evidence suggests that different cytokines, including interleukins, TNF-α, TGF-β and IFN-γ, are actively participated in AD pathogenesis and may serve as diagnostic or therapeutic targets for AD neurodegeneration. Here, we review the progress in understanding the important role that these cytokines or neuroinflammation has played in AD etiology and pathogenesis.

Keywords

Alzheimer’s disease Cytokines Interleukins TNF-α TGF-β IFN-γ

Background

Dementia has become a global challenge for public health. Currently, over 40 million people worldwide live with this condition and this number would double by 2030 and more than triple by 2050 [1]. Alzheimer’s disease (AD) is the most prevalent cause of dementia, characterized by progressive cognitive and functional impairments and as well as memory deterioration. Although much effort has been made in the past several decades to uncover the mechanism of AD pathogenesis and to further translate these findings into the clinic, there are still no mechanism-based treatments approved for this devastating disease and the current therapies only provide transient symptomatic release.

The two most well-known pathological hallmarks of AD are extracellular amyloid plaques comprised of aggregated Aβ, and intracellular neurofibrillary tangles (NFTs) generated by hyperphosphorylated microtubule-associated protein tau. Increasing evidence indicates that neuroinflammation can act as an independent factor at very early stage of AD, where the immune-related genes and cytokines are the key participants.

Cytokines are a heterogeneous group of proteins with molecular weights ranging from 8 to 40 kDa. These multifunctional molecules can be synthesized by nearly all nucleated cells and generally act locally in a paracrine or autocrine manner. Many of them are referred to as interleukins (ILs), indicating that they are secreted by and act on leukocytes. Other important types of cytokines, such as tumor necrosis factors (TNFs), interferons (IFNs) and transforming growth factors (TGFs) that can cause cell death, activate natural killer cells and macrophages, and induce phenotypic transformation and act as a negative autocrine growth factor, respectively. Another member of the big cytokine family is the chemokines, which can attract and activate leukocytes. In view of their relatively exclusive functions, chemokines are usually discussed separately.

As cytokines are rapidly changed in response to infections or trauma, they have been classified as either “pro-inflammatory” or “anti-inflammatory”. The balance between the two types of cytokines guarantees immediate elimination of the invading pathogens and the timely withdraw of excessive reaction, which is the key to preventing many diseases including the neurodegenerative diseases. The expression of cytokine receptors is temporally and spatially regulated in the central nervous system (CNS) [2], and they are closely involved in cell proliferation, gliogenesis, neurogenesis, cell migration, apoptosis, and synaptic release of neurotransmitters [3, 4].

Cytokines have attracted much attention towards their exact roles in different stages of AD and the possibility for therapeutics. However, cytokines levels detected in AD patients were inconsistent among different research groups, while regulating the expression of cytokines in AD animal models yielded unexpected results as well. Here, we will focus on the most extensively studied cytokines, including ILs, TNF-α, TGF-β and IFN-γ, looking for the commonness, reasoning the disagreement among recent studies and give suggestions about how to translate these precious findings from the laboratories to the clinic in AD.

Evidence from AD patients

The postmortem analysis of the AD brains has provided pioneering evidence for involvement of inflammation in AD pathology. IL-1β [5], IL-6 [6] and TGF-β [7] and many other cytokines have been found to accumulate around the amyloid plaques in the brain of AD patients, which led to numerous studies investigating the levels of pro-inflammatory and anti-inflammatory cytokines in the cerebral spinal fluid (CSF) or serum of patients with mild cognitive impairment (MCI) or AD. Although results are inconclusive, there appears a trend that pro-inflammatory (IL-1β, IL-6, TNF-α) and anti-inflammatory cytokines (IL-1 receptor antagonist (IL-1ra), IL-10) are both elevated in the CSF and plasma of AD patients [8]. The alterations of cytokine levels reflect the disturbance of immune system in AD, however, the evidence from the body fluid is insufficient to decide whether these changes are a initiating or secondary event of the disease, thus more approaches should be adopted to illustrate a more reliable picture for the role of cytokines.

Although the established genetic causes such as gene mutations encoding amyloid precursor protein (APP), presenelin 1 (PSEN1) and PSEN2 are only dominant to a minority of familial type of AD, these risk genes have deepened our understanding of AD mechanisms in many aspects. For instance, the heterozygous rare variants in gene coding triggering receptor expressed on myeloid cells 2 (TREM2) increases risk of AD with an unfavorable inflammatory condition for Aβ clearance [9], thus shedding a light on the possible initiating role of inflammation in AD pathogenesis.

To date, at least 23 cytokine polymorphisms involving 13 types of cytokines have been identified to be associated with AD. Based on the following three conditions (1) having polymorphisms that are significantly associated with AD, (2) having corresponding genotype/phenotype data, and (3) having previous records of the changed levels in AD patients, these cytokines can be divided into five groups as follows: (i) Cytokines like IL-1β, IL-6, IL-18 and TNF-α have the above three conditions. (ii) Cytokines like IL-4, IL-12, IL-23 and IFN-γ have the first two conditions but have no level change or the related data in AD, demanding new strategies to measure the cytokine level in AD patients, especially in those with the polymorphisms. (iii) Cytokines like IL-10 have conditions 1 and 3, calling for future studies. (iv) Cytokines like IL-1ra and TGF-β only meet condition 3 but have numerous evidence from both in vivo and in vitro studies, indicating that the genetic factor may not be crucial for their actions in AD or need further studies. (v) Cytokines like IL-16, IL-15 and IL-17 that either only have condition 1 or lack all three conditions still needs more evidence to confirm their involvement in AD.

Although many studies have discussed the polymorphism-related cytokine level changes, the data are mostly referenced from other research fields than AD, such as cancer. The direct evidence for the cytokine levels in different populations is also not convincing enough to draw a definite conclusion.

In the subgroup meta-analysis of cytokine polymorphisms, many grouping factors could decrease heterogeneity and improve significance, such as races [1014], apolipoprotein E (ApoE) ε4 allele and time of AD onset. As for races, it is rare to find significance in Asian and Caucasian populations, and in more extreme cases, a polymorphism indicates higher risk of AD in a population while shows lower risk in the other [12, 13]. This may be a result of the different frequencies of the polymorphism between different races and interplay of the variant with other unknown race-specific genes, or even with the environment. Of course, the influence from limited sample size of certain population cannot be excluded [15]. ApoE ε4 allele, the widely recognized late-onset AD triggering factor, is associated with at least 5 cytokine polymorphisms [1620], indicating a potential synergistic interaction between them. ApoE ε4 can modify AD risk in patients with diabetes or cardiovascular disease, which could be attributable to related hyperlipidemia and hypercholesterolemia. ApoE4 could also independently cause neurovascular dysfunction through triggering inflammatory cascades [21]. Thus, it would be necessary to know whether cytokines play the initiating or secondary role in the interaction with ApoE. In addition, although few studies clarified the time of AD onset in their samples, it seems from the present studies the alteration cytokine levels have more influence on the late-onset AD (LOAD). As many cytokines have a close interaction with ApoE, whether this potential synergistic effect is the sole reason to the onset-time association deserves further investigation.

When single polymorphism of a cytokine does not always guarantee significance, the haplotype of one or more different types of cytokines may show associations with AD [20, 22, 23]. There is also a positive and linear relation between the numbers of the pro-inflammatory cytokine polymorphisms and AD risk [24], which suggests that their corresponding proteins might interact with each other in a cumulative manner [25].

Compared with the widely recognized genetic risk factors like TREM2 or CD33 [26], the genetic evidence from cytokines may be insufficient to prove that cytokines levels imbalance alone is able to trigger AD. However, a polymorphism of IFN-γ is associated with fast progressing AD makes it certain that cytokines could play an active role in exacerbating the AD course [27]. Together, the cytokine polymorphisms may not markedly assist in predicting AD risk, but they have irreplaceable value in identifying pathways involved in the disorder and potential drug targets. The relationship between cytokines with races and ApoE and some of the AD-related cytokine polymorphisms are summarized in Table 1.
Table 1

Cytokine polymorphisms and levels in serum or CSF

Cytokinesa

Levelsb

Polymorphisms/haplotypes

Corresponding cytokine expressionc

Resultsd

Methods

Ref.

MCI

AD

Plasma/serum

CSF

Plasma/serum

CSF

IL-1 family [144]

IL-1α

=

\

= or ↓

\

-889 C/T (rs1800587)

T: ↑

* ↑ in EOAD

Meta-analysis

[145]

No * in LOAD.

* ↑ in Caucasians

Meta-analysis

[14]

No * in Asians.

IL-1β

=

↑or =

= or ↑

-511 C/T (rs16944)

?

no*

Meta-analysis

[15]

-31 T/C (rs1143627)

C: ?

*↓ in Italians

Case–control

[25]

−511C/−31 T/IL1RN2

?

*↓ in elderly group of Brazilians

Case–control

[23]

−511C/−31C/IL1RN1

?

* ↑ in Brazilians

Case–control

+3953 C/T (rs1143634)

T: ↑

* ↑ in non-Asians

Meta-analysis

[15], [14]

Exon 5 E1/E2

\

No* in Taiwan population

Case–control

[146]

IL-1ra

\

\

-

↓ [139]

Intron 2 I/II/IV

\

IL-18 [71]

=

\

= or ↑

-607 A/C (rs1946518)

C: ↑

* ↑ in LOAD of Han Chinese.

Case–control

[20]

*↑↑ in ApoE ε4 carrier.

-137 C/G (rs187238)

G: ↑

-607 C or -137 G

* ↑ in LOAD of Han Chinese.

IL-33 [147]

\

\

\

\

rs11792633 C/T

T: ↑

*↓ in non-ApoE ε4 carrier in both Caucasians and Han Chinese.

Case–control

[19],[148]

 

IL-4 [149]

\

\

\

\

-1098 T/G (rs2243248)

G: Possibly ↓

*↑ in Han Chinese

Case–control

[150]

T: Possibly ↓

*↑ in Caucasians

[151]

-590 C/T (rs2243250)

C: ↓

*↑ in Han Chinese and Caucasians

[150], [151]

IL-6 family

IL-6 [152, 153]

=

\

↑or =

= or ↑

-174 G/C (rs1800795)

C: ↓

*↓ in Asians, No* in Caucasians.

Meta-analysis

[10].

*↓ in Italians.

Case–control

[25]

-572 C/G (rs1800796)

C: ?

*↑ in ApoE ε4 carriers.

Case–control

[16]

IL-11 [154]

=

\

= or ↑

\

\

\

\

\

 

IL-10 [155, 156]

=

= or ↑

=

-1082 A/G (rs1800896)

A: ?

*↑ in Caucasians, No* in Asians.

Meta- analysis

[11]

G: ↑

↓ in Caucasians

Meta- analysis

[22]

-819 T/C (rs1800871)

?

no *

-592 A/C (rs1800872)

-1082G/-819C/-592C

?

IL-12 family [157]

IL-12A

=

\

=

=

rs2243115 T/G

G: ↓

*↓ in LOAD in ApoE ε4 carrier of Northern Han Chinese

Case–control

[17]

rs568408 G/A

A: ↓

*↓ in LOAD of Northern Han Chinese

IL-12B

=

\

=

=

rs3212227 A/C

C: ↓

*↓ in LOAD of Northern Han Chinese

IL-23

\

\

\

\

rs10889677 A/C (L-23R)

C: ↓

*↓ risk in Northern Han Chinese.

Case–control

[18]

rs1884444 T/G (IL-23R)

G: ↓

*↑ in ApoE ε4 carrier of Northern Han Chinese.

Case–control

 

IL-15 [158]

\

\

=

=[159]

\

\

\

\

\

 

IL-16 [160]

\

\

\

\

rs4072111 C/T

T: ?

*↓ in LOAD of Iranians.

Case–control

[161]

 

IL-17 [162]

\

\

\

\

\

\

\

\

\

 

TNF-α [163]

= or ↑

= or ↑ or ↓

= or ↑ or ↓

-308 G/A (rs1800629)

A: ↑

*↑ in East Asian

Meta-analysis

[12], [13]

*↓ in Northern European population.

No* in Italians

Case–control

[25]

 

TGF-β [164]

\

↑ or ↓ or =

↑ or ↓ or =

\

\

\

\

\

 

IFN-γ [165]

\

\

=

=

-874 T/A (rs62559044)

A: ↓

*↑ in fast progressing AD

Case–control

[27]

Abbreviation: IL-1 ra IL-1 receptor antagonist, EOAD early-onset Alzheimer’s disease, LOAD late-onset Alzheimer’s disease

aEach cytokine or cytokine family was supplemented with a latest review for detailed information of physiological parameters

b↑: up-regulated, ↓: down-regulated, =: no change, \: no data. Unless otherwise noted, all the data of cytokine levels is from Brosseron et al. 2014 [8]

c↑: enhance the cytokine expression, ↓: attenuate the cytokine expression, ?: unknown yet

d*: significant, ↑: higher risk of AD onset, ↓: lower risk of AD onset

Cytokines related to AD-like Aβ abnormalities

As one of the most well-known hallmarks of AD, Aβ is actively involved in the neuroinflammation. It is believed that Aβ has a predominant role in launching the detrimental self-exaggerated inflammation process that is responsible for the disease progression. The Aβ peptide is derived from amyloid precursor protein (APP) by sequential cleavages of two membrane-bound proteases. Aβ of different length, especially Aβ1-42 then form soluble oligomers and fibrils, the latter is the major component of extracellular amyloid plaques. Soluble Aβ can be degraded by various extracellular proteases, while fibrillary Aβ is phagocytosed by microglia, the resident phagocytes of CNS, then enter the endolysosomal pathway [28]. Astrocytes are also capable of degrading Aβ, primarily the cerebrovascular Aβ [29]. The dysregulation of Aβ clearance process resulted from the skewing of microglia or astrocytes to pro-inflammatory state, characterized by elevated levels of pro-inflammatory cytokines and compromised ability in Aβ clearance, will lead to Aβ accumulation and a sustained immune activation.

Several environmental factors, including diabetes, obesity, aging that are associated with immune disturbance could trigger the phenotype transformation of glial cells [28] through either direct modulation of the relevant mediators [30] or epigenetic modification [31]. Then, elicited by a self-propagating circle through the interaction between Aβ and pro-inflammatory cytokines [3234], the chronic inflammation state is ultimately independent of the primary stimulus, which is a possible explanation to the failure of anti-amyloid treatment strategies in late stage of AD [35].

Several anti-TNF-α biologic medications have rescued Aβ deposition, behavioral impairments and inflammation in AD animal models [3639], suggesting that TNF-α is a detrimental factor in AD course and can serve as a reliable AD target. However, hippocampal expression of TNF-α in APP transgenic mice at early stage induced robust glial activation that attenuate Aβ plaques without altering the APP levels [40]. Although there was only a suspicious infiltration of peripheral immune cells, increased major histocompatibility complex class II (MHC-II) cells were detected in the TNF-α expressing mice, indicating an enhanced antigen-presenting efficiency and more frequent communication with infiltrating T cells, which may facilitate Aβ removal.

Several studies indicate that overexpression of IL-1β in APP/PS1 mice reduces Aβ plaque accompanied by an activated population of microglia with greater phagocytosis [41, 42]. It is proposed that this group of microglia might be endogenous Arg-1+ M2a phenotype induced by Th2 cytokines, such as IL-4, secreted by a group of cells recruited to the Aβ plaques during the sustained IL-1β neuroinflammation [42]. The mice deficient in IL-1R had lower recruitment of microglia to amyloid plaques, implying that IL-1β can mediate microglial chemotaxis [43]. Moreover, IL-4 can down-regulate TNF-α and up-regulate MHC-II, insulin-like growth factor (IGF)-1 and CD36 in microglia [44], and thus not only decrease the neurotoxicity but also promote the ability of presenting antigen to T cells [45]. Similar results were also seen in IL-6 [46]. These studies indicate that overexpressing pro-inflmmatory cytokines in CNS may generate Aβ-clearance-promoting effect with a peripheral responses involved. However, it is noteworthy that none of these studies have relevant behavioral results (see Table 2), thus we cannot assess the overall result of this type of cytokine modulation. It is reported that chronic neuronal TNF-α expression in 3xTg AD mice led to large amount of neuronal death [47]. Whether the enhanced local inflammation and direct neurotoxicity or periphery-mediated Aβ reduction has larger impact on the cognitive performance needs further studies. Moreover, as the expressions of human APP or tau in AD animal models are driven by various unnatural transgene promoters, the possibility that some anti-cytokine molecules may act through interacting with these regulatory elements cannot be ruled out [37]. Therefore, a critical verification with alternative AD models is needed.
Table 2

Methods and results from in vivo studies of cytokines

Cytokinesa

Animals

Main AD-like Pathology and initiating time

Cytokines Expression System

Expression Duration

Resultsb

Ref.

Delivery Method

Administration Routes

Immuno-histochemistry

Behaviors

IL-1β

3xTg AD mice (9 months old)

Aβ plaque: 6 mo. Tau: 12 -15 mo.

anti-IL-1R blocking antibody

Peritoneal Injection

every 8-9 days for 6 months

Aβ deposition ↓; Tau phosphorylation ↓

Cognition ↑

[83]

Rats adult

-

IL-1β injections

Cerebral ventricles

1 d

TNF-α, IL-10 ↑

No significance

[34]

8 d

TNF-α, IL-1β ↑ IL-10 ↓; APP mRNA ↑

Memory ↓

3xTg AD mice (8 months old)

Aβ plaque: 6 mo. Tau:12 -15 mo.

IL-1β-XAT cassette

Subiculum

1 and 3 mo.

Aβ deposition ↓; Tau phosphorylation ↑

\

[41]

APPswe/PSEN1dE9 mice (8 months old)

Aβ plaque: 6 mo.

rAAV2-IL-1β

Hippocampi

1 mo.

Aβ deposition ↓

\

[42]

IL-6

TgCRND8 mice (0 -12 h old (P0)/36 -48 h old (P2))

Early Aβ plaque: 3mo. Dense-cored plaques: 5 mo.

rAAV2/1-IL-6

Cerebral ventricles

5 mo.

Aβ deposition ↓

\

[46]

TgCRND8 mice (4 mo.)

rAAV2/1-IL-6

Hippocampi

1-1.5 mo.

Aβ deposition ↓

\

Tg2576 mice (P0)

Numerous Aβ plaques:11-13 mo.

rAAV2/1-IL-6

Hippocampi

3 mo.

Aβ deposition ↓

\

IL-4

Tg2576 + PS1 mice (3 months old)

Aβ plaques: 6 mo.

rAAV2/1-IL-4

Hippocampi

5 mo.

Aβ↓; Gliosis ↓; Neurogenesis ↑

Spatial learning ↑

[54]

TgCRND8 mice (4 months old)

Early Aβ plaque: 3 mo.

rAAV2/1-IL-4

Hippocampi

1.5 mo.

Aβ↑; Gliosis ↑

\

[55]

APPswe/PSEN1dE9 mice (3 months old)

Aβ plaque: 6 mo.

rAAV2/1-IL-4

Frontal cortex, Hippocampi

43 d.

Aβ↓ with no significance; Enhanced M2a phenotype of microglia

\

[56]

IL-10

APPswe/PSEN1dE9 mice (3 months old)

Aβ plaques: 6 mo.

rAAV2/1-IL-10

Hippocampi

5 mo.

Aβ =; Gliosis ↓; Neurogenesis ↑.

Spatial learning ↑

[52]

TgCRND8 mice (P0/P2)

Early Aβ plaque: 3mo.

rAAV2/1-IL-10

Cerebral ventricles

6 mo.

Aβ deposition ↑

Cognition ↓

[51]

Tg2576 mice (8 months old)

Numerous Aβ plaques: 11-13 mo.

rAAV2/1-IL-10

Hippocampi

5 mo.

Aβ deposition ↑

Cognition ↓

APPswe/PSEN1dE9 mice

Aβ plaque: 6 mo.

Bred with IL-10 KO mice

The whole body

12-13 mo.

Aβ deposition ↓

Cognition ↑

[53]

IL-12/IL-23

APPswe/PSEN1dE9 mice

Aβ plaque: 6 mo.

Bred with p40 (IL-12 and IL-23 shared) KO, p35 (IL-12) KO or p19 (IL-23) KO mice

The whole body

4 mo.

Aβ deposition ↓ (especially with p40 KO)

Cognition ↑

[65]

Senescence accelerated mouse (SAMP8) mice (6 months old)

Accelerated aging.

siRNA KO of p40

Dorsal third ventricle

1 mo.

Aβ deposition ↓

Cognition ↑

[66]

TNF-α

TgCRND8 mice (4 months old)

Early Aβ plaque: 3 mo.

rAAV2/1-TNF-α

Hippocampi

1.5 mo.

Aβ deposition ↓

\

[40]

3xTg AD mice (10, 17 months old)

Aβ plaque: 6 mo. Tau: 12 -15 mo.

TNF-α-lowering agent (3,6'-dithiothalidomide)

Peritoneal Injection

1.5 mo.

APP, Aβ peptide and Aβ deposition ↓; Tau phosphorylation ↓

Cognition ↑

[37]

3xTg AD mice (6 months old)

TNF-α-lowering agent (IDT)

Oral administration

10 mo.

Fibrillar Aβ↓; PHF-tau ↓

Cognition ↑

[39]

TGF-β

hAPP J9 line mice

Aβ plaques :5-7 mo.

Bred with transgenic expressing astrocytes-induced TGF-β1 mice

Brain

12-15 mo.

Aβ deposition ↓; Perivascular Aβ deposition ↑

\

[57]

Transgenic mice with inducible neuron-specific expression of TGF-β1 (3 months old)

-

The heterologous tTA system

Neocortex, hippocampi, striatum

54 d

Perivascular Aβ deposition ↑

\

[62]

24 d

Death of neurons induced by 3-nitropropionic acid ↓

\

SD rats with Aβ1-42 injection in bilateral hippocampus

TGF-β1 injection 7 d after Aβ injection

Left cerebral ventricles

3d

APP ↓

Cognition ↑

[166]

SD rats with Aβ1-42 injection in bilateral hippocampus

TGF-β1 administration1h prior to Aβ injection

Cerebral ventricles

7 d

APP ↓; PP2A ↑; TNF-α, IL-1β, iNOS, IFN-γ, IL-2, IL-17 and IL-22 ↓.

Cognition ↑

[58]

TGF-β1 administration7 d after Aβ injection

Nares

7 d

PP2A ↑; IL-1β, iNOS, IFN-γ, IL-2 and IL-17 ↓.

Cognition ↑

IFN-γ

APP Tg J20 mice

Aβ plaques : 5-7 mo.

Bred with Tg SJL mice expressing IFN-γ

The whole body

9 mo.

Oligodendrogenesis ↓

\

[167]

3xTg AD mice (2 months old)

Aβ plaque: 6 mo. Tau:12 -15 mo.

rAAV2/1- IFN-γ

Hippocampi

10 mo.

Aβ deposition ↑; Tau phosphorylation ↓

\

[168]

TgCRND8 mice P2

Early Aβ plaque: 3mo. Dense-cored plaques: 5 mo.

rAAV2/1- IFN-γ

Cerebral ventricles

5 mo.

Aβ deposition ↓; Gliosis ↑; Complement expression ↑; Peripheral monocytes infiltration ↑

\

[63]

TgCRND8 mice (4 months old)

Hippocampi

1.5 mo.

JNPL3 mice (P2), rTg4510 mice (P2)

Tau:4 mo.

rAAV2/1- IFN-γ

Cerebral ventricles

3 mo.

Soluble tau phosphorylation ↑

\

[87]

Abbreviation: PHF-tau Paired helical filament tau, KO knockout

aCytokines with controversial results are in bold.

b↑: increase or improve, ↓: decrease or exacerbate, =: no change, \: no data

For more detailed information for the model animals mentioned above, please refer to http://www.alzforum.org/research-models [169]

On the other hand, the typical anti-inflammatory cytokines such as IL-4 and IL-10 suppress the inflammation through inhibiting the secretion of IL-1β, IL-6, TNF-α by microglia [4850] in vitro. In contrast to IL-4 that triggers M2a activation state associated with development of an anti-inflammatory environment and enhanced phagocytosis, IL-10 drives M2c polarization that is associated with deactivation of microglia. Overexpressing IL-10 in several AD animal models weakened the phagocytosis of soluble Aβ by microglia and exacerbeted Aβ deposits with cognitive impairment [5153]. Although inconsistent outcomes do exist, a recent study using IL-10 knockout mice supports the benefit of IL-10 removal. Considering that the IL-10 level increased in AD patients [53], it appears that the imbalance of pro- and anti- inflammatory activity co-exist in AD. Whether there is a corresponding, sequential transfer of microglia from M1 to M2c or mixed phenotype is unclear. It is also interesting to know whether this kind of transformation indicate exacerbation of the disease and “a point of no return” of the disease. As the previous in vivo studies of IL-10 all gave intervention before the formation of typical AD pathology (see Table 2), more data of the IL-10 impact on the late stage of AD is required.

The in vivo IL-4 studies generated more controversial results: One shows that overexpression of IL-4 in pre-deposition phase of AD animal models resulted in attenuation of Aβ pathology and improved behavior [54], while another one with short-term IL-4 expression in mice exacerbated amyloid deposition [55]. The acute suppression of glial clearance activity due to the relative short duration of IL-4 exposure is a possible explanation to the inconsistency. IL-4 expression initiating time is another major difference of the two studies that worth further investigation. It worth mentioning that a IL-4 study has to be terminated prematurely due to the increased animal death after the intervention [56]. One possible interpretation for the death was the multiple cortex injection sites and resultant higher virus and cytokine load.

TGF-β, an immunosuppressive cytokine which protects neurons against damages, has a complex role in modulating Aβ pathology. Long-term overexpressing TGF-β by astrocytes in transgenic mice led to increased clearance of Aβ plaque by activated microglia [57] and improvement of Aβ-induced behavior impairment [58]. However, TGF-β can also promote astrocytes aggregating around brain microvessels and Aβ deposits on the vascular basement membranes [5962]. Therefore, TGF-β can reduce Aβ pathology of brain parenchyma while at the same time cause the blood perfusion impairment in the associated regions.

IFN-γ is a pleiotropic cytokine which has a similar but weaker function to IL-4 in upregulating glial MHC class II [44], implying an immunosuppressive feature of the cytokine. The level change of IFN-γ in AD patients has not been reported, however, overexpressing IFN-γ results in a significant decrease of Aβ deposits and infiltration of peripheral monocytes [63], which is consistent to the observations that IFN-γ increases Aβ uptake by microglia and activates microglia to facilitate T cell motility and synapse formation in vitro [64].

The microglia-derived IL-12 and IL-23 is up-regulated in APP/PS1 transgenic mice and blocking these cytokines reverses the Aβ burden and the cognitive impairment [65]. Another study using accelerated senescence mice (SAMP8) reproduced the results [66]. In addition, a linear correlation of cognitive performance and CSF levels of p40, the common unit of IL-12 and IL-23, in AD subjects further supports the role of IL-12 and IL-23 in AD pathogenesis. IL-18, a member of IL-1 family, was elevated in LPS-stimulated blood mononuclear cells and brains of AD patients, and a significant correlation between IL-18 production and cognitive decline was observed [67, 68]. IL-18 promotes APP processing [69], tau phosphorylation [70] and can modulate the production of other cytokines [71]. Similarly, another IL-1 family member, IL-33 and its receptor ST2, showed strong expression in the AD brains, and incubation with Aβ increased astrocytic IL-33 expression [72]. The in vivo evidence of IL-18 and IL-33 in AD pathogenesis is currently missing and further studies may also explore whether these cytokines are detectable in CSF or serum of AD.

Cytokines related to AD-like tau abnormalities

Abnormal post-translational modification of tau proteins plays a crucial role in AD neurodegeneration, and hyperphosphorylation is one of them that has been most extensively studied [73, 74]. Accumulating studies suggest that targeting the down-regulated protein phosphatase-2A (PP2A) [75, 76] or up-regulated glycogen synthase kinase-3β (GSK-3β) [7780] or modulating the upstream membranous receptors may attenuate tau hyperphosphorylation [81, 82]. Currently, the role of tau in the neuroinflammation process of AD remains poorly understood and is far less studied compared to Aβ. However, the interplay between tau and cytokines has shed a light on the relevant mechanisms.

Pro-inflammatory cytokines have shown a consistent impact on tau pathology. Overexpression of IL-1β in 3xTg AD mice exacerbated tau hyperphosphorylation within one month [41], while blocking IL-1β signaling via IL-1 receptor antagonist (IL-1ra) or anti-IL-1β antibody reversed the cognitive impairment with a diminished tau pathology [83, 84]. The decreased activity of IL-1β-dependent tau kinases, such as cyclin-dependent kinase-5 (CDK5)/p25, GSK-3β and p38-mitogen activated protein kinase (MAPK) contributed to the reduction of phosphorylated tau [41, 83]. Additionally, a recent study showed that microglia can drive tau pathology, pathological tau spreading and memory impairment in the human tau40 mice through a IL-1β-dependent pathway since the inclusion of IL-1ra significantly reduced microglia-induced tau pathology [85]. 3, 6'-dithiothalidomide, a TNF-α-lowering agent, had no effect on total tau levels, but reduced phosphorylated tau in 3xTg AD mice [37]. Another study used a different TNF-α modulator, IDT in the same animal models also reduced paired helical filament tau (PHF-tau) and improved the cognition [39]. Treating hippocampal neurons with physiologic dose of IL-6 exhibited an increase in the amount of hyperphosphorylated tau of AD type, which may be attributed to an increased activity of CDK5/p35 complex [86].

In primary glial cultures, recombinant adeno-associated virus (rAAV)-mediated expression of IFN-γ did not alter endogenous tau production or phosphorylation. However, IFN-γ increased hyperphosphorylation and conformational changes of soluble tau in two animal models with tauopathy [87]. In turn, overexpressing tau40 increased secretion of TNF-α, IL-1β, IL-6, IL-10 and NO in rat microglia, which show greater phagocytosis of microspheres [88]. However, the phenotype of the microglia and how this phenotype would influence the Aβ pathology need further studies. Moreover, upregulating PP2A in astrocytes stimulates astrocytes migration via inhibiting p38-MAPK in Tg2576 mice [89], indicating that the tau-associated pathology may be involved in the impaired Aβ clearance.

It seems that tau pathology can be consequence of the deregulated inflammation, or serve as an inflammation promoter like Aβ to exacerbate inflammation. Nevertheless, to what extent tau may influence the inflammation, and what will be the sum effects of tau, Aβ and inflammation are mostly unknown. Besides, no related studies so far have examined the influence of anti-inflammatory cytokines on tau pathology. Cytokines also have important influence on neuron survival [9093], blood brain barrier (BBB) integrity [94] and other normal physiological events in the CNS [3, 4], which cannot be reflected in animal models of single type of pathology. Thus, a more careful examination of the current animal models [95] and developing novel models more close to the real pathology of AD are needed [28].

The adaptive immune system in AD

The most recent evidence has shown presence of a classical lymphatic system in the CNS [96], suggesting a frequent communication of the immune activities between periphery and the CNS on a regular basis. Over 80 % of the T cells in the CSF are CD4+ that can be classified into four subsets, including type 1 helper-inducer T (Th1) cells and Th17 cells defined as pro-inflammatory; and Th2 cells and regulatory T (Treg) cells defined as anti-inflammatory. The activating state and subtype of T cells in the circulation, CSF and parenchyma are modified in AD patients [97, 98]. In an immune-deficient AD mouse model, lack of T, B, and natural killer cells exhibits an increased Aβ with decreased phagocytic efficiency of microglia and significant elevation of several key pro-inflammatory cytokines including IL-1β, IL-6 and TNF-α [99]. These findings strongly suggest the active involvement of the adaptive immune system in AD pathogenesis.

Previous studies have highlighted the importance of cytokines in mediating the activity of peripheral immune cells in AD. Cytokines can facilitate the peripheral immune cells infiltration into the brain, resulting in direct Aβ phagocytosis by recruiting immune cells or inducing phagocytic activity of other cell types, such as microglia. The choroid plexus (CP) stroma is enriched with CD4+ T cells that are able to produce IL-4 and IFN-γ [98], and the IFN-γ plays an essential role in assisting leukocyte trafficking [100]. Decreased IFN-γ level in both 5XFAD and APP/PS1 mice were reversed by transient depletion of Treg cells at intermediate stage of AD, which at the same time led to increased leukocyte infiltration and recruitment to Aβ plaques, and attenuation of the AD pathology [101]. However, amplification of Treg cells at early disease stages through peripheral low-dose IL-2 treatment increased numbers of plaque-associated microglia, and restored cognitive functions in APP/PS1 mice [102]. Therefore, a more careful examination of Treg cells in different stages of the disease may help determining the proper therapeutic strategies.

Furthermore, when co-cultured with Aβ-treated microglia, the secretion of Th1 and Th17 cells increases, which then up-regulates MHC II, co-stimulatory molecules and pro-inflammatory cytokines in microglia [103, 104], thus improving the efficiency of presenting antigens to the T cells of microglia and enhancing Aβ clearance by both. However, IL-17 and IL-22, which are exclusively produced by Th17 cells, can also cause BBB disruption and infiltration of Th17 cells, but led to a direct injury to the neurons by Th17 cells via Fas/FasL pathway in Aβ-induced AD model rats [105]. In addition, respiratory infection of APP/PS1 mice increased infiltration of IFN-γ + and IL-17+ T cells into the brains of older mice and this was correlated with an increased Aβ level [106]. Together, these studies indicate that future studies should consider the complex interplay among many participants as seen in the real situation of AD.

The basal level of anti-inflammatory cytokines in CSF may help skewing the infiltrating T cells to the Th2 or Treg phenotype in physiological condition [98]. In AD patients, the pro-inflammatory cytokines in CSF increases, which induces more Th1 or Th17 cells that can be detrimental. Several in vivo studies via cerebral ventricles or systemic administration to examine the impact of cytokines or the relevant antibodies on AD pathology (see Table 2), the concomitant influence on the transformation of T cells phenotypes and following effects should be taken into consideration for a more reasonable interpretation of the outcomes.

Cytokines as potential biomarkers for AD diagnosis

So far, a CSF signature of low Aβ1-42 and high tau concentrations and significant retention in PET imaging with amyloid tracers are suggested as the standard diagnostic criteria, with the highest specificity and accuracy [107]. However, lumbar puncture required for CSF has limited its application. Thus, novel biomarkers based on more accessible materials, such as plasma, are attractive in improving AD diagnosis. Several cytokines have shown disease progression-dependent manner, which suggests that cytokines may serve as potential disease predictors. For instance, data collected from a 20-years cohort study demonstrate greater possibility of cognitive impairment in individuals with increased IL-6 [108]. After reviewing 118 research articles and comparing 66 cytokines in plasma or CSF obtained from MCI and AD, it was found that the cytokines increased steadily or had peak level upon the transformation from MCI to AD. This may help predicting the risk of suffering from AD and recognizing AD subgroups, such as IL-1β, IL-6, TNF-α, IL-18, monocyte chemotactic protein (MCP)-1 and IL-10 [8]. However, in the latest meta-analysis, no significant differences in cytokines such as IL-1β, IL-6, IL-8, IL-10 or TNF-α were found between subjects with MCI and healthy controls, while significant heterogeneity was observed in some comparisons [109].

Considering the unstable outcome of single cytokine level, combinational use of multiple proteins is a more reasonable approach. However, since the first AD predicting model made up of 18 plasma biomarkers containing multiple cytokines has been proposed [110], few biomarker sets have shown stable performance and good reproducibility [111, 112]. Nevertheless, by using multiplex assays, two research groups have independently set up a panel of plasma proteins recently. These two panels are of high reproducibility and diagnostic accuracy, which were strongly associated with severity and progression of AD [113, 114]. Although no cytokines were involved in neither of the panels, one of the studies found positive correlations between the biomarkers and some cytokines altered in AD [114]. In addition, after screening 120 inflammatory molecules in CSF and serum of AD, MCI and healthy controls through protein-array analysis, a combination of soluble IL-6 receptor (sIL-6R), tissue inhibitor of metalloproteinases-1 (TIMP-1) and soluble TNF-α receptor I (sTNFR-I) in CSF was found to provide the best prediction to AD among other molecules [115].

Certainly, these results still need further verification by other research groups, while the heterogeneity in BBB integrity, physical state and disease stage of patients should be taken into consideration at the same time [8, 116]. Besides, the lack of standardization of sample collections or detections remains the dominant cause of failure of developing serum-based AD biomarkers. To address this problem, many organizations raise guidelines for standardization of blood-based biomarker studies in AD, covering the pre-blood draw, blood collecting, processing and storage [117]. Furthermore, longitudinal sampling over years [8] is a better approach to eliminate heterogeneity but needs optimization of its feasibility.

Although no evidence supports a direct association of systemic infections with AD [118120], some specific pathogens have been identified as potential risks for AD, such as Herpes simplex virus type 1, Chlamydophila pneumoniae, Helicobacter pylori and periodontal bacteria [121]. A recent study shows that the infection burden (IB) consisting of common pathogens is associated with AD after adjusted for ApoE genotype and various comorbidities. AD patients or healthy controls with more seropositivities have significantly higher serum levels of IFN-γ, TNF-α and IL-6 [122]. As IB is a relatively stable indicator of systemic inflammation burden, the practical value of combinational use of IB with other biomarkers worth further investigations. Overall, single type of biomarker is far from enough to classify all phenotypes and stages of AD, the combination of plasma cytokines and other factor is the most realistic and promising approach to develop convenient and practical plasma biomarkers for AD.

Cytokines as potential targets for AD therapy

The anti-inflammatory therapies using non-steroidal anti-inflammatory drugs (NSAIDs) were once considered promising. However, after the positive reports from the pioneering randomized trial of indomethacin [123, 124], the followed trials have not reached a definitive conclusion [28]. Lately, two meta-analyses have been conducted to reevaluate the role of NSAIDs in AD. Although it supported the use of NSAIDs for prevention of AD, there were no positive results from the randomized control trials (RCTs) [125, 126]. Moreover, in a follow-up evaluation study of the randomized AD anti-inflammatory prevention trial (ADAPT) and its follow-up study (ADAPT-FS) that treatment for 1 to 3 years with naproxen, a nonselective cyclooxygenase (COX) inhibitor, or celecoxib (a selective COX-2 inhibitor), the results show no prevention for the onset of dementia or no attenuation for the cognitive functions in older adults with a family history of AD [127]. Many reasons to the failure have been proposed, including duration of treatment [127], ApoE ε4 allele [128, 129], ages [127], disease stages [130] and disease progressing speeds [131]. Therefore, long-term and large-scale RCTs based on more tolerable novel NSAIDs are needed for understanding the positive findings from molecular and epidemiologic studies. In the absence of such RCTs, indirect treatment comparisons or mixed treatment comparisons may also help to reach more robust conclusions [125].

As the broad anti-inflammatory medications are not promising, more specific immune pathways or molecules that are not affected by NSAIDs may be targeted. Etanercept is a TNF-α inhibitor originally used in the treatment of rheumatoid arthritis (RA). A noticeable clinical improvement was observed in AD patients minutes after perispinal administration of etanercept [132]. To explain the rapid effect of etanercept, the authors propose that the vertebral venous system may be an anatomical route to bypass the BBB and to deliver high molecular drugs to the CNS [133]. However, a recent study has challenged this claim, as three radio iodinated drugs including etanercept, were perispinally injected but the drug was not visualized in all but one of the rats using PET [134]. Recent studies indicate that intravenously-administered etanercept has no apparent clinical benefit to AD patients, although good tolerability of subcutaneous etanercept over a 24-week period was observed [133, 135], suggesting better effects by perispinal administrating compared to peripheral route. Together, these studies confirm the pathogenic role of TNF-α in AD and show great potential of anti-TNF-α therapies through various administration routes.

Although targeting cytokines is a relatively new approach compared to other anti-inflammatory therapies in AD, it is noteworthy that a great number of cytokine inhibitors have already been successfully used in the treatments of autoimmune diseases and cancers [136, 137], and more biologics are under development [138]. Repurposing these drugs in AD treatments could be a reasonable approach. For instance, IL-1ra is decreased in CSF of AD patients [139] and its protecting effect towards AD has been confirmed in animal models [84, 85]. Although there is still no clinical evidence supporting the use of IL-1ra in AD patients, the success in treating RA and cortical infarcts [140] makes it a very promising target in AD treatments. Similarly, p40-neutralizing antibodies, which block the IL-12/IL-23 signaling pathway, have been approved by Food and Drug Administration (FDA) for the treatment of psoriasis, thus may be ideal for the initiation of clinical trials [65].

Besides, indirect approaches such as targeting upstream regulators of the cytokine expression seem also attractive. For instance, the Aβ-dependent induction of IL-1β requires two sequential signals. The first signal is triggered by Aβ binding to the toll-like receptors (TLRs) and leads to the production of IL-1β precursor. The second signal occurs via NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome activation, which requires cathepsin B leakage from phagolysosomes or mitochondrial damage, and the subsequent reactive oxygen species (ROS) production. Then the NLRP3 inflammasome can activate caspase-1, which processes the pro-IL-1β into its bioactive form [141]. Although there are no FDA-approved drugs that exclusively and specifically target NLRP3, a small molecule inhibitor of NLRP3 has been identified [142]. Therefore, more initiative attempts of repurposing anti-cytokine drugs in AD treatments and more careful assessments of the results may lead to unexpected cheerful outcomes.

Conclusions

The cytokines are involved in various physiological and pathological pathways, therefore, inconsistent results have been observed in AD pathologies and treatment. The present evidence strongly indicates that dysregulation of the cytokines drives pathogenic process primarily through influencing the phenotype of microglia, and co-existence of both pro-inflammatory cytokines and the suppressing state of microglia may represent an irreversible point of the disease. Future studies on AD should extend to more pathogens than Aβ, and investigate the interplay between cytokine and other participators. The genome-wide association studies and the online database analysis will provide continuously updated polymorphism information associated with AD, while development of brain banks is critical for identification of new genes and proteins [143]. Given that increasing studies have proven the role of adaptive immune system in AD, the impact of peripheral T cells and relevant cytokines cannot be ignored in future studies. As the immune events may change during the disease course and the heterogeneity in AD, it is not necessarily that all individuals with AD exhibit neuroinflammation, or at all-time points in the course of the disease. To learn from the existing therapy strategies of other related inflammatory diseases or to develop novel cytokine inhibitors could be reasonable approaches to making progress in AD anti-inflammatory therapies.

Abbreviations

AD: 

Alzheimer’s disease

ADAPT: 

anti-inflammatory prevention trial

ADAPT-FS: 

anti-inflammatory prevention trial-follow-up study

ApoE: 

apolipoprotein E

APP: 

amyloid precursor protein

Aβ: 

beta amyloid

BBB: 

blood brain barrier

CDK5: 

cyclin-dependent kinase-5

CNS: 

central nervous system

COX: 

cyclooxygenase

CP: 

choroid plexus

CSF: 

cerebral spinal fluid

FDA: 

food and drug administration

GSK: 

glycogen synthase kinase

htau40: 

human tau40 protein

IDE: 

insulin-degrading enzyme

IFNs: 

interferons

IGF-1: 

insulin-like growth factor-1

IL-1ra: 

IL-1 receptor antagonist

ILs: 

interleukins

MAPK: 

mitogen activated protein kinase

MCI: 

mild cognitive impairment

MCP-1: 

monocyte chemotactic protein -1

MHC-II: 

major histocompatibility complex class II

NFTs: 

neurofibrillary tangles

NSAIDs: 

non-steroidal anti-inflammatory drugs

PHF-tau: 

paired helical filament tau

PP2A: 

protein phosphatase-2A

PSEN: 

presenelin

RA: 

rheumatoid arthritis

rAAV: 

recombinant adeno associated virus

ROS: 

reactive oxygen species

SAMP8: 

senescence accelerated mouse

sIL-6R: 

soluble IL-6 receptor

sTNFR-I: 

soluble TNF-α receptor I

TGFs: 

transforming growth factors

Th1 cells: 

type 1 helper-inducer T cells

TIMP-1: 

tissue inhibitor of metalloproteinases-1

TLRs: 

toll-like receptors

TNFs: 

tumor necrosis factors

Treg cells: 

regulatory T cells

TREM2: 

triggering receptor expressed on myeloid cells 2

α1-ACT: 

α1-antichymotrypsin

Declarations

Acknowledgement

This work was supported in parts by grants from Natural Science Foundation of China (91132305, 81261120570, 81528007 and 81171195) and The National Key Technology Research and Development Program of the Ministry of Science and Technology of China (2013DFG32670, 2012BAI10B03).

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology
(2)
Co-innovation Center of Neuroregeneration

References

  1. Martin P, Matthew P, Maëlenn G. World Alzheimer Report 2013: Journey of Caring a analysis of long-term care for dementia 2013 [cited 2016 6 Feb]; 1-92]. Available from: http://www.alz.co.uk/research/WorldAlzheimerReport2013.pdf?m.
  2. Szelényi J. Cytokines and the central nervous system. Brain Res Bull. 2001;54(4):329–38.PubMedView ArticleGoogle Scholar
  3. Borsini A, Zunszain PA, Thuret S, Pariante CM. The role of inflammatory cytokines as key modulators of neurogenesis. Trends Neurosci. 2015;38(3):145–57.PubMedView ArticleGoogle Scholar
  4. Boulanger LM. Immune proteins in brain development and synaptic plasticity. Neuron. 2009;64(1):93–109.PubMedView ArticleGoogle Scholar
  5. Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, et al. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A. 1989;86(19):7611–5.PubMedPubMed CentralView ArticleGoogle Scholar
  6. Hull M, Berger M, Volk B, Bauer J. Occurrence of interleukin-6 in cortical plaques of Alzheimer's disease patients may precede transformation of diffuse into neuritic plaques. Ann N Y Acad Sci. 1996;777:205–12.PubMedView ArticleGoogle Scholar
  7. van der Wal EA, Gomez-Pinilla F, Cotman CW. Transforming growth factor-beta 1 is in plaques in Alzheimer and Down pathologies. Neuroreport. 1993;4(1):69–72.PubMedView ArticleGoogle Scholar
  8. Brosseron F, Krauthausen M, Kummer M, Heneka MT. Body fluid cytokine levels in mild cognitive impairment and Alzheimer's disease: a comparative overview. Mol Neurobiol. 2014;50(2):534–44.PubMedPubMed CentralView ArticleGoogle Scholar
  9. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer's disease. Lancet. 2011;377(9770):1019–31.PubMedView ArticleGoogle Scholar
  10. Hua Y, Guo X, Huang Q, Kong Y, Lu X. Association between interleukin-6 -174G/C polymorphism and the risk of Alzheimer's disease: a meta-analysis. Int J Neurosci. 2013;123(9):626–35.PubMedView ArticleGoogle Scholar
  11. Zhang Y, Zhang J, Tian C, Xiao Y, Li X, He C, et al. The -1082G/A polymorphism in IL-10 gene is associated with risk of Alzheimer's disease: a meta-analysis. J Neurol Sci. 2011;303(1-2):133–8.PubMedView ArticleGoogle Scholar
  12. Wang T. TNF-alpha G308A polymorphism and the susceptibility to Alzheimer's disease: an updated meta-analysis. Arch Med Res. 2015;46(1):24–30 e1.PubMedView ArticleGoogle Scholar
  13. Lee YH, Choi SJ, Ji JD, Song GG. Association between TNF-alpha promoter -308 A/G polymorphism and Alzheimer's disease: a meta-analysis. Neurol Sci. 2015;36(6):825–32.PubMedView ArticleGoogle Scholar
  14. Dong X, Zhang L, Meng Q, Gao Q. Association Between Interleukin-1A, Interleukin-1B, and Bridging integrator 1 Polymorphisms and Alzheimer’s Disease: a standard and Cumulative Meta-analysis. Mol Neurobiol. 2016;15:1–12.Google Scholar
  15. Di Bona D, Plaia A, Vasto S, Cavallone L, Lescai F, Franceschi C, et al. Association between the interleukin-1beta polymorphisms and Alzheimer's disease: a systematic review and meta-analysis. Brain Res Rev. 2008;59(1):155–63.PubMedView ArticleGoogle Scholar
  16. Wang M, Jia JP. The interleukin-6 gene −572C/G promoter polymorphism modifies Alzheimer's risk in ApoE ɛ4 carriers. Neurosci Lett. 2010;482(3):260–3.PubMedView ArticleGoogle Scholar
  17. Zhu XC, Tan L, Jiang T, Tan MS, Zhang W, Yu JT. Association of IL-12A and IL-12B polymorphisms with Alzheimer's disease susceptibility in a Han Chinese population. J Neuroimmunol. 2014;274(1-2):180–4.PubMedView ArticleGoogle Scholar
  18. Liu Y, Yu JT, Zhang W, Zong Y, Lu RC, Zhou J, et al. Interleukin-23 receptor polymorphisms are associated with Alzheimer's disease in Han Chinese. J Neuroimmunol. 2014;271(1-2):43–8.PubMedView ArticleGoogle Scholar
  19. Chapuis J, Hot D, Hansmannel F, Kerdraon O, Ferreira S, Hubans C, et al. Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's disease. Mol Psychiatry. 2009;14(11):1004–16.PubMedPubMed CentralView ArticleGoogle Scholar
  20. Yu JT, Tan L, Song JH, Sun YP, Chen W, Miao D, et al. Interleukin-18 promoter polymorphisms and risk of late onset Alzheimer's disease. Brain Res. 2009;1253:169–75.PubMedView ArticleGoogle Scholar
  21. Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9(2):106–18.PubMedPubMed CentralView ArticleGoogle Scholar
  22. Di Bona D, Rizzo C, Bonaventura G, Candore G, Caruso C. Association between interleukin-10 polymorphisms and Alzheimer's disease: a systematic review and meta-analysis. J Alzheimers Dis. 2012;29(4):751–9.PubMedGoogle Scholar
  23. Payao SL, Goncalves GM, de Labio RW, Horiguchi L, Mizumoto I, Rasmussen LT, et al. Association of interleukin 1beta polymorphisms and haplotypes with Alzheimer's disease. J Neuroimmunol. 2012;247(1-2):59–62.PubMedView ArticleGoogle Scholar
  24. Kang HJ, Kim JM, Kim SW, Shin IS, Park SW, Kim YH, et al. Associations of cytokine genes with Alzheimer's disease and depression in an elderly Korean population. J Neurol Neurosurg Psychiatry. 2015;86(9):1002–7.PubMedView ArticleGoogle Scholar
  25. Flex A, Giovannini S, Biscetti F, Liperoti R, Spalletta G, Straface G, et al. Effect of proinflammatory gene polymorphisms on the risk of Alzheimer's disease. Neurodegener Dis. 2014;13(4):230–6.PubMedGoogle Scholar
  26. Griciuc A, Serrano-Pozo A, Parrado AR, Lesinski AN, Asselin CN, Mullin K, et al. Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron. 2013;78(4):631–43.PubMedPubMed CentralView ArticleGoogle Scholar
  27. Asselineau D, Benlhassan K, Arosio B, Mari D, Ferri E, Casati M, et al. Interleukin-10 production in response to amyloid-beta differs between slow and fast decliners in patients with Alzheimer's disease. J Alzheimers Dis. 2015;46(4):837–42.PubMedView ArticleGoogle Scholar
  28. Heneka MT, Carson MJ, Khoury JE, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol. 2015;14(4):388–405.PubMedView ArticleGoogle Scholar
  29. Avila-Munoz E, Arias C. When astrocytes become harmful: functional and inflammatory responses that contribute to Alzheimer's disease. Ageing Res Rev. 2014;18:29–40.PubMedView ArticleGoogle Scholar
  30. Bastard JP, Maachi M, Lagathu C, Kim MJ, Caron M, Vidal H, et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw. 2006;17(1):4–12.PubMedGoogle Scholar
  31. Gjoneska E, Pfenning AR, Mathys H, Quon G, Kundaje A, Tsai LH, et al. Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease. Nature. 2015;518(7539):365–9.PubMedPubMed CentralView ArticleGoogle Scholar
  32. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer's disease. Neurobiol Aging. 2000;21(3):383–421.PubMedPubMed CentralView ArticleGoogle Scholar
  33. Griffin WS, Sheng JG, Royston MC, Gentleman SM, McKenzie JE, Graham DI, et al. Glial-neuronal interactions in Alzheimer's disease: the potential role of a 'cytokine cycle' in disease progression. Brain Pathol. 1998;8(1):65–72.PubMedView ArticleGoogle Scholar
  34. Song C, Zhang Y, Dong Y. Acute and subacute IL-1beta administrations differentially modulate neuroimmune and neurotrophic systems: possible implications for neuroprotection and neurodegeneration. J Neuroinflammation. 2013;10:59.PubMedPubMed CentralView ArticleGoogle Scholar
  35. Minter MR, Taylor JM, Crack PJ. The contribution of neuroinflammation to amyloid toxicity in Alzheimer's disease. J Neurochem. 2016;136(3):457–74.PubMedView ArticleGoogle Scholar
  36. Russo I, Caracciolo L, Tweedie D, Choi SH, Greig NH, Barlati S, et al. 3,6'-Dithiothalidomide, a new TNF-alpha synthesis inhibitor, attenuates the effect of Abeta1-42 intracerebroventricular injection on hippocampal neurogenesis and memory deficit. J Neurochem. 2012;122(6):1181–92.PubMedPubMed CentralView ArticleGoogle Scholar
  37. Tweedie D, Ferguson RA, Fishman K, Frankola KA, Van Praag H, Holloway HW, et al. Tumor necrosis factor-alpha synthesis inhibitor 3,6'-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer's disease. J Neuroinflammation. 2012;9:106.PubMedPubMed CentralView ArticleGoogle Scholar
  38. Detrait ER, Danis B, Lamberty Y, Foerch P. Peripheral administration of an anti-TNF-alpha receptor fusion protein counteracts the amyloid induced elevation of hippocampal TNF-alpha levels and memory deficits in mice. Neurochem Int. 2014;72:10–3.PubMedView ArticleGoogle Scholar
  39. Gabbita SP, Johnson MF, Kobritz N, Eslami P, Poteshkina A, Varadarajan S, et al. Oral TNFalpha modulation alters neutrophil infiltration, improves cognition and diminishes tau and amyloid pathology in the 3xTgAD mouse model. PLoS One. 2015;10(10):e0137305.PubMedPubMed CentralView ArticleGoogle Scholar
  40. Chakrabarty P, Herring A, Ceballos-Diaz C, Das P, Golde TE. Hippocampal expression of murine TNFalpha results in attenuation of amyloid deposition in vivo. Mol Neurodegener. 2011;6:16.PubMedPubMed CentralView ArticleGoogle Scholar
  41. Ghosh S, Wu MD, Shaftel SS, Kyrkanides S, LaFerla FM, Olschowka JA, et al. Sustained interleukin-1beta overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer's mouse model. J Neurosci. 2013;33(11):5053–64.PubMedPubMed CentralView ArticleGoogle Scholar
  42. Cherry JD, Olschowka JA, O'Banion MK. Arginase 1+ microglia reduce Abeta plaque deposition during IL-1beta-dependent neuroinflammation. J Neuroinflammation. 2015;12:203.PubMedPubMed CentralView ArticleGoogle Scholar
  43. Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol. 2008;9(8):857–65.PubMedPubMed CentralView ArticleGoogle Scholar
  44. Butovsky O, Talpalar AE, Ben-Yaakov K, Schwartz M. Activation of microglia by aggregated beta-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-gamma and IL-4 render them protective. Mol Cell Neurosci. 2005;29(3):381–93.PubMedView ArticleGoogle Scholar
  45. Shimizu E, Kawahara K, Kajizono M, Sawada M, Nakayama H. IL-4-induced selective clearance of oligomeric -amyloid Peptide1-42 by rat primary type 2 microglia. J Immunol. 2008;181(9):6503–13.PubMedView ArticleGoogle Scholar
  46. Chakrabarty P, Jansen-West K, Beccard A, Ceballos-Diaz C, Levites Y, Verbeeck C, et al. Massive gliosis induced by interleukin-6 suppresses A deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J. 2009;24(2):548–59.PubMedView ArticleGoogle Scholar
  47. Janelsins MC, Mastrangelo MA, Park KM, Sudol KL, Narrow WC, Oddo S, et al. Chronic neuron-specific tumor necrosis factor-alpha expression enhances the local inflammatory environment ultimately leading to neuronal death in 3xTg-AD mice. Am J Pathol. 2008;173(6):1768–82.PubMedPubMed CentralView ArticleGoogle Scholar
  48. Szczepanik AM, Funes S, Petko W, Ringheim GE. IL-4, IL-10 and IL-13 modulate A beta(1--42)-induced cytokine and chemokine production in primary murine microglia and a human monocyte cell line. J Neuroimmunol. 2001;113(1):49–62.PubMedView ArticleGoogle Scholar
  49. Ledeboer A, Breve JJ, Wierinckx A, van der Jagt S, Bristow AF, Leysen JE, et al. Expression and regulation of interleukin-10 and interleukin-10 receptor in rat astroglial and microglial cells. Eur J Neurosci. 2002;16(7):1175–85.PubMedView ArticleGoogle Scholar
  50. Pousset F, Cremona S, Dantzer R, Kelley K, Parnet P. Interleukin-4 and interleukin-10 regulate IL1-β induced mouse primary astrocyte activation: A comparative study. Glia. 1999;26(1):12–21.PubMedView ArticleGoogle Scholar
  51. Chakrabarty P, Li A, Ceballos-Diaz C, Eddy JA, Funk CC, Moore B, et al. IL-10 Alters Immunoproteostasis in APP Mice, Increasing Plaque Burden and Worsening Cognitive Behavior. Neuron. 2015;85(3):519–33.PubMedPubMed CentralView ArticleGoogle Scholar
  52. Kiyota T, Ingraham KL, Swan RJ, Jacobsen MT, Andrews SJ, Ikezu T. AAV serotype 2/1-mediated gene delivery of anti-inflammatory interleukin-10 enhances neurogenesis and cognitive function in APP+PS1 mice. Gene Ther. 2012;19(7):724–33.PubMedPubMed CentralView ArticleGoogle Scholar
  53. Guillot-Sestier MV, Doty KR, Gate D, Rodriguez Jr J, Leung BP, Rezai-Zadeh K, et al. Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology. Neuron. 2015;85(3):534–48.PubMedPubMed CentralView ArticleGoogle Scholar
  54. Kiyota T, Okuyama S, Swan RJ, Jacobsen MT, Gendelman HE, Ikezu T. CNS expression of anti-inflammatory cytokine interleukin-4 attenuates Alzheimer’s disease-like pathogenesis in APP+PS1 bigenic mice. FASEB J. 2010;24(8):3093–102.PubMedPubMed CentralView ArticleGoogle Scholar
  55. Chakrabarty P, Tianbai L, Herring A, Ceballos-Diaz C, Das P, Golde TE. Hippocampal expression of murine IL-4 results in exacerbation of amyloid deposition. Mol Neurodegener. 2012;7:36.PubMedPubMed CentralView ArticleGoogle Scholar
  56. Latta CH, Sudduth TL, Weekman EM, Brothers HM, Abner EL, Popa GJ, et al. Determining the role of IL-4 induced neuroinflammation in microglial activity and amyloid-beta using BV2 microglial cells and APP/PS1 transgenic mice. J Neuroinflammation. 2015;12:41.PubMedPubMed CentralView ArticleGoogle Scholar
  57. Wyss-Coray T, Lin C, Yan F, Yu GQ, Rohde M, McConlogue L, et al. TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat Med. 2001;7(5):612–8.PubMedView ArticleGoogle Scholar
  58. Chen JH, Ke KF, Lu JH, Qiu YH, Peng YP. Protection of TGF-beta1 against neuroinflammation and neurodegeneration in Abeta1-42-induced Alzheimer's disease model rats. PLoS One. 2015;10(2):e0116549.PubMedPubMed CentralView ArticleGoogle Scholar
  59. Wyss-Coray T, Feng L, Masliah E, Ruppe MD, Lee HS, Toggas SM, et al. Increased central nervous system production of extracellular matrix components and development of hydrocephalus in transgenic mice overexpressing transforming growth factor-beta 1. Am J Pathol. 1995;147(1):53–67.PubMedPubMed CentralGoogle Scholar
  60. Wyss-Coray T, Masliah E, Mallory M, McConlogue L, Johnson-Wood K, Lin C, et al. Amyloidogenic role of cytokine TGF-beta1 in transgenic mice and in Alzheimer's disease. Nature. 1997;389(6651):603–6.PubMedView ArticleGoogle Scholar
  61. Wyss-Coray T, Lin C, von Euw D, Masliah E, Mucke L, Lacombe P. Alzheimer's disease-like cerebrovascular pathology in transforming growth factor-beta 1 transgenic mice and functional metabolic correlates. Ann N Y Acad Sci. 2000;903:317–23.PubMedView ArticleGoogle Scholar
  62. Ueberham U, Ueberham E, Bruckner MK, Seeger G, Gartner U, Gruschka H, et al. Inducible neuronal expression of transgenic TGF-beta1 in vivo: dissection of short-term and long-term effects. Eur J Neurosci. 2005;22(1):50–64.PubMedView ArticleGoogle Scholar
  63. Chakrabarty P, Ceballos-Diaz C, Beccard A, Janus C, Dickson D, Golde TE, et al. IFN-gamma promotes complement expression and attenuates amyloid plaque deposition in amyloid beta precursor protein transgenic mice. J Immunol. 2010;184(9):5333–43.PubMedPubMed CentralView ArticleGoogle Scholar
  64. Monsonego A, Imitola J, Petrovic S, Zota V, Nemirovsky A, Baron R, et al. Abeta-induced meningoencephalitis is IFN-gamma-dependent and is associated with T cell-dependent clearance of Abeta in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2006;103(13):5048–53.PubMedPubMed CentralView ArticleGoogle Scholar
  65. Vom Berg J, Prokop S, Miller KR, Obst J, Kalin RE, Lopategui-Cabezas I, et al. Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease-like pathology and cognitive decline. Nat Med. 2012;18(12):1812–9.PubMedView ArticleGoogle Scholar
  66. Tan MS, Yu JT, Jiang T, Zhu XC, Guan HS, Tan L. IL12/23 p40 inhibition ameliorates Alzheimer's disease-associated neuropathology and spatial memory in SAMP8 mice. J Alzheimers Dis. 2014;38(3):633–46.PubMedGoogle Scholar
  67. Bossu P, Ciaramella A, Salani F, Bizzoni F, Varsi E, Di Iulio F, et al. Interleukin-18 produced by peripheral blood cells is increased in Alzheimer's disease and correlates with cognitive impairment. Brain Behav Immun. 2008;22(4):487–92.PubMedView ArticleGoogle Scholar
  68. Ojala J, Alafuzoff I, Herukka SK, van Groen T, Tanila H, Pirttila T. Expression of interleukin-18 is increased in the brains of Alzheimer's disease patients. Neurobiol Aging. 2009;30(2):198–209.PubMedView ArticleGoogle Scholar
  69. Sutinen EM, Pirttila T, Anderson G, Salminen A, Ojala JO. Pro-inflammatory interleukin-18 increases Alzheimer's disease-associated amyloid-beta production in human neuron-like cells. J Neuroinflammation. 2012;9:199.PubMedPubMed CentralView ArticleGoogle Scholar
  70. Ojala JO, Sutinen EM, Salminen A, Pirttila T. Interleukin-18 increases expression of kinases involved in tau phosphorylation in SH-SY5Y neuroblastoma cells. J Neuroimmunol. 2008;205(1-2):86–93.PubMedView ArticleGoogle Scholar
  71. Alboni S, Cervia D, Sugama S, Conti B. Interleukin 18 in the CNS. J Neuroinflammation. 2010;7:9.PubMedPubMed CentralView ArticleGoogle Scholar
  72. Xiong Z, Thangavel R, Kempuraj D, Yang E, Zaheer S, Zaheer A. Alzheimer's disease: evidence for the expression of interleukin-33 and its receptor ST2 in the brain. J Alzheimers Dis. 2014;40(2):297–308.PubMedPubMed CentralGoogle Scholar
  73. Wang JZ, Wang ZH, Tian Q. Tau hyperphosphorylation induces apoptotic escape and triggers neurodegeneration in Alzheimer's disease. Neurosci Bull. 2014;30(2):359–66.PubMedView ArticleGoogle Scholar
  74. Wang JZ, Liu F. Microtubule-associated protein tau in development, degeneration and protection of neurons. Prog Neurobiol. 2008;85(2):148–75.PubMedView ArticleGoogle Scholar
  75. Zhu LQ, Zheng HY, Peng CX, Liu D, Li HL, Wang Q, et al. Protein phosphatase 2A facilitates axonogenesis by dephosphorylating CRMP2. J Neurosci. 2010;30(10):3839–48.PubMedView ArticleGoogle Scholar
  76. Liu GP, Wei W, Zhou X, Shi HR, Liu XH, Chai GS, et al. Silencing PP2A inhibitor by lenti-shRNA interference ameliorates neuropathologies and memory deficits in tg2576 mice. Mol Ther. 2013;21(12):2247–57.PubMedPubMed CentralView ArticleGoogle Scholar
  77. Li XH, Lv BL, Xie JZ, Liu J, Zhou XW, Wang JZ. AGEs induce Alzheimer-like tau pathology and memory deficit via RAGE-mediated GSK-3 activation. Neurobiol Aging. 2012;33(7):1400–10.PubMedView ArticleGoogle Scholar
  78. Liu SJ, Zhang JY, Li HL, Fang ZY, Wang Q, Deng HM, et al. Tau becomes a more favorable substrate for GSK-3 when it is prephosphorylated by PKA in rat brain. J Biol Chem. 2004;279(48):50078–88.PubMedView ArticleGoogle Scholar
  79. Zhu LQ, Liu D, Hu J, Cheng J, Wang SH, Wang Q, et al. GSK-3 beta inhibits presynaptic vesicle exocytosis by phosphorylating P/Q-type calcium channel and interrupting SNARE complex formation. J Neurosci. 2010;30(10):3624–33.PubMedView ArticleGoogle Scholar
  80. Zhu LQ, Wang SH, Liu D, Yin YY, Tian Q, Wang XC, et al. Activation of glycogen synthase kinase-3 inhibits long-term potentiation with synapse-associated impairments. J Neurosci. 2007;27(45):12211–20.PubMedView ArticleGoogle Scholar
  81. Jiang J, Wang ZH, Qu M, Gao D, Liu XP, Zhu LQ, et al. Stimulation of EphB2 attenuates tau phosphorylation through PI3K/Akt-mediated inactivation of glycogen synthase kinase-3beta. Sci Rep. 2015;5:11765.PubMedPubMed CentralView ArticleGoogle Scholar
  82. Liu D, Wei N, Man HY, Lu Y, Zhu LQ, Wang JZ. The MT2 receptor stimulates axonogenesis and enhances synaptic transmission by activating Akt signaling. Cell Death Differ. 2015;22(4):583–96.PubMedPubMed CentralView ArticleGoogle Scholar
  83. Kitazawa M, Cheng D, Tsukamoto MR, Koike MA, Wes PD, Vasilevko V, et al. Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal beta-catenin pathway function in an Alzheimer's disease model. J Immunol. 2011;187(12):6539–49.PubMedPubMed CentralView ArticleGoogle Scholar
  84. Ben Menachem-Zidon O, Ben Menahem Y, Ben Hur T, Yirmiya R. Intra-hippocampal transplantation of neural precursor cells with transgenic over-expression of IL-1 receptor antagonist rescues memory and neurogenesis impairments in an Alzheimer's disease model. Neuropsychopharmacology. 2015;40(2):524.PubMedPubMed CentralView ArticleGoogle Scholar
  85. Maphis N, Xu G, Kokiko-Cochran ON, Jiang S, Cardona A, Ransohoff RM, et al. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain. 2015;138(Pt 6):1738–55.PubMedView ArticleGoogle Scholar
  86. Quintanilla RA, Orellana DI, Gonzalez-Billault C, Maccioni RB. Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway. Exp Cell Res. 2004;295(1):245–57.PubMedView ArticleGoogle Scholar
  87. Li A, Ceballos-Diaz C, DiNunno N, Levites Y, Cruz PE, Lewis J, et al. IFN-gamma promotes tau phosphorylation without affecting mature tangles. FASEB J. 2015;29(10):4384–98.PubMedView ArticleGoogle Scholar
  88. Wang L, Jiang Q, Chu J, Lin L, Li XG, Chai GS, et al. Expression of Tau40 induces activation of cultured rat microglial cells. PLoS One. 2013;8(10):e76057.PubMedPubMed CentralView ArticleGoogle Scholar
  89. Liu XP, Zheng HY, Qu M, Zhang Y, Cao FY, Wang Q, et al. Upregulation of astrocytes protein phosphatase-2A stimulates astrocytes migration via inhibiting p38 MAPK in tg2576 mice. Glia. 2012;60(9):1279–88.PubMedView ArticleGoogle Scholar
  90. Caraci F, Battaglia G, Busceti C, Biagioni F, Mastroiacovo F, Bosco P, et al. TGF-beta 1 protects against Abeta-neurotoxicity via the phosphatidylinositol-3-kinase pathway. Neurobiol Dis. 2008;30(2):234–42.PubMedView ArticleGoogle Scholar
  91. Mrak RE, Sheng JG, Griffin WS. Correlation of astrocytic S100-beta expression with dystrophic neurites in amyloid plaques of Alzheimer's disease. J Neuropathol Exp Neurol. 1996;55(3):273–9.PubMedPubMed CentralView ArticleGoogle Scholar
  92. Qiu ZH, Gruol DL. Interleukin-6, β-amyloid peptide and NMDA interactions in rat cortical neurons. J Neuroimmunol. 2003;139(1–2):51–7.PubMedView ArticleGoogle Scholar
  93. Combs CK, Karlo JC, Kao SC, Landreth GE. beta-Amyloid stimulation of microglia and monocytes results in TNFalpha-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J Neurosci. 2001;21(4):1179–88.PubMedGoogle Scholar
  94. Wang Y, Jin S, Sonobe Y, Cheng Y, Horiuchi H, Parajuli B, et al. Interleukin-1beta induces blood–brain barrier disruption by downregulating Sonic hedgehog in astrocytes. PLoS One. 2014;9(10):e110024.PubMedPubMed CentralView ArticleGoogle Scholar
  95. Nazem A, Sankowski R, Bacher M, Al-Abed Y. Rodent models of neuroinflammation for Alzheimer’s disease. J Neuroinflammation. 2015;12(1):74–89.PubMedPubMed CentralView ArticleGoogle Scholar
  96. Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523(7560):337–41.PubMedPubMed CentralView ArticleGoogle Scholar
  97. Lueg G, Gross CC, Lohmann H, Johnen A, Kemmling A, Deppe M, et al. Clinical relevance of specific T-cell activation in the blood and cerebrospinal fluid of patients with mild Alzheimer's disease. Neurobiol Aging. 2015;36(1):81–9.PubMedView ArticleGoogle Scholar
  98. Schwartz M, Baruch K. The resolution of neuroinflammation in neurodegeneration: leukocyte recruitment via the choroid plexus. EMBO J. 2014;33(1):7–22.PubMedPubMed CentralView ArticleGoogle Scholar
  99. Marsh SE, Abud EM, Lakatos A, Karimzadeh A, Yeung ST, Davtyan H, et al. The adaptive immune system restrains Alzheimer's disease pathogenesis by modulating microglial function. Proc Natl Acad Sci U S A. 2016;113(9):E1316–25.PubMedPubMed CentralView ArticleGoogle Scholar
  100. Kunis G, Baruch K, Rosenzweig N, Kertser A, Miller O, Berkutzki T, et al. IFN-gamma-dependent activation of the brain's choroid plexus for CNS immune surveillance and repair. Brain. 2013;136(Pt 11):3427–40.PubMedView ArticleGoogle Scholar
  101. Baruch K, Rosenzweig N, Kertser A, Deczkowska A, Sharif AM, Spinrad A, et al. Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer's disease pathology. Nat Commun. 2015;6:7967.PubMedPubMed CentralView ArticleGoogle Scholar
  102. Dansokho C, Ait Ahmed D, Aid S, Toly-Ndour C, Chaigneau T, Calle V, et al. Regulatory T cells delay disease progression in Alzheimer-like pathology. Brain. 2016;139(Pt 4):1237–51.PubMedView ArticleGoogle Scholar
  103. McQuillan K, Lynch MA, Mills KH. Activation of mixed glia by Abeta-specific Th1 and Th17 cells and its regulation by Th2 cells. Brain Behav Immun. 2010;24(4):598–607.PubMedView ArticleGoogle Scholar
  104. Prajeeth CK, Lohr K, Floess S, Zimmermann J, Ulrich R, Gudi V, et al. Effector molecules released by Th1 but not Th17 cells drive an M1 response in microglia. Brain Behav Immun. 2014;37:248–59.PubMedView ArticleGoogle Scholar
  105. Vitorica J, Zhang J, Ke KF, Liu Z, Qiu YH, Peng YP. Th17 cell-mediated neuroinflammation is involved in neurodegeneration of AÎ21-42-induced alzheimer’s disease model rats. PLoS One. 2013;8(10):e75786.View ArticleGoogle Scholar
  106. McManus RM, Higgins SC, Mills KH, Lynch MA. Respiratory infection promotes T cell infiltration and amyloid-beta deposition in APP/PS1 mice. Neurobiol Aging. 2014;35(1):109–21.PubMedView ArticleGoogle Scholar
  107. Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K, et al. Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurol. 2014;13(6):614–29.PubMedView ArticleGoogle Scholar
  108. Wichmann MA, Cruickshanks KJ, Carlsson CM, Chappell R, Fischer ME, Klein BE, et al. Long-term systemic inflammation and cognitive impairment in a population-based cohort. J Am Geriatr Soc. 2014;62(9):1683–91.PubMedPubMed CentralView ArticleGoogle Scholar
  109. Saleem M, Herrmann N, Swardfager W, Eisen R, Lanctot KL. Inflammatory markers in mild cognitive impairment: a meta-analysis. J Alzheimers Dis. 2015;47(3):669–79.PubMedView ArticleGoogle Scholar
  110. Ray S, Britschgi M, Herbert C, Takeda-Uchimura Y, Boxer A, Blennow K, et al. Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins. Nat Med. 2007;13(11):1359–62.PubMedView ArticleGoogle Scholar
  111. Marksteiner J, Kemmler G, Weiss EM, Knaus G, Ullrich C, Mechtcheriakov S, et al. Five out of 16 plasma signaling proteins are enhanced in plasma of patients with mild cognitive impairment and Alzheimer's disease. Neurobiol Aging. 2011;32(3):539–40.PubMedPubMed CentralView ArticleGoogle Scholar
  112. Latta CH, Brothers HM, Wilcock DM. Neuroinflammation in Alzheimer's disease; A source of heterogeneity and target for personalized therapy. Neuroscience. 2015;302:103–11.PubMedView ArticleGoogle Scholar
  113. Hye A, Riddoch-Contreras J, Baird AL, Ashton NJ, Bazenet C, Leung R, et al. Plasma proteins predict conversion to dementia from prodromal disease. Alzheimers Dement. 2014;10(6):799–807. e2.PubMedPubMed CentralView ArticleGoogle Scholar
  114. Richens JL, Vere KA, Light RA, Soria D, Garibaldi J, Smith AD, et al. Practical detection of a definitive biomarker panel for Alzheimer’s disease; comparisons between matched plasma and cerebrospinal fluid. Int J Mol Epidemiol Genet. 2014;5(2):53–70.PubMedPubMed CentralGoogle Scholar
  115. Delaby C, Gabelle A, Blum D, Schraen-Maschke S, Moulinier A, Boulanghien J, et al. Central nervous system and peripheral inflammatory processes in Alzheimer's disease: biomarker profiling approach. Front Neurol. 2015;6:181.PubMedPubMed CentralView ArticleGoogle Scholar
  116. Khan TK, Alkon DL. Peripheral biomarkers of Alzheimer's disease. J Alzheimers Dis. 2015;44(3):729–44.PubMedGoogle Scholar
  117. O'Bryant SE, Gupta V, Henriksen K, Edwards M, Jeromin A, Lista S, et al. Guidelines for the standardization of preanalytic variables for blood-based biomarker studies in Alzheimer's disease research. Alzheimers Dement. 2015;11(5):549–60.PubMedView ArticleGoogle Scholar
  118. Krstic D, Madhusudan A, Doehner J, Vogel P, Notter T, Imhof C, et al. Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice. J Neuroinflammation. 2012;9:151.PubMedPubMed CentralView ArticleGoogle Scholar
  119. Maheshwari P, Eslick GD. Bacterial infection and Alzheimer's disease: a meta-analysis. J Alzheimers Dis. 2015;43(3):957–66.PubMedGoogle Scholar
  120. Sandiego CM, Gallezot JD, Pittman B, Nabulsi N, Lim K, Lin SF, et al. Imaging robust microglial activation after lipopolysaccharide administration in humans with PET. Proc Natl Acad Sci U S A. 2015;112(40):12468–73.PubMedView ArticleGoogle Scholar
  121. Holmes C. Review: systemic inflammation and Alzheimer's disease. Neuropathol Appl Neurobiol. 2013;39(1):51–68.PubMedView ArticleGoogle Scholar
  122. Bu XL, Yao XQ, Jiao SS, Zeng F, Liu YH, Xiang Y, et al. A study on the association between infectious burden and Alzheimer's disease. Eur J Neurol. 2015;22(12):1519–25.PubMedView ArticleGoogle Scholar
  123. de Jong D, Jansen R, Hoefnagels W, Jellesma-Eggenkamp M, Verbeek M, Borm G, et al. No effect of one-year treatment with indomethacin on Alzheimer's disease progression: a randomized controlled trial. PLoS One. 2008;3(1):e1475.PubMedPubMed CentralView ArticleGoogle Scholar
  124. Rogers J, Kirby LC, Hempelman SR, Berry DL, McGeer PL, Kaszniak AW, et al. Clinical trial of indomethacin in Alzheimer's disease. Neurology. 1993;43(8):1609–11.PubMedView ArticleGoogle Scholar
  125. Gupta PP, Pandey RD, Jha D, Shrivastav V, Kumar S. Role of traditional nonsteroidal anti-inflammatory drugs in Alzheimer's disease: a meta-analysis of randomized clinical trials. Am J Alzheimers Dis Other Demen. 2015;30(2):178–82.PubMedView ArticleGoogle Scholar
  126. Wang J, Tan L, Wang HF, Tan CC, Meng XF, Wang C, et al. Anti-inflammatory drugs and risk of Alzheimer's disease: an updated systematic review and meta-analysis. J Alzheimers Dis. 2015;44(2):385–96.PubMedGoogle Scholar
  127. Group A-FR. Follow-up evaluation of cognitive function in the randomized Alzheimer's Disease Anti-inflammatory Prevention Trial and its Follow-up Study. Alzheimers Dement. 2015;11(2):216–25 e1.View ArticleGoogle Scholar
  128. Szekely CA, Breitner JC, Fitzpatrick AL, Rea TD, Psaty BM, Kuller LH, et al. NSAID use and dementia risk in the Cardiovascular Health Study: role of ApoE and NSAID type. Neurology. 2008;70(1):17–24.PubMedPubMed CentralView ArticleGoogle Scholar
  129. Pasqualetti P, Bonomini C, Dal Forno G, Paulon L, Sinforiani E, Marra C, et al. A randomized controlled study on effects of ibuprofen on cognitive progression of Alzheimer’s disease. Aging Clin Exp Res. 2009;21(2):102–10.PubMedView ArticleGoogle Scholar
  130. Breitner JC, Baker LD, Montine TJ, Meinert CL, Lyketsos CG, Ashe KH, et al. Extended results of the Alzheimer's disease anti-inflammatory prevention trial. Alzheimers Dement. 2011;7(4):402–11.PubMedPubMed CentralView ArticleGoogle Scholar
  131. Leoutsakos JMS, Han D, Mielke MM, Forrester SN, Tschanz JT, Corcoran CD, et al. Effects of general medical health on Alzheimer's progression: the Cache County Dementia Progression Study. Int Psychogeriatr. 2012;24(10):1561–70.PubMedPubMed CentralView ArticleGoogle Scholar
  132. Tobinick EL, Gross H. Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration. J Neuroinflammation. 2008;5:2.PubMedPubMed CentralView ArticleGoogle Scholar
  133. Tobinick E. Deciphering the physiology underlying the rapid clinical effects of perispinal etanercept in Alzheimer's disease. Curr Alzheimer Res. 2012;9(1):99–109.PubMedView ArticleGoogle Scholar
  134. Roerink ME, Groen RJ, Franssen G, Lemmers-van de Weem B, Boerman OC, van der Meer JW. Central delivery of iodine-125-labeled cetuximab, etanercept and anakinra after perispinal injection in rats: possible implications for treating Alzheimer's disease. Alzheimers Res Ther. 2015;7(1):70.PubMedPubMed CentralView ArticleGoogle Scholar
  135. Tufan AN, Tufan F, Holmes C. Etanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, phase 2 trial. Neurology. 2015;85(23):2083–4.PubMedView ArticleGoogle Scholar
  136. Dinarello CA, van der Meer JW. Treating inflammation by blocking interleukin-1 in humans. Semin Immunol. 2013;25(6):469–84.PubMedPubMed CentralView ArticleGoogle Scholar
  137. Yao X, Huang J, Zhong H, Shen N, Faggioni R, Fung M, et al. Targeting interleukin-6 in inflammatory autoimmune diseases and cancers. Pharmacol Ther. 2014;141(2):125–39.PubMedView ArticleGoogle Scholar
  138. Astrakhantseva IV, Efimov GA, Drutskaya MS, Kruglov AA, Nedospasov SA. Modern anti-cytokine therapy of autoimmune diseases. Biochemistry (Mosc). 2014;79(12):1308–21.View ArticleGoogle Scholar
  139. Tarkowski E, Liljeroth AM, Nilsson A, Minthon LB, Lennow K. Decreased levels of intrathecal interleukin 1 receptor antagonist in Alzheimer's disease. Dement Geriatr Cogn Disord. 2001;12(5):314–7.PubMedView ArticleGoogle Scholar
  140. Smith JA, Das A, Ray SK, Banik NL. Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res Bull. 2012;87(1):10–20.PubMedView ArticleGoogle Scholar
  141. Taneo J, Adachi T, Yoshida A, Takayasu K, Takahara K, Inaba K. Amyloid beta oligomers induce interleukin-1beta production in primary microglia in a cathepsin B- and reactive oxygen species-dependent manner. Biochem Biophys Res Commun. 2015;458(3):561–7.PubMedView ArticleGoogle Scholar
  142. Coll RC, Robertson AA, Chae JJ, Higgins SC, Munoz-Planillo R, Inserra MC, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015;21(3):248–55.PubMedPubMed CentralGoogle Scholar
  143. Gomez-Nicola D, Boche D. Post-mortem analysis of neuroinflammatory changes in human Alzheimer's disease. Alzheimers Res Ther. 2015;7(1):42.PubMedPubMed CentralView ArticleGoogle Scholar
  144. Garlanda C, Dinarello CA, Mantovani A. The interleukin-1 family: back to the future. Immunity. 2013;39(6):1003–18.PubMedPubMed CentralView ArticleGoogle Scholar
  145. Li BH, Zhang LL, Yin YW, Pi Y, Guo L, Yang QW, et al. Association between interleukin-1alpha C(-889)T polymorphism and Alzheimer's disease: a meta-analysis including 12,817 subjects. J Neural Transm (Vienna). 2013;120(3):497–506.View ArticleGoogle Scholar
  146. Wang WF, Liao YC, Wu SL, Tsai FJ, Lee CC, Hua CS. Association of interleukin-I beta and receptor antagonist gene polymorphisms with late onset Alzheimer's disease in Taiwan Chinese. Eur J Neurol. 2005;12(8):609–13.PubMedView ArticleGoogle Scholar
  147. Yasuoka S, Kawanokuchi J, Parajuli B, Jin S, Doi Y, Noda M, et al. Production and functions of IL-33 in the central nervous system. Brain Res. 2011;1385:8–17.PubMedView ArticleGoogle Scholar
  148. Yu JT, Song JH, Wang ND, Wu ZC, Zhang Q, Zhang N, et al. Implication of IL-33 gene polymorphism in Chinese patients with Alzheimer's disease. Neurobiol Aging. 2012;33(5):1014. e11-4.PubMedView ArticleGoogle Scholar
  149. Van Dyken SJ, Locksley RM. Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: roles in homeostasis and disease. Annu Rev Immunol. 2013;31:317–43.PubMedPubMed CentralView ArticleGoogle Scholar
  150. Li W, Qian X, Teng H, Ding Y, Zhang L. Association of interleukin-4 genetic polymorphisms with sporadic Alzheimer's disease in Chinese Han population. Neurosci Lett. 2014;563:17–21.PubMedView ArticleGoogle Scholar
  151. Ribizzi G, Fiordoro S, Barocci S, Ferrari E, Megna M. Cytokine polymorphisms and Alzheimer disease: possible associations. Neurol Sci. 2010;31(3):321–5.PubMedView ArticleGoogle Scholar
  152. Spooren A, Kolmus K, Laureys G, Clinckers R, De Keyser J, Haegeman G, et al. Interleukin-6, a mental cytokine. Brain Res Rev. 2011;67(1-2):157–83.PubMedView ArticleGoogle Scholar
  153. Erta M, Quintana A, Hidalgo J. Interleukin-6, a major cytokine in the central nervous system. Int J Biol Sci. 2012;8(9):1254–66.PubMedPubMed CentralView ArticleGoogle Scholar
  154. Garbers C, Scheller J. Interleukin-6 and interleukin-11: same same but different. Biol Chem. 2013;394(9):1145–61.PubMedView ArticleGoogle Scholar
  155. Sabat R, Grutz G, Warszawska K, Kirsch S, Witte E, Wolk K, et al. Biology of interleukin-10. Cytokine Growth Factor Rev. 2010;21(5):331–44.PubMedView ArticleGoogle Scholar
  156. Sabat R. IL-10 family of cytokines. Cytokine Growth Factor Rev. 2010;21(5):315–24.PubMedView ArticleGoogle Scholar
  157. Vignali DA, Kuchroo VK. IL-12 family cytokines: immunological playmakers. Nat Immunol. 2012;13(8):722–8.PubMedPubMed CentralView ArticleGoogle Scholar
  158. Rentzos M, Rombos A. The role of IL-15 in central nervous system disorders. Acta Neurol Scand. 2012;125(2):77–82.PubMedView ArticleGoogle Scholar
  159. Bishnoi RJ, Palmer RF, Royall DR. Serum interleukin (IL)-15 as a biomarker of Alzheimer's disease. PLoS One. 2015;10(2):e0117282.PubMedPubMed CentralView ArticleGoogle Scholar
  160. Richmond J, Tuzova M, Cruikshank W, Center D. Regulation of cellular processes by interleukin-16 in homeostasis and cancer. J Cell Physiol. 2014;229(2):139–47.PubMedView ArticleGoogle Scholar
  161. Anvar NE, Saliminejad K, Ohadi M, Kamali K, Daneshmand P, Khorshid HR. Association between polymorphisms in Interleukin-16 gene and risk of late-onset Alzheimer's disease. J Neurol Sci. 2015;358(1-2):324–7.PubMedView ArticleGoogle Scholar
  162. Miossec P, Kolls JK. Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug Discov. 2012;11(10):763–76.PubMedView ArticleGoogle Scholar
  163. Probert L. TNF and its receptors in the CNS: The essential, the desirable and the deleterious effects. Neuroscience. 2015;302:2–22.PubMedView ArticleGoogle Scholar
  164. Massague J. TGFbeta signalling in context. Nat Rev Mol Cell Biol. 2012;13(10):616–30.PubMedPubMed CentralView ArticleGoogle Scholar
  165. Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75(2):163–89.PubMedView ArticleGoogle Scholar
  166. Shen WX, Chen JH, Lu JH, Peng YP, Qiu YH. TGF-beta1 protection against Abeta1-42-induced neuroinflammation and neurodegeneration in rats. Int J Mol Sci. 2014;15(12):22092–108.PubMedPubMed CentralView ArticleGoogle Scholar
  167. Baron R, Nemirovsky A, Harpaz I, Cohen H, Owens T, Monsonego A. IFN-gamma enhances neurogenesis in wild-type mice and in a mouse model of Alzheimer's disease. FASEB J. 2008;22(8):2843–52.PubMedView ArticleGoogle Scholar
  168. Mastrangelo MA, Sudol KL, Narrow WC, Bowers WJ. Interferon-{gamma} differentially affects Alzheimer's disease pathologies and induces neurogenesis in triple transgenic-AD mice. Am J Pathol. 2009;175(5):2076–88.PubMedPubMed CentralView ArticleGoogle Scholar
  169. Alzforum Research Models. Biomedical Research Forum, LLC. 2016. http://www.alzforum.org/research-models. Accessed 6 Feb 2016.

Copyright

© Zheng et al. 2016