Table 1 Transplantation of BMMSCs for the treatment of animal models with Alzheimer’s disease. Keywords “Alzheimer’s disease” and “stem cell transplantation” were utilized to screen database PubMed, Medline, and Embase respectively. Studies eligible for inclusion were restricted to the bone marrow mesenchymal stem cells. Primary studies with complete data were retained in the current meta-analytic review

Bae, 2013

Random APP/PS1 mice, in vivo study.

Decline of amyloid-beta deposits and and the improvement of synaptic transmission

Significant decrease in the cerebral Aβ deposition; Expression of dynamin 1 and Synapsin 1, key pre-synaptic proteins.

Curr Alzheimer Res. 2013 Jun;10 [5]:524–31

Garcia, 2014

Random 2xTg-AD male congenic mice, in vivo study. BMMSCs over expressed VEGF (human VEGF 165 cDNA from uP-VEGF)

Behavioral benefits included the recovery of memory loss and cognitive deficits as demonstrated by open-field evaluation, social recognition test, and plus-maze discriminative avoidance task (PM-DAT).

Mechanisms involved neovascularization, reduction of amyloid-beta plaques, and to decrease astrocytes and microglial cells

Front Aging Neurosci. 2014 Mar 7;6:30

Harach, 2017

Random APP/PS1 mice, in vivo study. Stem cells were obtained from Stemedica Cell Technologies (SanDiego, USA). The cells are equivalent to commercially available stem cells from ThermoFisher Scientific “StemPro BM MSC” (part number A15653)(ischemia-tolerant mesenchymal stem cells)

Significant reduction of cerebral Ab plaques and neuroinflammation

Reduced cerebral Aβ plaques,increasing NPE,IDE and ECE Aβ-degrading enzymes;reduced TNFa,IL-12p70 and IL-10.

Neurobiol Aging. 2017 Mar;51:83–96.

Kanamaru, 2015

Random APP/DAL101 mice,in vivo study. To confirm preventive effect of BMMSCs against neuronal degenerationr or therapeutic effect of BMMCs on neuronal degeneration respectively.

To suppress neuronal loss and restore memory impairment of DAL mice,to reduce Aβdeposition and improve cognitive behavior in APP mice.

To prevent neurodegeneration and Aβ deposition.

Brain Res. 2015 Apr 24;1605:49–58.

Lampron, 2013

Random APP/PS1 mice, in vivo study.

Bone marrow-derived cells (BMDC) under stimulaton of M-CSF could infiltrate the CNS in animal models for stroke and Alzheimer’s disease. They were confined in diseased sites for several weeks.

Hypoxic-ischemic injury sites or amyloid plaques could induce the entry of BMDC cells.

J Comp Neurol. 2013 Dec 1;521 [17]:3863–76.

Lee, 2010

Random C57BL/6 mice were injected with aggregated Aβto make AD model, in vivo study. The bone marrow cells were cultured for 1 week, and the plastic-adherent population was used for subsequent experiments.

To attenuate memory impairment and to inhibit neuronal apoptosis.

To reduce aβ deposition, stimulate microglial activation, switch the microglial phenotype into alternative form, decrease tau hyperphosphorylation, and diminish Aβ-induced oxidative stress in model animals.

Curr Alzheimer Res. 2010 Sep;7 [6]:540–8

Lee, 2010

Random APP/PS1 mice. The bone marrow cells were cultured for 1 week, and the plastic-adherent population was used for subsequent experiments.

To ameliorate Abeta-induced neuropathology and improve the cognitive decline associated with Abeta deposits.

To modulate immune/inflammatory responses and to restore defective microglial functionin AD mice, as evidenced by increased Abeta-degrading factors, decreased inflammatory responses, elevation of alternatively activated microglial markers, and diminished tau hyperphosphorylation.

Stem Cells. 2010 Feb;28 [2]:329–43.

Lee, 2012

Random APP/PS1-GFP chimeric mice,in vivo study;Therapeutic effect;

Alternative microglia activation to eliminate Abeta deposition in the AD brain, and further improve behavior.

The icroglial activation and migration into the brains of Abeta-deposited AD mice via elevation of the chemoattractive factor, CCL5.Neprilysin and interleukin-4 derived from the alternative microglia were associated with a reduction in Abeta deposition and memory impairment in AD mice.

Stem Cells. 2012 Jul;30 [7]:1544–55.

Li, 2011

Random APP/PS1 mice,mechanistic study.

Systemic administration of SCF + G-CSF reduced beta-amyloid deposition in AD mice, and increased the number of bone marrow-derived microglial cells in the brain.

Decreased β-amyloid deposition, enhanced microglial

Alzheimers Res Ther. 2011 Mar 15;3 [2]:8

Li, 2012

Random rat experiments,in vivo study; Therapeutic effect;

To improve spatial learning and memory ability as demonstrated by Morris water maze experiment

BM-MSCc could migrate through the blood-brain barrier and survived in the hippocampus of AD rats

Zhejiang Da Xue Xue Bao Yi Xue Ban. 2012 Nov;41 [6]:659–64

Liu, 2015

Random APP/PS1 mice; Overexpression of as-miR-937 in MSCs may improve the therapeutic effects of MSCs on AD

MSCs reduced the deposition of amyloid-beta peptide aggregates (Aβ) and improved behavior as proved by social recognition test (SR) and plus-maze discriminative avoidance task (PM-DAT).

MSCs significantly increased Brn-4 protein levels, which reduced the deposition of Aβand upregulated the levels of BDNF in AD mice.

Cell Physiol Biochem. 2015;37 [1]:321–30

Magga, 2012

Transgenic APdE9 mice, BM-derived haematopoietic stem cells (HSC)

HSC-derived monocytic cells (HSCM) could be genetically modified and contributed to Abeta reduction in APdE9 mouse model of AD .

HSC-derived monocytic cells (HSCM) uptook Abeta protein and reduced Aβburden in AD mouse brain.

J Cell Mol Med. 2012 May;16 [5]:1060–73

Matchynski-Franks, 2016

Random 5xFAD mice; the optimal location for transplanting MSCs; Injection into the lateral ventricles was better than the injection into hippocampus.

MSC transplants effectively reduced learning deficits in the 5xFAD mouse model as demonstrated by radial-arm water maze 8-choice memory task, water t-maze two-choice learning task, spontaneous motor activity, motor coordination, and prepulse inhibition.

Significantly to decrease the level of Abeta42 in the brains of 5xFAD mice subsequent to transplantation of MSCs.

Cell Transplant. 2016;25 [4]:687–703.

Naaldijk, 2017

Random APP/PS1 mice,in vivo study. Therapeutic effect of BMMCs

MSCs may affect AD pathology (neuroinflammation) via an immune-modulatory function that includes an effect on microglial cells.

To reduce the expressional levels of TNF-alpha, IL-6, MCP-1, and NGF in MSC recipients. Also,to reduce the size of pE3-Abeta plaques in the hippocampus.

Neuropathol Appl Neurobiol. 2017 Jun;43 [4]:299–314.

Ruzicka, 2016

Random 3xTg-AD mice treated by human MSCs. Therapeutic effect of BMMCs

Learning Deficits improved; reduced Amyloid β (Aβ*56); increased neurogenesis;

Clusters of proliferating cells in the subventricular zone; the level of glutamine synthetase; downregulation of Abeta*56 levels in the entorhinal cortex

Int J Mol Sci. 2016 Jan 25;17 [2]. pii: E152.

Safar, 2016

Adult male Wistar rats, effects of bone marrow-derived (BM) EPCs transplantation,endothelial progenitor cells (EPCs)

Improved the learning and memory deficits, and mitigated the deposition of amyloid plaques and downregulation of p-tau. To correct memory deficits and AD-like pathological dysfunction

Downregulation of p-tau and its upstream glycogen synthase kinase-3beta (GSK-3beta); corrected the perturbations of neurotransmitter levels including acetylcholine, dopamine, GABA, and the neuroexitatory glutamate; to boost the expression of vascular endothelial growth factor (VEGF), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and its upstream cAMP response element binding (CREB); suppression of the proinflammatory tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta); upregulation of interleukin-10 (IL-10), Nrf2 and seladin-1.

Mol Neurobiol. 2016 Apr;53 [3]:1403–1418

Selem, 2014

Adult female Sprague–Dawley rats,,in vivo study. Therapeutic effect of BMMCs

To remove beta-amyloid plaques from hippocampus; anti-apoptotic, neurogenic and immunomodulatory properties

Proliferating the number of positive cells for choline acetyltransferase (ChAT) and survivin expression, as well as selective AD indicator-1 (seladin-1) and nestin gene expression. Histopathological examination indicated the removal of beta-amyloid plaques from hippocampus. Significant improvement in these biomarkers was similar to or better sometimes than the reference drugs.

Cell Biol Int. 2014 Dec;38 [12]:1367–83

Wu, 2011

Random SD rat experiments via hippocampal fimbria-farnix (FF) amputation model, Ginsenoside Rg1 treatment,in vivo study. Therapeutic effect of BMMCs

Spatial learning-memory ability of dementia rats was improved as demonstrated by by Morris water maze and the escape latency test.

The mechanism might be possibly correlated with mRNA expression level of NGF that was up-regulated in basal forebrain.

Zhongguo Zhong Xi Yi Jie He Za Zhi. 2011 Jun;31 [6]:799–802.

Yu, 2018

Random experiments, Sprague-Dawley female rats,in vivo study. Therapeutic effect of BMMCs

The expression of Seladin-1 and nestin were lower in the AD group when compared with the control group, whereas the BM-MSC transplantation reversed their down-regulation.

BM-MSC transplantation enhanced Seladin-1 and nestin expression potentially via a mechanism associated with the activation of the PI3K/Akt and ERK1/2 signaling pathways.

Oncol Lett. 2018 May;15 [5]:7443–7449.

Zhang, 2012

Sprague-Dawley rats,in vivo study. Therapeutic effect of BMMCs

BMMSCs plus BDNF resulted in significant attenuation of nerve cell damage in the hippocampal CA1 region. Tyrosine kinase B mRNA and protein levels were significantly increased, and learning and memory ability were significantly improved.

Increasing the levels of brain-derived neurotrophic factor and tyrosine kinase B in the hippocampus.

Neural Regen Res. 2012 Feb 5;7 [4]:245–50