Table 1 Candidate molecules of exercise mimetics for the treatment of neurodegenerative disorders

Myokines

Irisin

Recombinant irisin

(1) Attenuate glial activation by binding αVβ5 integrin receptor; improve spatial learning and memory

(2) Decrease tau phosphorylation, α-synuclein, and inflammatory cytokine levels

(3) Rescue synaptic plasticity and improve impairment in NOR and fear conditioning memory

Anti-neuroinflammation, neuronal protection and memory promotion for AD and PD

[181, 190,191,192]

AMPK

Metformin

(1) Improve cognitive function

(2) Reduce the risk of dementia

AD prevention and cognitive promotion for AD and PD

[337,338,339, 354]

AICAR

(1) Increase IDE and reduce Aβ or α-synuclein deposition; enhance spatial learning and cognitive performance

(2) Inhibit neuroinflammation and promote neurite growth

Neuroinflammation inhibition, neuronal protection and cognitive improvement for AD and PD

[330,331,332, 355, 356]

PPARδ

GW501516

(1) Increase AHN and cognition

(2) Reduce neuroinflammation

Brain health and cognitive promotion for AD

[347, 348]

Neurotrophic factor

BDNF

Recombinant BDNF,

Recombinant BDNF + ADTC5,

DHF

(1) Up-regulate α-secretase, ameliorate Aβ levels and increase sAPPα levels

(2) Reduce α-synuclein level

(3) Increase phosphorylation of TrkB and restore synaptic plasticity and memory function

(4) Increase AHN and memory performance

(5) Increase NG2 glial cells and EGR1 and ARC gene expression; enhance cognitive performance and NOR assessments

Neuronal protection and cognitive improvement for AD, PD, and HD

[36, 155, 167, 357,358,359]

Noncoding RNAs

miRNAs

miRNA-132, miRNA-146, miRNA-155, miRNA-7, miRNA-21, miRNA-339, miRNA-29, miRNA-129–1-3p, miRNA-144-5p, miRNA-708-5p, miRNA-135a, miRNA-21, miRNA-34a

(1) Rescue AHN and memory impairment

(2) Alleviate the accumulation of α-synuclein or Aβ and Tau hyperphosphorylation; restore AHN and cognitive function

(3) Ameliorate neuroinflammation

(4) Ameliorate the activation of microglial cells and neurodegeneration

Anti-neuroinflammation; brain and memory improvement for AD, PD and HD

[147, 272, 276, 277, 284, 286, 300, 306, 360,361,362,363,364,365,366]

Methyl donor

Methylation

SAM

(1) Ameliorate AD pathology and improve cognitive function

(2) Restore normal gene expression, reduce presenilin1 expression, and decrease Aβ levels。

(3) Increase secretases and ApoE expression

(4) Increase GSH and decrease ROS and toxic xenobiotics

(5) Prevent neuronal loss, elevate BDNF levels, and inhibit neuroinflammation

Brain health and memory promotion for AD and PD

[250,251,252,253, 255, 257, 367]

Metabolism mediators

Apolipoprotein J

Clusterin

(1) Inhibit neuroinflammation, promote AHN, and improve contextual learning and memory function

(2) Increase excitatory neurotransmission, reverse synaptic damage and alleviate AD pathology

(3) Reduce cell apoptosis and increase neuronal differentiation

Hippocampal neurogenesis and memory improvement for AD

[34, 315, 368]

GPI

Gpld1

Increase AHN, BDNF level, and memory function

Brain and memory promotion for AD

[37]

Other candidates

Gut microbiome

SCFAs

(1) Increase gut health and preserve microbiota community

diversity

(2) Enrich SCFAs, Firmicutes phylum

(3) Decrease gut inflammation and improve cognition

Gut-brain health and cognitive improvement for AD, PD and HD

[224, 227, 369,370,371,372,373,374,375]

VEGF

SU1498

Promote AHN and cognition

Brain health and memory promotion

[376,377,378]

Serotonin

TPH2,

5-HT3 receptor, SERT

Increase neuronal proliferation and outgrowth

Brain health promotion

[324, 379,380,381]