Steven Jacob

 Introduction. Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder characterized by synapse failure and memory impairment.^1-2 It is the most common form of dementia worldwide, primarily affecting elderly populations and caused by both Familial genetic mutations in amyloid-beta generating genes or sporadic risk factors linked to aging, stress, or apolipoprotein gene mutations.^1-2 A major key hallmark of AD is Amyloid Beta oligomer (AβO) deposition, and AD patients commonly have observed decreased Brain-Derived Neurotrophic Factor (BDNF) in the hippocampus.^1-6 No effective treatment currently exists for curing AD, yet there are hypotheses on neuroprotective effects of exercise on learning and memory.^2-5 In 2019, a study found that upregulated expression of a transmembrane precursor protein Fibronectin Type III Domain-Containing Protein 5 (FNDC5) and an exercise-induced skeletal muscle myokine Irisin cleaved from FNDC5 rescued long-term potentiation and memory recognition in AD swiss mice models via enhanced hippocampal BDNF levels.^3-5 Other studies investigated FNC5 and a transcription coactivator regulating FNDC5 called Peroxisome proliferator-activated receptor-ɣ coactivator 1α (PGC-1 α) modulating effects on AβO deposits in transgenic mice, reversing decreased BDNF expression.^6-8 Another study found that moderate treadmill exercise enhanced hippocampal BDNF, FNDC5, and PGC-1 α mRNA in Aβ₁₋₄₂  mice models.⁹ These findings suggest that enhancing the expression of the exercise-induced PGC-1 α/FNDC5 pathway has promise for reversing AβO deposition and rescuing memory deficits in AD. Methods. Wild Type and AβO injected swiss mice hippocampi were compared for FNDC5/irisin protein expression using Western blot.³ Synaptic plasticity and memory recognition were tested between WT and Short Hairpin-Loop FNDC5 mRNA knockdown mice using the novel object recognition (NOR) and field electrical post-synaptic potential (fEPSP) tests, respectively. The tests were repeated with Irisin injected/adenoviral expressed FNDC5 in AβO mice.³ Furthermore, western blots were performed on Human Embryonic Kidney 29 (HEK29) cells transfected with FNDC5.⁶ Studies also compared BDNF expression with PGC-1 α and FNDC5 mRNA between WT and AβO mouse models before and after controlled treadmill exercise.^8-9 All results were quantified with ANOVA.^3,6,8-9 Results. Increased FNDC5/Irisin levels rescued synaptic plasticity and memory deficits in AD models.³ PGC-1α or FNDC5 expression reversed decreased BDNF expression despite AβO deposition.^6,8 Moderate Exercise promoted upregulation of PGC-1α/FNDC5/BDNF levels.⁹ Conclusions. Studies have shown that the upregulated expression of PGC-1α/FNDC5/BDNF may have therapeutic implications in sustaining memory and synaptic plasticity in AD. Exercise or Pharmaceutical mimetics could be potential avenues for preventing and treating AD.

1. Crous-Bou M, Minguillón C, Gramunt N, Molinuevo J. Alzheimer’s disease prevention: from risk factors to early intervention. Alzheimers Res Ther. 2017;9(1). doi:10.1186/s13195-017-0297-z
2. Pluvinage J, Wyss-Coray T. Systemic factors as mediators of brain homeostasis, ageing and neurodegeneration. Nature Reviews Neuroscience. 2020;21(2):93-102. doi:10.1038/s41583-019-0255-9
3. Lourenco M, Frozza R, de Freitas G et al. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models. Nat Med. 2019;25(1):165-175. doi:10.1038/s41591-018-0275-4
4. Cui M, Lin Y, Sheng J, Zhang X, Cui R. Exercise Intervention Associated with Cognitive Improvement in Alzheimer’s Disease. Neural Plast. 2018;2018:1-10. doi:10.1155/2018/9234105
5. Choi S, Bylykbashi E, Chatila Z et al. Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model. Science. 2018;361(6406): eaan8821. doi:10.1126/science. Aan8821
6. Noda Y, Kuzuya A, Tanigawa K, et al. Fibronectin type III domain-containing protein 5 interacts with APP and decreases amyloid β production in Alzheimer’s disease. Molecular Brain. 2018;11(1). doi:10.1186/s13041-018-0401-8
7. Liang H, Ward W. PGC-1α: a key regulator of energy metabolism. Adv Physiol Educ. 2006;30(4):145-151. doi:10.1152/advan.00052.2006
8. Xia D-Y, Huang X, Bi C-F, Mao L-L, Peng L-J, Qian H-R. PGC-1α or FNDC5 Is Involved in Modulating the Effects of Aβ1−42 Oligomers on Suppressing the Expression of BDNF, a Beneficial Factor for Inhibiting Neuronal Apoptosis, Aβ Deposition and Cognitive Decline of APP/PS1 Tg Mice. Frontiers in Aging Neuroscience. 2017;9. doi:10.3389/fnagi.2017.00065
9. Azimi M, Gharakhanlou R, Naghdi N, Khodadadi D, Heysieattalab S. Moderate treadmill exercise ameliorates amyloid-β-induced learning and memory impairment, possibly via increasing AMPK activity and up-regulation of the PGC-1α/FNDC5/BDNF pathway. Peptides. 2018;102:78-88. doi:10.1016/j.peptides.2017.12.027