Daniel R Brophy

 Introduction. Alzheimer’s disease (AD) is the most common form of dementia in the elderly and affects millions of people worldwide.¹ Current research and understanding of Alzheimer’s pathology recognizes “the amyloid hypothesis” as the cellular and molecular basis of the disease. Specifically, amyloid-B oligomers (ABOs) contribute to synapse failure and neuronal dysfunction.^1,2 Multiple exercise-induced myokines, including FNDC5/Irisin and cathepsin B have cellular effects that make them potential therapies for combating the specific amyloid-based processes that are currently theorized to govern cognitive decline in AD. These myokines were hypothesized to support neurogenesis through BDNF (FNDC5/Irisin), prevention of amyloid binding and neuronal dendritic cell loss (FNDC5/Irisin) and upregulate lysosomal proteases that cleave ABOs (Cathepsin B).^3-6 Methods. To establish that FNDC5/Irisin promotes BDNF expression, a study examined primary cortical neurons transduced with either FNDC5 adenovirus or a GFP adenovirus as control. Forty-eight hours later mRNA was prepared and gene expression was assessed by qPCR.^1,4 In another study of FNDC5/Irisin, recombinant Irisin and prepared synthetic ABOs were combined in various combinations with hippocampal neuronal cultures.¹ After the combination, the neuronal cells were stained, processed, and had their dendritic spines isolated from the neurons. Researchers blind to the experimental conditions manually determined the number of spines in each sample of cells.¹ Lastly, in a study of the myokine Cathepsin B, progenitor neurons were infected with recombinant adenovirus to express differing combinations of Cathepsin B, APP (amyloid precursor protein), and controls.⁶ After transduction with individual adenoviruses, the progenitor neurons were then subject to ELISA to quantify specific levels of ABO protein.⁶ Results. Forced expression of FNDC5 increased BDNF gene expression in the cortical neuron by a factor of 4 compared to GFP controls.^1,4 In the study of Irisin and ABO, the research demonstrated that when recombinant Irisin was added to neuronal cells, they prevented dendritic spine loss in cultured hippocampal neurons exposed to ABOs.¹ Lastly, in the study of Cathepsin B demonstrated that cells infected with the control adenovirus demonstrated ABO retention in the neurons, while cells with Cathepsin B were shown to suppress ABO production from mouse progenitor neurons.⁶ Conclusions. These studies demonstrated that a number of specific exercise-associated myokines have mechanisms that target the amyloid-mediated pathways of AD and have promising therapeutic potential against the currently theorized causal agents of memory decline in Alzheimer’s disease.

1. Ferreira, S., Lourenco, M., Oliveira, M. and De Felice, F. (2015). Soluble amyloid-oligomers as synaptotoxins leading to cognitive impairment in Alzheimers disease. Front Cell Neurosci. 2015;9. doi:10.3389/fncel.2015.00191
2. Lane, C., Hardy, J. and Schott, J. (2017). Alzheimer’s disease. European Journal of Neurology, 25(1), pp.59-70.
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. Wrann C, White J, Salogiannnis J et al. Exercise Induces Hippocampal BDNF through a PGC-1α/FNDC5 Pathway.Cell Metab. 2013;18(5):649-659. doi:10.1016/j.cmet.2013.09.008
5. Moon H, Becke A, Berron D et al. Running-Induced Systemic Cathepsin B Secretion Is Associated with Memory Function.Cell Metab. 2016;24(2):332-340. doi:10.1016/j.cmet.2016.05.025
6. Embury C, Dyavarshetty B, Lu Y et al. Cathepsin B Improves ß-Amyloidosis and Learning and Memory in Models of Alzheimer’s Disease. Journal of Neuroimmune Pharmacology. 2016;12(2):340-352. doi:10.1007/s11481-016-9721-6