Amyloid-β protein deposition is a pathological feature of Alzheimer's disease. It is known that physical exercise can reduce amyloid-β deposition. A protein secreted by muscles plays a role in this process: Irisin. It regulates lipid and glucose metabolism in adipose tissue and increases energy consumption. The formation of irisin is stimulated by exercise. Low levels of irisin have been found in Alzheimer's patients. 

Irisin increased the production of neprilysin, which reduced amyloid-β pathology in Alzheimer's disease cell culture. Neprilysin is an enzyme with crucial importance in human amyloid metabolism. It metabolizes the Alzheimer's-causing protein β-amyloid in the human brain. Deficiency of the enzyme due to genetic mutation of the MME gene or other enzyme deficiency could promote the occurrence of Alzheimer's disease.

On the astrocytes of the Alzheimer cell culture model, the receptor integrin αV/β5 was the binding site for irisin: when the protein binds, neprilysin is released and can thus exert its effect. At the same time, irisin blocks interleukin-6/ERK signaling, increases secNEP release, and thus reduces STAT3 levels.

As a result, the researchers have found a cellular and molecular mechanism by which irisin attenuates amyloid-β pathology, which could provide a new approach to therapies for the prevention and treatment of Alzheimer's disease.

Original publication:
Kim E, Kim H, Jedrychowski MP, Bakiasi G, Park J, Kruskop J, Choi Y, Kwak SS, Quinti L, Kim DY, Wrann CD, Spiegelman BM, Tanzi RE, Choi SH.(2023). Irisin reduces amyloid-β by inducing the release of neprilysin from astrocytes following downregulation of ERK-STAT3 signaling. Neuron. Aug 30:S0896-6273(23)00623-2. doi: 10.1016/j.neuron.2023.08.012. Epub ahead of print. PMID: 37689059.

Additional information:
Lourenco, M.V., Frozza, R.L., de Freitas, G.B. et al. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer's models. Nat Med 25, 165-175 (2019). https://doi.org/10.1038/s41591-018-0275-4
https://www.nature.com/articles/s41591-018-0275-4
https://researchers.mgh.harvard.edu/profile/3824747/Rudolph-Tanzi
https://www.genengnews.com/topics/translational-medicine/new-approach-to-alzheimers-disease-treatment-may-come-from-exercise-induced-hormone/