Exercise and BDNF reduce Aβ production by enhancing α‐secretase processing of APP

• Published in: Journal of neurochemistry 2017-07, Vol.142 (2), p.286-296
• Main Authors: Nigam, Saket M., Xu, Shaohua, Kritikou, Joanna S., Marosi, Krisztina, Brodin, Lennart, Mattson, Mark P.
• Format: Article
• Language: English
• Subjects: alpha‐secretase; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - biosynthesis; amyloid precursor protein; Amyloid Precursor Protein Secretases - metabolism; Animals; Aspartic Acid Endopeptidases - metabolism; BDNF; Brain - metabolism; Brain-Derived Neurotrophic Factor - metabolism; Disease Models, Animal; exercise; Medicin och hälsovetenskap; Mice, Transgenic; Physical Conditioning, Animal; Signal Transduction - physiology
• ISSN: 0022-3042; 1471-4159; 1471-4159
• DOI: 10.1111/jnc.14034

Alzheimer's disease (AD) is an age‐related neurodegenerative disorder characterized by aggregation of toxic forms of amyloid β peptide (Aβ). Treatment strategies have largely been focused on inhibiting the enzymes (β‐ and γ‐secretases) that liberate Aβ from the amyloid precursor protein (APP). While evidence suggests that individuals who exercise regularly are at reduced risk for AD and studies of animal models demonstrate that running can ameliorate brain Aβ pathology and associated cognitive deficits, the underlying mechanisms are unknown. However, considerable evidence suggests that brain‐derived neurotrophic factor (BDNF) mediates beneficial effects of exercise on neuroplasticity and cellular stress resistance. Here, we tested the hypothesis that BDNF promotes non‐amyloidogenic APP processing. Using a transgenic mouse model of Alzheimer's disease and cultured human neural cells, we demonstrate that exercise and BDNF reduce production of toxic Aβ peptides through a mechanism involving enhanced α‐secretase processing of APP. This anti‐amyloidogenic APP processing involves subcellular redistribution of α‐secretase and an increase in intracellular neuroprotective APP peptides capable of binding and inhibiting β‐secretase. Moreover, our results suggest that BDNF's ability to promote neurite outgrowth is primarily exerted through pathways other than APP processing. Exercise and other factors that enhance BDNF signaling may therefore have both therapeutic and prophylactic value in the battle against AD. Read the Editorial Highlight for this article on page 191. The findings of Nigam et al. demonstrate that running wheel exercise and brain‐derived neurotrophic factor (BDNF) enhance cleavage of the β‐amyloid precursor protein (APP) by α‐secretase to generate secreted APPα (sAPPα) in neural cells. This enzymatic processing of APP occurs in an intracellular compartment where sAPPα may also inhibit β‐secretase, thereby preventing production of the neurotoxic amyloid β‐peptide. These findings suggest a novel mechanism whereby exercise may protect the brain against Alzheimer's disease by BDNF‐mediated non‐amyloidogenic processing of APP. Read the Editorial Highlight for this article on page 191.