Fibronectin type III domain-containing protein 5 interacts with APP and decreases amyloid β production in Alzheimer's disease

The deposition of Amyloid-beta peptides (A) is detected at an earlier stage in Alzheimer's disease (AD) pathology. Thus, the approach toward A metabolism is considered to play a critical role in the onset and progression of AD. Mounting evidence suggests that lifestyle-related diseases are closely associated with AD, and exercise is especially linked to the prevention and the delayed progression of AD. We previously showed that exercise is more effective than diet control against A pathology and cognitive deficit in AD mice fed a high-fat diet; however, the underlying molecular mechanisms remain poorly understood. On the other hand, a report suggested that exercise induced expression of fibronectin type III domain-containing protein 5 (FNDC5) in the hippocampus of mice through PGC1 pathway. Thus, in the current study, we investigated a possibility that FNDC5 interacts with amyloid precursor protein (APP) and affects A metabolism. As a result, for the first time ever, we found the interaction between FNDC5 and APP, and forced expression of FNDC5 significantly decreased levels of both A(40) and A(42) secreted in the media. Taken together, our results indicate that FNDC5 significantly affects -cleavage of APP via the interaction with APP, finally regulating A levels. A deeper understanding of the mechanisms by which the interaction between APP and FNDC5 may affect A production in an exercise-dependent manner would provide new preventive strategies against the development of AD.