Fibronectin type III domain-containing protein 5 interacts with APP and decreases amyloid \u03b2 production in Alzheimer\u2019s disease

Yasuha Noda,Yoko Sasakura,Akira Kuzuya,Ryoko Kawai,Yasushi Okuno,Masakazu Miyamoto,Yoshitaka Tashiro,Kyousuke Tanigawa,Masato Maesako,Ayae Kinoshita,Mitsugu Araki,Kengo Uemura,Biao Ma

doi:10.1186/s13041-018-0401-8

Abstract

The deposition of Amyloid-beta peptides (Aβ) is detected at an earlier stage in Alzheimer’s disease (AD) pathology. Thus, the approach toward Aβ 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 Aβ 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 PGC1α pathway. Thus, in the current study, we investigated a possibility that FNDC5 interacts with amyloid precursor protein (APP) and affects Aβ 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 Aβ40 and Aβ42 secreted in the media. Taken together, our results indicate that FNDC5 significantly affects β-cleavage of APP via the interaction with APP, finally regulating Aβ levels. A deeper understanding of the mechanisms by which the interaction between APP and FNDC5 may affect Aβ production in an exercise-dependent manner would provide new preventive strategies against the development of AD.

Highlights

Alzheimer’s disease (AD) is pathologically characterized by senile plaques, neurofibrillary tangles, and neuronal cell death
fibronectin type III domain-containing protein 5 (FNDC5) interacts with amyloid precursor protein We hypothesized that exercise may modulate Alzheimer’s pathology via modulating Amyloid precursor protein (APP) metabolism
To probe for possible changes in Amyloid β (Aβ) production in response to myokines which are released from muscles, we tested whether FNDC5, glucose regulating molecules may bind to APP and affect Aβ production

Summary

Introduction

Alzheimer’s disease (AD) is pathologically characterized by senile plaques, neurofibrillary tangles, and neuronal cell death. Amyloid β (Aβ), a major component of senile plaques, is known to be cleaved from its precursor protein Amyloid precursor protein (APP) and secreted extracellularly. APP is a single transmembrane protein that is expressed in a number of different cell types, including neurons. According to the widely accepted ‘amyloid cascade hypothesis’ [1], a sequential processing of APP by β-secretase and γ-secretase leads to the generation of several types of amyloid β (Aβ). The largest risk factor for sporadic AD is aging, which is unavoidable; there are reported to be several modifiable factors including high blood pressure, diabetes mellitus, physical inactivity, low education, smoking, and so on [4]. Epidemiological and clinical studies clearly indicate that type diabetes mellitus elevates the morbidity rates of AD [5]. In vivo experiments using APP-overexpressing transgenic mice (AD model mice)

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Conclusion