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

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.Electronic supplementary materialThe online version of this article (10.1186/s13041-018-0401-8) contains supplementary material, which is available to authorized users.

FNDC5/Irisin System in Neuroinflammation and Neurodegenerative Diseases: Update and Novel Perspective

“…A recent in vitro study, by means of biochemical and in silico simulation assay, showed the possible involvement of FNDC5/irisin in the mechanisms of Aβ generation [ 82 ]. In particular, the authors showed that APP/FNDC5 interaction, occurring by the binding of FNDC5 to a specific domain between β- and α-secretase cleavage sites of APP, could reduce Aβ formation, leading to a decreased secretion of both Aβ40 and Aβ42 peptides in the culture media.…”

“…This could imply the involvement of FNDC5 in the prevention of AD, acting in the initial phases of the disease development when Aβ accumulation begins and before the onset of dementia. Indeed, when AD is in the clinical stage, Aβ and tau accumulations have already induced extensive neuronal damage in multiple areas of the brain and could be too late for the possible FNDC5 role as of any other compound in AD treatment [ 82 ]. In vivo studies performed in animal models and in humans by Lourenco et al [ 10 , 30 ] demonstrated that irisin levels were reduced in the cerebrospinal fluid (CSF) of AD mice and patients.…”

Integrin-Ligand Interactions in Inflammation, Cancer, and Metabolic Disease: Insights Into the Multifaceted Roles of an Emerging Ligand Irisin

“…Boosting of brain irisin by intracerebroventricular infusion rescues memory impairment and provides protection against synaptic plasticity in AD mice (Lourenco et al, 2019). Another group showed that irisin binds with amyloid precursor protein at the N-terminal and that overexpression of FNDC5 in cells significantly decreased the secretion of amyloid-β protein into the media in vitro (Noda et al, 2018). In addition, pharmacological, but not physiological, concentrations of irisin (50-100 nM) increase the proliferation of a mouse hippocampal cell line, H19-7 HN, without influencing markers of neurite outgrowth or synaptogenesis in vitro.…”

Molecular and Functional Interaction of the Myokine Irisin with Physical Exercise and Alzheimer’s Disease

“…One recent study has reported the interaction between FNDC5 and APP, and resultant decreases in Aβ formation. According to the study, although FNDC5 has no effect on full APP length, it decreases C-terminal fragment C99 of APP [76]. Since this fragment has Aβ formation-suppressing characteristic, FNDC5 expression seems to diminish Aβ production [76].…”

“…According to the study, although FNDC5 has no effect on full APP length, it decreases C-terminal fragment C99 of APP [76]. Since this fragment has Aβ formation-suppressing characteristic, FNDC5 expression seems to diminish Aβ production [76]. In this regards, both the irisin precursor, FNDC5, and its upstream factor, PGC-1α, are involved in the regulation of AD pathogenesis.…”