CPNE7 Regulates Amyloidogenesis Through CAP1‐Dependent ADAM10 Translation

• Published in: Journal of neurochemistry Vol. 169; no. 3; pp. e70026 - n/a
• Main Authors: Yang, Jie, Pu, Ya‐Lan, Pan, Qiu‐Lin, Wang, Lu, Li, Chen‐Lu, Xie, Xiao‐Yong, Chen, Xue, Li, Xiao‐Yun, Bai, Ding‐Qun, Zhu, Bing‐Lin, Chen, Guo‐Jun
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.03.2025
• Subjects: 5' Untranslated regions; Actin; ADAM10; ADAM10 Protein - biosynthesis; ADAM10 Protein - genetics; ADAM10 Protein - metabolism; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Alzheimer's disease (AD); Amyloid; Amyloid beta-Protein Precursor - genetics; Amyloid Precursor Protein Secretases - biosynthesis; Amyloid Precursor Protein Secretases - genetics; Amyloid Precursor Protein Secretases - metabolism; Amyloidogenesis; Animals; Binding; CAP1; CPNE7; Cytoskeleton; HEK293 Cells; Hippocampus - metabolism; Humans; Male; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurodegenerative diseases; Plaque, Amyloid - metabolism; Presenilin 1; Protein Biosynthesis - physiology; Proteins; RNA‐binding protein (RBP); Secretase; Senile plaques; Transcriptomes; Translation; β-Amyloid; CAP1; ADAM10; Alzheimer's disease (AD); RNA‐binding protein (RBP); CPNE7
• ISSN: 0022-3042; 1471-4159; 1471-4159
• DOI: 10.1111/jnc.70026

ABSTRACT The accumulation of amyloid plaques is a pathological hallmark of Alzheimer's disease (AD), in which ADAM10, the α‐secretase that catalyzes APP and facilitates the non‐amyloidogenesis pathway, plays an important role. We have previously reported that the expression of copine‐7 (Cpne7) in the hippocampus of APP/PS1 mice is significantly upregulated by nicotine, whereas the potential role of CPNE7 in AD remains largely unknown. Here, we report that CPNE7 protein levels are significantly decreased in APP/PS1 mice and HEK293 cells stably expressing full‐length APP. CPNE7 is shown to reduce Aβ levels by favoring ADAM10 activity, and the elevated ADAM10 protein by CPNE7 involves a translational mechanism. Further transcriptome profiling reveals that CPNE7 differentially regulates genes associated with neuronal function. Among these, cyclase‐associated actin cytoskeleton regulatory protein 1 (CAP1) is identified as a target gene of CPNE7, which controls ADAM10 translation through binding to the 5′ untranslated region (5′UTR). Collectively, the CPNE7‐CAP1 axis could be critical in the amyloidogenic pathway by regulating ADAM10 translation, in which the RNA binding activity of CAP1 is highlighted. This study reveals a novel mechanism by which copine‐7 (CPNE7) regulates amyloid beta (Aβ) levels in amyloid pathology models. CPNE7 enhances the activity of the α‐secretase ADAM10, favoring the non‐amyloidogenic pathway. Mechanistically, CPNE7 promotes ADAM10 protein expression via a translational mechanism mediated by the RNA‐binding protein CAP1, which binds to the 5′ untranslated region (5′UTR) of ADAM10 mRNA. These findings highlight the CPNE7–CAP1 axis as a critical regulator of ADAM10 translation and a potential therapeutic target for Alzheimer's disease (AD).