BIN1 LOAD mutants increase intracellular Aβ by interfering with BACE1 recycling

• Published in: Alzheimer's & dementia Vol. 17; no. S3; pp. e054178 - n/a
• Main Authors: Barata, Mariana Afonso, Perdigão, Catarina, Almeida, Claudia G.
• Format: Journal Article
• Language: English
• Published: United States 01.12.2021
• DOI: 10.1002/alz.054178
• ISSN: 1552-5260

Background Amyloid β (Aβ) accumulation and endosome dysfunction play an early role in Alzheimer’s disease (AD), an untreatable synaptic disorder. APP cleavage by BACE1 generates Aβ and is regulated by the endocytic trafficking of BACE1 and APP (Vassar et al., 1999). AD commonly has a late‐onset (LOAD) linked to genetic‐susceptibility. Bin1 is the most frequent of the one third of LOAD risk genes that regulate endocytic trafficking. We previously, shown that Bin1 knockdown increases Aβ generation by inducing BACE1 accumulation at endosomes via reducing BACE1 recycling. We are now investigating whether LOAD Bin1 mutations interfere with Aβ generation and endosome morphology and function. Method We used an overexpression and rescue approach of mutagenized wild‐type (WT) Bin1 with Bin1 LOAD mutations in a mouse neuroblastoma cell line. We performed immunofluorescence and biochemistry techniques, to assay endogenous intracellular Aβ42 accumulation, BACE1 endocytic trafficking, and early endosome size. Result We discovered that LOAD mutations in BIN1 likely cause its loss of function in Aβ production since they did not rescue augmented Aβ42 levels induced by BIN1 loss. Moreover, the KR mutant did not rescue early endosomes enlargement. Bin1 mutant’s overexpression recapitulated Aβ intracellular accumulation and endosomes defects. Bin1 mutants affected BACE1 trafficking. Conclusion The LOAD mutations in Bin1 interfere with its role as BACE1 trafficking regulator. Thus, leading to Aβ42 intracellular accumulation as well as endosome enlargement. We corroborate that endocytic recycling defects are an early mechanism of AD.