Alzheimer’s disease BIN1 coding variants increase intracellular Aβ by interfering with BACE1 recycling

Abstract

Genetics identified BIN1 as the second most important risk locus associated with late-onset Alzheimer's disease after APOE4. Here we show the consequences of two coding variants in BIN1 (rs754834233 and rs138047593), both in terms of intracellular beta-amyloid accumulation (iAbeta) and early endosome enlargement, two interrelated early cytopathological Alzheimer's disease phenotypes, supporting their association with LOAD risk. We previously found that Bin1 deficiency potentiates beta-amyloid production by decreasing BACE1 recycling and enlarging early endosomes. Here, we demonstrate that the expression of the two LOAD mutant forms of Bin1 did not rescue the iAbeta accumulation and early endosome enlargement induced by Bin1 knockdown and recovered by wild-type Bin1. The LOAD coding variants reduced Bin1 interaction with BACE1 likely causing a dominant-negative effect since Bin1 mutants, but not wild-type Bin1, overexpression increased iAbeta42 due to defective BACE1 recycling and accumulation in early endosomes. Endocytic recycling of transferrin was similarly affected by Bin1 wild-type and mutants, indicating that Bin1 is a general regulator of endocytic recycling. These data show that the LOAD mutations in Bin1 lead to a loss of function, suggesting that endocytic recycling defects are an early causal mechanism of Alzheimer's disease.

Endosomal trafficking and related genetic underpinnings as a hub in Alzheimer's disease

“…Moreover, it has been also shown that BIN1 depletion impacts BACE1 trafficking, causing its endosomal accumulation and, consequently, favoring Aβ production (Ubelmann et al, 2017). In line with this evidence, rare coding variants including rs754834233 or rs138047593 impact on AD risk reducing BACE1 recycling and causing early endosome enlargement recapitulating the same phenotype of Bin1 knockdown (Perdigão et al, 2021;. Beside this, BIN1 expression correlates also with tau pathology (Calafate et al, 2016), indeed it directly interacts with tau and such interaction is downregulated by tau phosphorylation on Thr231 (Sottejeau et al, 2015).…”