Alzheimer's disease BIN1 coding variants increase intracellular Aβ levels by interfering with BACE1 recycling.

ABSTRACT: Genetic studies have identified BIN1 as the second most important risk locus associated with late-onset Alzheimer's disease (LOAD). However, it is unclear how mutation of this locus mechanistically promotes Alzheimer's disease (AD) pathology. Here we show the consequences of two coding variants in BIN1 (rs754834233 and rs138047593), both in terms of intracellular beta-amyloid (iAbeta) accumulation and early endosome enlargement, two interrelated early cytopathological AD phenotypes, supporting their association with LOAD risk. We previously found that Bin1 deficiency potentiates iAbeta production by enabling BACE1 cleavage of the amyloid precursor protein in enlarged early endosomes due to decreased BACE1 recycling. Here, we discovered that the expression of the two LOAD mutant forms of Bi

SUBMITTER: Perdigao C 

PROVIDER: S-EPMC8413894 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature