The recycling endosome biogenesis machinery coordinates BACE1 endosomal sorting and amyloid-Beta production

Abstract

Alzheimers disease (AD) is the most common form of dementia worldwide. One of ADs main pathological hallmarks is the cerebral plaque deposits of {beta}-amyloid (A{beta}). A{beta} is generated through sequential enzymatic cleavage of the amyloid precursor protein (APP). The {beta}-secretase or {beta}-site APP-cleaving enzyme 1 (BACE1) initiates this cleavage and is thus key to regulate A{beta} formation. Both APP and BACE1 transit through the endolysosomal system but the exact nature of the compartment(s) where APP cleavage occurs as well as the molecular mechanisms that govern their endosomal sorting remain poorly known. Here we show that RAB11 not only regulates BACE1 transport from early/sorting endosomes (EEs/SEs) and drives the exocytosis of BACE1-containing recycling carriers. Moreover, recycling endosome-associated KIF13A, as well as its closely related homolog KIF13B, which are known RAB11 effectors involved in the biogenesis of recycling endosome (RE) from EEs/SEs, also participate in BACE1 endosomal sorting. Importantly, depletion of KIF13A or KIF13B leads to an increase in A{beta} generation. Depletion of the BLOC-1 complex, previously described as an essential partner for KIF13A-dependent RE biogenesis, also induces increased amount of A{beta}. Altogether, our findings support a model where the EEs/SEs represent a major organelle for A{beta} formation and identify the recycling endosome biogenesis machinery as a master coordinator of BACE1 endosomal sorting and transport.