Aims

The etiology of late-onset Alzheimer’s disease (LOAD) is multifactorial, with aging being the most significant risk factor and genetic predisposition accelerating the disease onset. While dominant mutations in the rare early-onset familial AD lead to excessive neuronal production of the longest form of beta-amyloid (Abeta42), in LOAD, it remains to be established if Ab42 production increases. Abeta is produced intracellularly upon APP processing in endosomes and controlled by the trafficking of APP and its secretases. We hypothesize that endosomal trafficking dysfunction is a causal mechanism of Abeta accumulation in LOAD.

We aim to dissect the mechanisms whereby LOAD risk factors and neuronal aging alter endocytic trafficking to potentiate Abeta42 production.

Methods

We analyzed wild-type primary mouse cortical neurons matured or aged in culture using a sensitive cell biological and neurobiological approach to determine APP and BACE1 trafficking alterations and their impact on the Abeta42 production.

Results

We have discovered that AD patients’ mutations in Bin1 and CD2AP (LOAD genetic risk factors) increase Abeta42 endocytic production, recapitulating the impact of Bin1 and CD2AP loss of function on BACE1 recycling and APP sorting to lysosomal degradation, indicating that the mutations may be pathological. Importantly, we discovered that neuronal aging alone potentiates clathrin and actin-mediated APP endocytosis, increasing intracellular Abeta42.

Conclusions

Our results highlight the importance of endocytic trafficking defects, driven by LOAD genetic risk factors and aging, as a central LOAD mechanism.