Bin1 and CD2AP polarise the endocytic generation of beta-amyloid

The mechanisms driving pathological beta-amyloid (Ab) generation in late-onset Alzheimer's disease (AD) are unclear. Two late-onset AD risk factors, Bin1 and CD2AP, are regulators of endocytic trafficking, but it is unclear how their endocytic function regulates Ab generation in neurons. We identify a novel neuron-specific polarisation of Ab generation controlled by Bin1 and CD2AP. We discover that Bin1 and CD2AP control Ab generation in axonal and dendritic early endosomes, respectively. Both Bin1 loss of function and CD2AP loss of function raise Ab generation by increasing APP and BACE1 convergence in early endosomes, however via distinct sorting events. When Bin1 levels are reduced, BACE1 is trapped in tubules of early endosomes and fails to recycle in axons. When CD2AP levels are reduced, APP is trapped at the limiting membrane of early endosomes and fails to be sorted for degradation in dendrites. Hence, Bin1 and CD2AP keep APP and BACE1 apart in early endosomes by distinct mechanisms in axon and dendrites. Individuals carrying variants of either factor would slowly accumulate Ab in neurons increasing the risk for late-onset AD.