The mechanisms driving pathological beta‐amyloid (Aβ) 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 Aβ generation in neurons. We identify a novel neuron‐specific polarisation of Aβ generation controlled by Bin1 and CD2AP. We discover that Bin1 and CD2AP control Aβ generation in axonal and dendritic early endosomes, respectively. Both Bin1 loss of function and CD2AP loss of function raise Aβ 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 Aβ in neurons increasing the risk for late‐onset AD.
This study shows that Bin1 and CD2AP, genetic risk factors for Alzheimer's disease, control Aβ generation by keeping APP and BACE1 apart in early endosomes via distinct sorting mechanisms in axon and dendrites.
Loss of function of Bin1 and CD2AP increases endogenous Aβ generation.
Loss of function of Bin1 and CD2AP increases APP and BACE1 convergence in early endosomes via distinct sorting events.
Bin1 is required for BACE1 exit from early endosomes by cutting off BACE1 tubules in axons.
CD2AP is required for an efficient sorting of APP, away from processing at the early endosomal membrane, for degradation in dendrites.
- Received May 18, 2016.
- Revision received October 14, 2016.
- Accepted October 19, 2016.
- © 2016 The Authors