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EMBO Rep. 2017 Jan;18(1):102-122. doi: 10.15252/embr.201642738. Epub 2016 Nov 28.

Bin1 and CD2AP polarise the endocytic generation of beta-amyloid.

Author information

1
Neuronal Trafficking in Aging Lab, CEDOC, Chronic Diseases Research Centre, NOVA Medical School/Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal.
2
Advance Imaging Lab, Instituto Gulbenkian de Ciência, Oeiras, Portugal.
3
Neuronal Trafficking in Aging Lab, CEDOC, Chronic Diseases Research Centre, NOVA Medical School/Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal claudia.almeida@nms.unl.pt.

Abstract

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.

KEYWORDS:

Alzheimer; endosomes; genetic risk factors; neuron

PMID:
27895104
PMCID:
PMC5210085
DOI:
10.15252/embr.201642738
[Indexed for MEDLINE]
Free PMC Article

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