title: Bin1 and CD2AP polarise the endocytic generation of beta-amyloid.
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.
authors.affiliation: Neuronal Trafficking in Aging Lab, CEDOC, Chronic Diseases Research Centre, NOVA Medical School/Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal.
authors.forename: Florent
authors.initials: F
authors.lastname: Ubelmann
authors.affiliation: Neuronal Trafficking in Aging Lab, CEDOC, Chronic Diseases Research Centre, NOVA Medical School/Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Burrinha
authors.affiliation: Neuronal Trafficking in Aging Lab, CEDOC, Chronic Diseases Research Centre, NOVA Medical School/Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal.
authors.forename: Laura
authors.initials: L
authors.lastname: Salavessa
authors.affiliation: Neuronal Trafficking in Aging Lab, CEDOC, Chronic Diseases Research Centre, NOVA Medical School/Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gomes
authors.affiliation: Neuronal Trafficking in Aging Lab, CEDOC, Chronic Diseases Research Centre, NOVA Medical School/Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal.
authors.forename: Cláudio
authors.initials: C
authors.lastname: Ferreira
authors.affiliation: Advance Imaging Lab, Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Nuno
authors.initials: N
authors.lastname: Moreno
authors.affiliation: 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.
authors.forename: Cláudia
authors.identifier: 0000-0001-9384-2896
authors.initials: C
authors.lastname: Guimas Almeida
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001369:Axons / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004705:Endocytosis; D011992:Endosomes; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D021381:Protein Transport; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C109221:Bin1 protein, mouse; C114545:CD2-associated protein; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D025521:Tumor Suppressor Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Alzheimer; endosomes; genetic risk factors; neuron