Bera, Sujoy, Camblor-Perujo, Santiago, Calleja Barca, Elena, Negrete-Hurtado, Albert, Racho, Julia, De Bruyckere, Elodie ORCID: 0000-0001-6056-376X, Wittich, Christoph, Ellrich, Nina, Martins, Soraia ORCID: 0000-0002-7894-6539, Adjaye, James and Kononenko, Natalia L. (2020). AP-2 reduces amyloidogenesis by promoting BACE1 trafficking and degradation in neurons. EMBO Rep., 21 (6). HOBOKEN: WILEY. ISSN 1469-3178

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Abstract

Cleavage of amyloid precursor protein (APP) by BACE-1 (beta-site APP cleaving enzyme 1) is the rate-limiting step in amyloid-beta (A beta) production and a neuropathological hallmark of Alzheimer's disease (AD). Despite decades of research, mechanisms of amyloidogenic APP processing remain highly controversial. Here, we show that in neurons, APP processing and A beta production are controlled by the protein complex-2 (AP-2), an endocytic adaptor known to be required for APP endocytosis. Now, we find that AP-2 prevents amyloidogenesis by additionally functioning downstream of BACE1 endocytosis, regulating BACE1 endosomal trafficking and its delivery to lysosomes. AP-2 is decreased in iPSC-derived neurons from patients with late-onset AD, while conditional AP-2 knockout (KO) mice exhibit increased A beta production, resulting from accumulation of BACE1 within late endosomes and autophagosomes. Deletion of BACE1 decreases amyloidogenesis and mitigates synapse loss in neurons lacking AP-2. Taken together, these data suggest a mechanism for BACE1 intracellular trafficking and degradation via an endocytosis-independent function of AP-2 and reveal a novel role for endocytic proteins in AD.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Bera, SujoyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Camblor-Perujo, SantiagoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Calleja Barca, ElenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Negrete-Hurtado, AlbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Racho, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Bruyckere, ElodieUNSPECIFIEDorcid.org/0000-0001-6056-376XUNSPECIFIED
Wittich, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ellrich, NinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martins, SoraiaUNSPECIFIEDorcid.org/0000-0002-7894-6539UNSPECIFIED
Adjaye, JamesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kononenko, Natalia L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-336576
DOI: 10.15252/embr.201947954
Journal or Publication Title: EMBO Rep.
Volume: 21
Number: 6
Date: 2020
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1469-3178
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
AMYLOID PRECURSOR PROTEIN; IPS CELL-LINE; SPORADIC ALZHEIMERS-DISEASE; BETA-SECRETASE BACE1; PLAQUE-FORMATION; MOUSE MODEL; ENDOCYTOSIS; APP; DEPOSITION; EXPRESSIONMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/33657

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