Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Bera, Sujoy UNSPECIFIED UNSPECIFIED UNSPECIFIED Camblor-Perujo, Santiago UNSPECIFIED UNSPECIFIED UNSPECIFIED Calleja Barca, Elena UNSPECIFIED UNSPECIFIED UNSPECIFIED Negrete-Hurtado, Albert UNSPECIFIED UNSPECIFIED UNSPECIFIED Racho, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED De Bruyckere, Elodie UNSPECIFIED orcid.org/0000-0001-6056-376X UNSPECIFIED Wittich, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Ellrich, Nina UNSPECIFIED UNSPECIFIED UNSPECIFIED Martins, Soraia UNSPECIFIED orcid.org/0000-0002-7894-6539 UNSPECIFIED Adjaye, James UNSPECIFIED UNSPECIFIED UNSPECIFIED Kononenko, Natalia L. UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language AMYLOID PRECURSOR PROTEIN; IPS CELL-LINE; SPORADIC ALZHEIMERS-DISEASE; BETA-SECRETASE BACE1; PLAQUE-FORMATION; MOUSE MODEL; ENDOCYTOSIS; APP; DEPOSITION; EXPRESSION Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/33657