AP-2 reduces amyloidogenesis by promoting BACE1 trafficking and degradation in neurons.
EMBO Rep
; 21(6): e47954, 2020 06 04.
Article
em En
| MEDLINE
| ID: mdl-32323475
ABSTRACT
Cleavage of amyloid precursor protein (APP) by BACE-1 (ß-site APP cleaving enzyme 1) is the rate-limiting step in amyloid-ß (Aß) 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 Aß 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 Aß 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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Secretases da Proteína Precursora do Amiloide
/
Doença de Alzheimer
Limite:
Animals
/
Humans
Idioma:
En
Revista:
EMBO Rep
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Alemanha