AP-2 reduces amyloidogenesis by promoting BACE1 trafficking and degradation in neurons.

Sujoy Bera,James Adjaye,Natalia L Kononenko,Elena Calleja Barca,Elodie De Bruyckere,Albert Negrete‐Hurtado,Christoph Wittich,Santiago Camblor‐Perujo,Julia Racho,Soraia Martins,Nina Ellrich

doi:10.15252/embr.201947954

Sujoy Bera, James Adjaye + Show 9 more

Open Access

https://doi.org/10.15252/embr.201947954

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Abstract

Cleavage of amyloid precursor protein (APP) by BACE‐1 (β‐site APP cleaving enzyme 1) is the rate‐limiting step in amyloid‐β (Aβ) 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 Aβ 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 Aβ 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.

Highlights

Alzheimer’s disease (AD) is the most prominent neurodegenerative disorder and a leading cause of dementia in the aging population [1]
Taken into account the fact that are controlled by the protein complex-2 (AP-2) and b-site APP cleaving enzyme 1 (BACE1) are found in a complex in the mouse brain (Fig EV1A and B), we asked whether AP-2 regulates BACE1 endocytosis in neurons
We measured the kinetics of BACE1 endocytosis in primary neurons isolated from the cortex of AP-2 knockout (KO) mice, where the loss of the entire AP-2 heterotetramer without a compensatory increase in AP-1 and AP-3 protein levels is achieved by a tamoxifen-inducible CAG-Cre-dependent recombination of floxed AP-2l allele (Ap-2llox/lox: CAG-Cre) [32]

Summary

Introduction

Alzheimer’s disease (AD) is the most prominent neurodegenerative disorder and a leading cause of dementia in the aging population [1]. The absence of Ab plaques is reported in BACE1 null mice engineered to overexpress human APP (Tg2576+) [11], while double-transgenic mice obtained by crossing the mice that overexpress BACE1 and APP show enhanced Ab generation and exacerbated Ab pathology [12] These data, along with the fact that both the activity and the expression pattern of BACE1 are elevated in human sporadic AD patients [13,14], provide a conceptual basis for a BACE1-dependent mechanism of Ab accumulation and suggest BACE1 as a primary drug target for AD therapy [10]. BACE1 cleavage of several other substrates besides APP [15] is important for normal physiology [16,17], putting the safety of BACE1 inhibitors in question These data taken together with the recent finding that oral BACE1 inhibitor Verubecestat does not slow disease progression in AD patients as compared with placebo [18] raise the demand for novel therapeutic targets in AD. Despite two decades passing since the discovery of BACE1 [19,20], the precise regulation of BACE1 intracellular trafficking in neurons remains incompletely understood

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Conclusion