α(2A) adrenergic receptor promotes amyloidogenesis through disrupting APP-SorLA interaction

Yunjia Chen, Yin Peng, Pulin Che, Mary Gannon, Yin Liu, Ling Li, Guojun Bu, Thomas van Groen, Kai Jiao, Qin Wang

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Accumulation of amyloid β (Aβ) peptides in the brain is the key pathogenic factor driving Alzheimer's disease (AD). Endocytic sorting of amyloid precursor protein (APP) mediated by the vacuolar protein sorting (Vps10) family of receptors plays a decisive role in controlling the outcome of APP proteolytic processing and Aβ generation. Here we report for the first time to our knowledge that this process is regulated by a G protein-coupled receptor, the α(2A) adrenergic receptor (α(2A)AR). Genetic deficiency of the α(2A)AR significantly reduces, whereas stimulation of this receptor enhances, Aβ generation and AD-related pathology. Activation of α(2A)AR signaling disrupts APP interaction with a Vps10 family receptor, sorting-related receptor with A repeat (SorLA), in cells and in the mouse brain. As a consequence, activation of α(2A)AR reduces Golgi localization of APP and concurrently promotes APP distribution in endosomes and cleavage by β secretase. The α(2A)AR is a key component of the brain noradrenergic system. Profound noradrenergic dysfunction occurs consistently in patients at the early stages of AD. α(2A)AR-promoted Aβ generation provides a novel mechanism underlying the connection between noradrenergic dysfunction and AD. Our study also suggests α(2A)AR as a previously unappreciated therapeutic target for AD. Significantly, pharmacological blockade of the α(2A)AR by a clinically used antagonist reduces AD-related pathology and ameliorates cognitive deficits in an AD transgenic model, suggesting that repurposing clinical α(2A)R antagonists would be an effective therapeutic strategy for AD.

Original languageEnglish (US)
Pages (from-to)17296-17301
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number48
DOIs
StatePublished - Dec 2 2014

Keywords

  • adrenergic receptor
  • amyloid
  • processing
  • SorLA
  • sorting

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