| First Author | Chen Y | Year | 2014 |
| Journal | Proc Natl Acad Sci U S A | Volume | 111 |
| Issue | 48 | Pages | 17296-301 |
| PubMed ID | 25404298 | Mgi Jnum | J:216651 |
| Mgi Id | MGI:5609181 | Doi | 10.1073/pnas.1409513111 |
| Citation | Chen Y, et al. (2014) alpha2A adrenergic receptor promotes amyloidogenesis through disrupting APP-SorLA interaction. Proc Natl Acad Sci U S A 111(48):17296-301 |
| abstractText | Accumulation of amyloid beta (Abeta) 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 Abeta generation. Here we report for the first time to our knowledge that this process is regulated by a G protein-coupled receptor, the alpha2A adrenergic receptor (alpha2AAR). Genetic deficiency of the alpha2AAR significantly reduces, whereas stimulation of this receptor enhances, Abeta generation and AD-related pathology. Activation of alpha2AAR 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 alpha2AAR reduces Golgi localization of APP and concurrently promotes APP distribution in endosomes and cleavage by beta secretase. The alpha2AAR is a key component of the brain noradrenergic system. Profound noradrenergic dysfunction occurs consistently in patients at the early stages of AD. alpha2AAR-promoted Abeta generation provides a novel mechanism underlying the connection between noradrenergic dysfunction and AD. Our study also suggests alpha2AAR as a previously unappreciated therapeutic target for AD. Significantly, pharmacological blockade of the alpha2AAR by a clinically used antagonist reduces AD-related pathology and ameliorates cognitive deficits in an AD transgenic model, suggesting that repurposing clinical alpha2AR antagonists would be an effective therapeutic strategy for AD. |
