α _2A adrenergic receptor promotes amyloidogenesis through disrupting APP-SorLA interaction

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 2 AR antagonists would be an effective therapeutic strategy for AD.adrenergic receptor | amyloid | processing | SorLA | sorting E xcess amyloid β (Aβ) peptides in the brain are a neuropathological hallmark of Alzheimer's disease (AD) and are generally accepted as the key pathogenic factor of the disease (1). Aβ is generated by two sequential cleavages of amyloid precursor protein (APP) by β and γ secretase, whereas cleavage by α secretase within the Aβ domain precludes Aβ generation (2, 3). APP and the secretases undergo endocytic sorting into various organelles, such as the trans-Golgi network, the plasma membrane, and endosomes (2-6). The initial step of APP processing by α versus β secretase preferentially occurs in distinct compartments of the cell. Although α secretase-mediated cleavage of APP occurs on the plasma membrane, β secretase primarily interacts with and cleaves APP in endosomes (2-6). Therefore, endocytic sorting of APP into different membranous compartments, causing it to coreside or avoid a particular secretase, plays a decisive role in APP proteolytic processing. Consistent with this notion, abnormalities of the endocytic pathway have been found to precede Aβ deposition in late-onset AD (7).Retrograde sorting of APP from endosomes to trans-Golgi network mediated by the vacuolar protein sorting-10 (Vps10) family proteins and the retromer complex represents a critical mechanism to prevent amyloidogenic processing of APP (8-10) and has recently emerged as a potential targe...

Disease-modifying effect of atipamezole in a model of post-traumatic epilepsy

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Causes, consequences, and cures for neuroinflammation mediated via the locus coeruleus: noradrenergic signaling system

“…Beneficial actions of an a2-antagonist have been described in the transgenic amyloid precursor protein (APP)/PS1 mouse model of AD (Chen et al 2014). In those studies, treatment with the a2-antagonist idazoxan for 10 weeks reduced Ab burden in the hippocampus and cortex, and improved short-term memory in a novel object recognition test and spatial memory in the Morris water maze test.…”

The amyloid precursor protein modulates α 2A ‐adrenergic receptor endocytosis and signaling through disrupting arrestin 3 recruitment

“…We have demonstrated that stimulation of a 2A AR promotes amyloidogenic processing of APP through activation of G i/o proteins (23). The direct interaction between APP and a 2A AR would bring APP to the proximity of a 2A AR downstream signaling to modulate its processing route.…”

“…Using the BbsI restriction enzyme, the primers were introduced to the pSpCas9(BB)-2A-GFP plasmid. An N2a-HA-a 2A AR stable cell line (23) was transfected with the resulting plasmid using Lipofectamine 2000 and selected for GFP expression by fluorescence-activated cell sorting. Single clones were allowed to grow and screened for loss of expression of APP.…”