The α2 Adrenergic Receptor as a Novel Target for Alzheimer's Disease

Alzheimer's disease (AD) is the most common form of dementia, and is the only cause of death within the top 10 in America that cannot be prevented, cured, or slowed. Alterations of the noradrenergic (NA) system occur early in AD. However, the relevance of NA dysfuntion to AD pathogenesis and the therapeutic potential of NA components for AD are unknown. We have previously shown that activation of the α 2 adrenergic receptor (α 2 AR) increases amyloidogenic processing of amyloid precursor protein (APP), and therefore amyloid β (Aβ) load in the brain. In this study, we sought to investigate α 2 AR expression and activity with AD advancement, and test whether a blockade of the α 2 AR slows AD progression using an AD transgenic mouse model. We examined α 2 AR coupling to G‐protein by use of a [ 35 S]GTPγS radioligand binding assay in both 5 week and 7.5 month old APP/PS1 mice and their nontransgenic littermates. At the earlier time point, prior to AD pathology, no difference was found between APP/PS1 and nontransgenic mice. However, at 7.5 months, after AD pathology is profound, increased α 2 AR‐G protein coupling efficiency was observed in APP/PS1 mice, suggesting that α 2 AR function is enhanced as AD progresses. Furthermore, we treated 8 month‐old APP/PS1 mice with an α 2 AR antagonist, idazoxan, for 8 weeks and evaluated their neuropathology and cognitive behaviors. Compared to saline treatment, treatment with idazoxan reduced Aβ load in both the hippocampus and cortex, and, more importantly, improved cognitive performance of APP/PS1 mice on the Morris water maze. In conclusion, our studies suggest that α 2 AR activity is upregulated in APP/PS1 mice with pathological progression and that a clinical α 2A AR antagonist is effective in decreasing Aβ plaque load and improving cognition, even when started after the accumulation of Aβ plaques. Therefore, targeting the α 2 AR represents a promising therapeutic strategy for AD. Support or Funding Information This study is supported by NIH Grant AG042716 (to Q.W.).