A positive allosteric modulator of M1 Acetylcholine receptors improves cognitive deficits in male and female APPswe/PSEN1ΔE9 mice via divergent mechanisms

Abstract

<b>Abstract ID 13830</b> <b>Poster Board 479</b> Alzheimer9s disease (AD) is an age-related neurodegenerative disorder characterized by progressive cognitive decline with no effective treatments to slow its progression. Beta-amyloid (Aβ) protein is considered the principal neurotoxic species in AD brains that accumulates as the disease progresses. The M1 muscarinic acetylcholine receptor (mAChR) plays a key role in learning and memory and has been identified as a promising therapeutic target for AD-associated cognitive decline. Indeed, M1 mAChR agonists showed pro-cognitive activity in clinical trials but was associated with many cholinergic adverse effects that hinder their clinical utility. A newly developed M1 mAChR positive allosteric modulator (PAM), VU0486846, is devoid of direct agonist activity and adverse effects but was not tested for efficacy in AD mice. Here, we tested the efficacy of VU0486846 in AD mice by treating 9-month-old male and female APPswe/PSEN1ΔE9 (APPswe) and wild-types with VU0486846 in drinking water (10mg/kg/day) for eight weeks. Cognitive function of all mice was assessed after treatment and brains were harvested for biochemical and immunohistochemical assessment. Eight-week treatment with VU0486846 improved cognitive function of male and female APPswe mice when tested in novel object recognition and Morris water maze. VU0486846 also improved the anxiety-like behavior of male and female APPswe mice in the open field arena. Interestingly, the improvement in cognitive function and anxiety-like behavior in APPswe mice was associated with a reduction in hippocampal soluble Aβ oligomer levels in female but not male mice. Our findings also show that VU0486846 can shift the proteolytic processing of amyloid precursor protein from amylogenic to non-amyloidogenic cleavage to reduce Aβ production in female but not male APPswe hippocampus. Thus, targeting M1 AChR using novel PAMs can improve cognitive deficits with minimal adverse effects in male and female AD patients via sex-specific mechanism(s).