A positive allosteric modulator of M1 Acetylcholine receptors improves cognitive deficits in male and female Alzheimer’s mice

Abstract ID 94315 Poster Board 352 Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive decline, for which there are currently 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), crucial for learning and memory, has emerged as a promising target for addressing the cognitive decline associated with AD. Clinical trials have revealed the pro-cognitive effects of M1 mAChR agonists, although their potential use has been hindered by numerous cholinergic side effects. 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. In this study, we evaluated the efficacy of VU0486846 in AD mice by treating 9-month-old male and female APPswe/PSEN1ΔE9 (APP/PS1) mice and their wild-type counterparts with VU0486846 in drinking water for 8 weeks. An eight-week regimen of VU0486846 resulted in enhanced cognitive abilities in both male and female APP/PS1 mice, as demonstrated through improved performance in tasks such as novel object recognition and the Morris water maze. Additionally, VU0486846 was found to mitigate anxiety-like behavior in male and female APP/PS1 mice within the open field arena. Interestingly, the improvement in cognitive function and anxiety-like behavior in APP/PS1 mice was associated with a reduction in hippocampal soluble Aβ oligomer levels in female but not male mice. Furthermore, our findings suggest that the disease-modifying mechanism(s) of VU0486846 is likely different between the hippocampi of male and female APP/PS1 mice. Thus, our findings show that targeting the M1 AChR using novel PAMs can potentially improve cognitive function in both male and female Alzheimer9s disease (AD) patients through sex-specific signaling pathways.