A positive allosteric modulator for the muscarinic receptor (M1 mAChR) improves pathology and cognitive deficits in female APPswe/PSEN1 Delta E9 mice

Background and Purpose: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, and women account for 60% of diagnosed cases. beta-Amyloid (A beta) oligomers are considered the principal neurotoxic species in AD brains. The M1 muscarinic ACh receptor (M1 mAChR) plays a key role in memory and learning. M1 mAChR agonists show pro-cognitive activity but cause many adverse off-target effects. A new orally bioavailable M1 mAChR positive allosteric modulator (PAM), VU0486846, is devoid of direct agonist activity or adverse effects but was not tested for disease-modifying efficacy in female AD mice. Experimental Approach: Nine-month-old female APPswe/PSEN1 Delta E9 (APPswe) and wildtype mice were treated with VU0486846 in drinking water (10 mg.kg(-1).day(-1)) for 4 or 8 weeks. Cognitive function of mice was assessed after treatment, and brains were harvested for biochemical and immunohistochemical assessment. Key Results: VU0486846 improved cognitive function of APPswe mice when tested in novel object recognition and Morris water maze. This was paralleled by a significant reduction in A beta oligomers and plaques and neuronal loss in the hippocampus. VU0486846 reduced A beta oligomer production in APPswe mice by increasing M1 mAChR expression and shifting the processing of amyloid precursor protein from amyloidogenic cleavage to non-amyloidogenic cleavage. Specifically, VU0486846 reduced the expression of beta-secretase 1 (BACE1), whereas it enhanced the expression of the alpha-secretase ADAM10 in APPswe hippocampus. Conclusion and Implications: Using M1 mAChR PAMs can be a viable disease-modifying approach that should be exploited clinically to slow AD in women.

Automated summary

This study suggests that using M1 mAChR positive allosteric modulator (PAM) VU0486846 can improve cognitive function and reduce Aβ oligomer production in female mice with Alzheimer's disease (AD). This treatment approach could be a viable disease-modifying strategy to slow down the progression of AD in women.