A positive allosteric modulator for the muscarinic receptor (M1 mAChR) improves pathology and cognitive deficits in female APPswe/PSEN1ΔE9 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.