University of Ottawa Brain and Mind Research Institute, Ottawa, Ontario, Canada.
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Br J Pharmacol. 2022 Apr;179(8):1769-1783. doi: 10.1111/bph.15750. Epub 2022 Feb 3.
Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, and women account for 60% of diagnosed cases. β-Amyloid (Aβ) 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.
Nine-month-old female APPswe/PSEN1ΔE9 (APPswe) and wildtype mice were treated with VU0486846 in drinking water (10 mg·kg ·day ) for 4 or 8 weeks. Cognitive function of mice was assessed after treatment, and brains were harvested for biochemical and immunohistochemical assessment.
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 Aβ oligomers and plaques and neuronal loss in the hippocampus. VU0486846 reduced Aβ 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 β-secretase 1 (BACE1), whereas it enhanced the expression of the α-secretase ADAM10 in APPswe hippocampus.
Using M1 mAChR PAMs can be a viable disease-modifying approach that should be exploited clinically to slow AD in women.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是认知能力进行性下降，女性占确诊病例的 60%。β-淀粉样蛋白（Aβ）寡聚体被认为是 AD 大脑中的主要神经毒性物质。M1 毒蕈碱乙酰胆碱受体（M1 mAChR）在记忆和学习中起着关键作用。M1 mAChR 激动剂具有促认知作用，但会引起许多不良的非靶点效应。一种新型口服生物利用度的 M1 mAChR 正变构调节剂（PAM），VU0486846，没有直接激动剂活性或不良反应，但在雌性 AD 小鼠中没有进行疾病修饰疗效的测试。
9 月龄雌性 APPswe/PSEN1ΔE9（APPswe）和野生型小鼠用 VU0486846 饮用水（10mg·kg·day）处理 4 或 8 周。治疗后评估小鼠的认知功能，并采集大脑进行生化和免疫组织化学评估。
VU0486846 改善了 APPswe 小鼠在新物体识别和 Morris 水迷宫中的认知功能。这与海马区 Aβ寡聚体和斑块以及神经元丢失的显著减少相平行。VU0486846 通过增加 M1 mAChR 表达并将淀粉样前体蛋白的加工从淀粉样蛋白切割转变为非淀粉样蛋白切割，从而减少 APPswe 小鼠中 Aβ寡聚体的产生。具体来说，VU0486846 降低了β-分泌酶 1（BACE1）的表达，同时增强了 APPswe 海马体中α-分泌酶 ADAM10 的表达。
使用 M1 mAChR PAMs 可能是一种可行的疾病修饰方法，应该在临床上加以利用，以减缓女性 AD 的进展。
