Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, 10962, USA.
Psychopharmacology (Berl). 2024 May;241(5):975-986. doi: 10.1007/s00213-024-06525-9. Epub 2024 Jan 10.
The β-secretase BACE1 initiates amyloid-β (Aβ) generation and represents a long-standing prime therapeutic target for the treatment of Alzheimer's disease (AD). However, BACE1 inhibitors tested to date in clinical trials have yielded no beneficial outcomes. In fact, prior BACE1 inhibitor trials targeted at ~ 50-90% Aβ reductions in symptomatic or prodromal AD stages have ended in the discontinuation due to futility and/or side effects, including cognitive worsening rather than expected improvement at the highest dose.
We tested whether a combination strategy with the selective BACE1 inhibitor GRL-8234 and the FDA-approved symptomatic drug memantine may provide synergistic cognitive benefits within their safe dose range.
The drug effects were evaluated in the advanced symptomatic stage of 5XFAD mice that developed extensive cerebral Aβ deposition.
Chronic combination treatment with 33.4-mg/kg GRL-8234 and 10-mg/kg memantine, but not either drug alone, rescued cognitive deficits in 5XFAD mice at 12 months of age (the endpoint after 60-day drug treatment), as assessed by the contextual fear conditioning, spontaneous alternation Y-maze and nest building tasks. Intact baseline performances of wild-type control mice on three cognitive paradigms demonstrated that combination treatment did not augment potential cognitive side effects of individual drugs. Biochemical and immunohistochemical examination showed that combination treatment did not synergistically reduce the β-amyloidogenic processing of amyloid precursor protein or Aβ levels in 5XFAD mouse brains.
A combination strategy with BACE1 inhibitors and memantine may be able to increase the effectiveness of individual drugs within their safe dose range in AD therapy.
β-分泌酶 BACE1 启动淀粉样蛋白-β（Aβ）的产生，是治疗阿尔茨海默病（AD）的长期主要治疗靶点。然而，迄今为止在临床试验中测试的 BACE1 抑制剂没有产生任何有益的结果。事实上，之前针对有症状或前驱 AD 阶段的 BACE1 抑制剂临床试验，由于无效和/或副作用（包括认知恶化而不是最高剂量下预期的改善）而停止，目标是 Aβ减少 50-90%。
我们测试了 BACE1 选择性抑制剂 GRL-8234 与 FDA 批准的对症药物美金刚联合使用的组合策略是否可以在其安全剂量范围内提供协同的认知益处。
在 5XFAD 小鼠的晚期有症状阶段评估药物作用，该模型小鼠出现广泛的大脑 Aβ 沉积。
用 33.4mg/kg 的 GRL-8234 和 10mg/kg 的美金刚进行慢性联合治疗，而不是单独使用任何一种药物，可挽救 5XFAD 小鼠的认知缺陷，这些小鼠在 12 个月大时（药物治疗 60 天后的终点），通过情景性恐惧条件反射、自发交替 Y 迷宫和筑巢任务进行评估。野生型对照小鼠在三种认知范式上的完整基线表现表明，联合治疗不会增强单独药物的潜在认知副作用。生化和免疫组织化学检查表明，联合治疗不会协同减少 5XFAD 小鼠大脑中淀粉样前体蛋白的 β-淀粉样蛋白生成加工或 Aβ 水平。
BACE1 抑制剂和美金刚的联合策略可能能够在 AD 治疗中增加个体药物在其安全剂量范围内的有效性。
