Bernardo Ashley M, Marcotte Michael, Wong Kayla, Sharmin Dishary, Pandey Kamal P, Cook James M, Sibille Etienne L, Prevot Thomas D
Campbell Family Mental Health Research Institute of CAMH, 250 college street, Toronto, ON M5T 1R8, Canada.
Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 N Cramer Street, WI 53211, USA.
Neurobiol Aging. 2025 Mar;147:49-59. doi: 10.1016/j.neurobiolaging.2024.12.001. Epub 2024 Dec 10.
Reduced somatostatin (SST) and SST-expressing GABAergic neurons are well-replicated findings in Alzheimer's disease (AD) and are associated with cognitive deficits. SST cells inhibit pyramidal cell dendrites through α5-GABA-A receptors (α5-GABAA-R). α5-GABAAR positive allosteric modulation (α5-PAM) has procognitive and neurotrophic effects in stress and aging models. We tested whether α5-PAM (GL-II-73) could prevent cognitive deficits and neuronal spine loss in early stages, and reverse them in late stages of β-amyloid deposition in the 5xFAD model (N = 48/study; 50 % female). Acute administration of GL-II-73 prevented spatial working memory deficits in 5xFAD mice at 2 months of age, while chronic administration reversed the deficits at 5 months of age. Chronic GL-II-73 treatment prevented 5xFAD-induced loss of spine density, spine count and dendritic length at both time points, despite β-amyloid accumulation. These results demonstrate procognitive and neurotrophic effects of GL-II-73 in early and late stages of Alzheimer-related β-amyloid deposition. This suggests α5-PAM as a novel β-amyloid-independent symptomatic therapeutic approach.
生长抑素（SST）减少以及表达SST的γ-氨基丁酸能神经元减少是阿尔茨海默病（AD）中反复出现的现象，且与认知缺陷有关。SST细胞通过α5-γ-氨基丁酸A受体（α5-GABAA-R）抑制锥体细胞树突。α5-GABAA-R正向变构调节（α5-PAM）在应激和衰老模型中具有促认知和神经营养作用。我们测试了α5-PAM（GL-II-73）是否能在早期预防5xFAD模型（每组N = 48只；50%为雌性）β-淀粉样蛋白沉积早期的认知缺陷和神经元棘突丢失，并在晚期逆转这些缺陷。急性给予GL-II-73可预防2月龄5xFAD小鼠的空间工作记忆缺陷，而慢性给予则可逆转5月龄小鼠的缺陷。尽管存在β-淀粉样蛋白积累，但慢性GL-II-73治疗在两个时间点均预防了5xFAD诱导的棘突密度、棘突数量和树突长度的丢失。这些结果证明了GL-II-73在阿尔茨海默病相关β-淀粉样蛋白沉积早期和晚期具有促认知和神经营养作用。这表明α5-PAM是一种新型的不依赖β-淀粉样蛋白的对症治疗方法。
