Procognitive and neurotrophic benefits of α5-GABA-A receptor positive allosteric modulation in a β-amyloid deposition mouse model of Alzheimer's disease pathology

  • Neurobiol Aging. 2025 Mar:147:49-59. doi: 10.1016/j.neurobiolaging.2024.12.001.
Ashley M Bernardo  1 ,  Michael Marcotte  1 ,  Kayla Wong  1 ,  Dishary Sharmin  2 ,  Kamal P Pandey  2 ,  James M Cook  2 ,  Etienne L Sibille  3 ,  Thomas D Prevot  4
Affiliations
  • 1. Campbell Family Mental Health Research Institute of CAMH, 250 college street, Toronto, ON M5T 1R8, Canada.
  • 2. Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 N Cramer Street, WI 53211, USA.
  • 3. Campbell Family Mental Health Research Institute of CAMH, 250 college street, Toronto, ON M5T 1R8, Canada; Department of Psychiatry, University of Toronto, 250 college street, Toronto, ON M5T 1R8, Canada; Department of Pharmacology and Toxicology, University of Toronto, Medical Sciences Building, 1 King's College Cir Room 4207, Toronto, ON M5S 1A8, Canada. Electronic address: [email protected].
  • 4. Campbell Family Mental Health Research Institute of CAMH, 250 college street, Toronto, ON M5T 1R8, Canada; Department of Psychiatry, University of Toronto, 250 college street, Toronto, ON M5T 1R8, Canada; Department of Pharmacology and Toxicology, University of Toronto, Medical Sciences Building, 1 King's College Cir Room 4207, Toronto, ON M5S 1A8, Canada. Electronic address: [email protected].
PMID: 39689527 DOI: 10.1016/j.neurobiolaging.2024.12.001
Abstract

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.

Keywords
Amyloid; Cognition; GABA; Neurotrophic effect; Positive allosteric modulator.
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