Journal
ALZHEIMERS & DEMENTIA
Volume 14, Issue 6, Pages 811-823Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jalz.2017.11.009
Keywords
Alzheimer's disease; Amyloid; Cholinergic; Cognition; Disease modifier; M1 muscarinic receptor; Neuroinflammation; Sigma-1 receptor
Categories
Funding
- Canadian Institute of Health and Research [285643]
- Fonds de Recherche du Quebec-Sante postdoctoral fellowship
- Richard and Edith Strauss Postdoctoral Fellowship in Medicine
- Alzheimer's Society of Canada
- Fonds de Recherche du Quebec-Nature et technologies
- CONACyT, Mexico
- Charles E. Frosst/Merck-endowed Chair in Pharmacology
- Merck Canada
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Introduction: AF710B (aka ANAVEX 3-71) is a novel selective allosteric M1 muscarinic and sigma-1 receptor agonist. In 3XTg-AD mice, AF710B attenuates cognitive deficits and decreases Alzheimer-like hallmarks. We now report on the long-lasting disease-modifying properties of AF710B in McGill-R-Thy1-APP transgenic (Tg) rats. Methods: Chronic treatment with AF710B (10 mu g/kg) was initiated in postplaque 13-month-old Tg rats. Drug or vehicle was administered orally daily for 4.5 months and interrupted 5 weeks before behavioral testing. Results: AF710B long-term treatment reverted the cognitive deficits associated with advanced Alzheimer-like amyloid neuropathology in Tg rats. These effects were accompanied by reductions in amyloid pathology and markers of neuroinflammation and increases in amyloid cerebrospinal fluid clearance and levels of a synaptic marker. Importantly, these effects were maintained following a 5-week interruption of the treatment. Discussion: With M1/sigma-1 activity and long-lasting disease-modifying properties at low dose, AF710B is a promising novel therapeutic agent for treating Alzheimer's disease. (C) 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
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