title: The selective positive allosteric M1 muscarinic receptor modulator PQCA attenuates learning and memory deficits in the Tg2576 Alzheimer's disease mouse model.
abstract: We have recently shown that the M1 muscarinic receptor positive allosteric modulator, PQCA, improves cognitive performance in rodents and non-human primates administered the muscarinic receptor antagonist scopolamine. The purpose of the present experiments was to characterize the effects of PQCA in a model more relevant to the disease pathology of Alzheimer's disease. Tg2576 transgenic mice that have elevated Aβ were tested in the novel object recognition task to characterize recognition memory as a function of age and treatment with the PQCA. The effects of PQCA were compared to the acetylcholinesterase inhibitor donepezil, the standard of care for Alzheimer's disease. In addition, the effect of co-administering PQCA and donepezil was evaluated. Aged Tg2576 mice demonstrated a deficit in recognition memory that was significantly attenuated by PQCA. The positive control donepezil also reversed the deficit. Furthermore, doses of PQCA and donepezil that were inactive on their own were found to improve recognition memory when given together. These studies suggest that M1 muscarinic receptor positive allosteric modulation can ameliorate memory deficits in disease relevant models of Alzheimer's disease. These data, combined with our previous findings demonstrating PQCA improves scopolamine-induced cognitive deficits in both rodents and non-human primates, suggest that M1 positive allosteric modulators have therapeutic potential for the treatment of Alzheimer's disease.
authors: Merck Research Laboratories, West Point, PA, USA. Electronic address: vanita_puri@merck.com.
authors: Vanita
authors: V
authors: Puri
authors: Merck Research Laboratories, West Point, PA, USA.
authors: Xiaohai
authors: X
authors: Wang
authors: Merck Research Laboratories, West Point, PA, USA.
authors: Joshua D
authors: JD
authors: Vardigan
authors: Merck Research Laboratories, West Point, PA, USA.
authors: Scott D
authors: SD
authors: Kuduk
authors: Merck Research Laboratories, West Point, PA, USA.
authors: Jason M
authors: JM
authors: Uslaner
mesh_terms: D000375:Aging / Q000187:drug effects / Q000523:psychology; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D018678:Cholinergic Agents / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D007189:Indans / Q000494:pharmacology; D008569:Memory Disorders / Q000188:drug therapy* / Q000503:physiopathology; D008822:Mice, Transgenic; D018697:Nootropic Agents / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011807:Quinolizines / Q000494:pharmacology*; D043643:Receptor, Muscarinic M1 / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology
chemical_list: C581536:1-((4-cyano-4-(pyridine-2-yl)piperidin-1-yl)methyl)-4-oxo-4H-quinolizine-3-carboxylic acid; D018678:Cholinergic Agents; D002800:Cholinesterase Inhibitors; D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D011807:Quinolizines; D043643:Receptor, Muscarinic M1; D000077265:Donepezil
keywords: Alzheimer's disease; Cognition; Muscarinic; Novel Object Recognition; Tg2576; Working memory