title: Intraneuronal Amyloid Beta Accumulation Disrupts Hippocampal CRTC1-Dependent Gene Expression and Cognitive Function in a Rat Model of Alzheimer Disease.
abstract: In Alzheimer disease (AD), the accumulation of amyloid beta (Aβ) begins decades before cognitive symptoms and progresses from intraneuronal material to extracellular plaques. To date, however, the precise mechanism by which the early buildup of Aβ peptides leads to cognitive dysfunction remains unknown. Here, we investigate the impact of the early Aβ accumulation on temporal and frontal lobe dysfunction. We compared the performance of McGill-R-Thy1-APP transgenic AD rats with wild-type littermate controls on a visual discrimination task using a touchscreen operant platform. Subsequently, we conducted studies to establish the biochemical and molecular basis for the behavioral alterations. It was found that the presence of intraneuronal Aβ caused a severe associative learning deficit in the AD rats. This coincided with reduced nuclear translocation and genomic occupancy of the CREB co-activator, CRTC1, and decreased production of synaptic plasticity-associated transcripts Arc, c-fos, Egr1, and Bdnf. Thus, blockade of CRTC1-dependent gene expression in the early, preplaque phase of AD-like pathology provides a molecular basis for the cognitive deficits that figure so prominently in early AD.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, QCCanadaH3G 1Y6.
authors.forename: Edward N
authors.initials: EN
authors.lastname: Wilson
authors.affiliation: Department of Psychology, McGill University, Montreal, QCCanadaH3A 1B1.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Abela
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, QCCanadaH3G 1Y6.
authors.forename: Sonia
authors.initials: S
authors.lastname: Do Carmo
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, QCCanadaH3G 1Y6.
authors.forename: Simon
authors.initials: S
authors.lastname: Allard
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, QCCanadaH3G 1Y6.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Marks
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, QCCanadaH3G 1Y6.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Welikovitch
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, QCCanadaH3G 1Y6.
authors.forename: Adriana
authors.initials: A
authors.lastname: Ducatenzeiler
authors.affiliation: Department of Psychology, McGill University, Montreal, QC Canada H3A 1B1.|Current address: National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Yogita
authors.initials: Y
authors.lastname: Chudasama
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, QC Canada H3G 1Y6.|Department of Anatomy and Cell Biology.|Department of Neurology and Neurosurgery, McGill University, Montreal, QC Canada.
authors.forename: A Claudio
authors.initials: AC
authors.lastname: Cuello
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D003071:Cognition / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D007395:Interneurons / Q000378:metabolism; D008297:Male; D009473:Neuronal Plasticity / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D055647:Rats, Transgenic; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C519510:Crtc1 protein, rat; D014157:Transcription Factors
keywords: Alzheimer disease; CRTC1; amyloid beta; learning and memory; touchscreen operant platform