title: Characterization of Aldh2 (-/-) mice as an age-related model of cognitive impairment and Alzheimer's disease.
abstract: BACKGROUND
  The study of late-onset/age-related Alzheimer's disease (AD)(sporadic AD, 95% of AD cases) has been hampered by a paucity of animal models. Oxidative stress is considered a causative factor in late onset/age-related AD, and aldehyde dehydrogenase 2 (ALDH2) is important for the catabolism of toxic aldehydes associated with oxidative stress. One such toxic aldehyde, the lipid peroxidation product 4-hydroxynonenal (HNE), accumulates in AD brain and is associated with AD pathology. Given this linkage, we hypothesized that in mice lacking ALDH2, there would be increases in HNE and the appearance of AD-like pathological changes.
  
  
  RESULTS
  Changes in relevant AD markers in Aldh2 (-/-) mice and their wildtype littermates were assessed over a 1 year period. Marked increases in HNE adducts arise in hippocampi from Aldh2 (-/-) mice, as well as age-related increases in amyloid-beta, p-tau, and activated caspases. Also observed were age-related decreases in pGSK3β, PSD95, synaptophysin, CREB and pCREB. Age-related memory deficits in the novel object recognition and Y maze tasks begin at 3.5-4 months and are maximal at 6.5-7 months. There was decreased performance in the Morris Water Maze task in 6 month old Aldh2 (-/-) mice. These mice exhibited endothelial dysfunction, increased amyloid-beta in cerebral microvessels, decreases in carbachol-induced pCREB and pERK formation in hippocampal slices, and brain atrophy. These AD-associated pathological changes are rarely observed as a constellation in current AD animal models.
  
  
  CONCLUSIONS
  We believe that this new model of age-related cognitive impairment will provide new insight into the pathogenesis and molecular/cellular mechanisms driving neurodegenerative diseases of aging such as AD, and will prove useful for assessing the efficacy of therapeutic agents for improving memory and for slowing, preventing, or reversing AD progression.
authors.affiliation: Department of Biomedical & Molecular Sciences, and Centre for Neuroscience Studies, Faculty of Health Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada. 2ypd@queensu.ca.
authors.forename: Yohan
authors.initials: Y
authors.lastname: D'Souza
authors.affiliation: Department of Biomedical & Molecular Sciences, and Centre for Neuroscience Studies, Faculty of Health Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada. 7ame@queensu.ca.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Elharram
authors.affiliation: Department of Biomedical & Molecular Sciences, and Centre for Neuroscience Studies, Faculty of Health Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada. raquel.soonshiong@queensu.ca.
authors.forename: Raquel
authors.initials: R
authors.lastname: Soon-Shiong
authors.affiliation: Department of Biomedical & Molecular Sciences, and Centre for Neuroscience Studies, Faculty of Health Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada. andrewd@queensu.ca.
authors.forename: R David
authors.initials: RD
authors.lastname: Andrew
authors.affiliation: Department of Biomedical & Molecular Sciences, and Centre for Neuroscience Studies, Faculty of Health Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada. bennett@queensu.ca.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Bennett
mesh_terms: D000375:Aging / Q000473:pathology*; D000444:Aldehyde Dehydrogenase / Q000172:deficiency* / Q000378:metabolism; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000447:Aldehydes / Q000378:metabolism; D000544:Alzheimer Disease / Q000150:complications* / Q000201:enzymology* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D003072:Cognition Disorders / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015151:Immunoblotting; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D015260:Neprilysin / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D055503:Protein Multimerization; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
chemical_list: D000447:Aldehydes; D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D017362:Cyclic AMP Response Element-Binding Protein; D008562:Membrane Glycoproteins; C413604:nicastrin protein; D002217:Carbachol; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000071679:Glycogen Synthase Kinase 3 beta; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D053829:Amyloid Precursor Protein Secretases; D015260:Neprilysin; C027576:4-hydroxy-2-nonenal