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Characterization of Aldh2(-/-) mice as an age-related model of cognitive impairment and Alzheimer’s disease

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...

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Autores principales: D’Souza, Yohan, Elharram, Ahmed, Soon-Shiong, Raquel, Andrew, R David, Bennett, Brian M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409701/
https://www.ncbi.nlm.nih.gov/pubmed/25910195
http://dx.doi.org/10.1186/s13041-015-0117-y
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author D’Souza, Yohan
Elharram, Ahmed
Soon-Shiong, Raquel
Andrew, R David
Bennett, Brian M
author_facet D’Souza, Yohan
Elharram, Ahmed
Soon-Shiong, Raquel
Andrew, R David
Bennett, Brian M
author_sort D’Souza, Yohan
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13041-015-0117-y) contains supplementary material, which is available to authorized users.
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spelling pubmed-44097012015-04-26 Characterization of Aldh2(-/-) mice as an age-related model of cognitive impairment and Alzheimer’s disease D’Souza, Yohan Elharram, Ahmed Soon-Shiong, Raquel Andrew, R David Bennett, Brian M Mol Brain Research 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13041-015-0117-y) contains supplementary material, which is available to authorized users. BioMed Central 2015-04-25 /pmc/articles/PMC4409701/ /pubmed/25910195 http://dx.doi.org/10.1186/s13041-015-0117-y Text en © D'Souza et al.; licensee BioMed Central. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
D’Souza, Yohan
Elharram, Ahmed
Soon-Shiong, Raquel
Andrew, R David
Bennett, Brian M
Characterization of Aldh2(-/-) mice as an age-related model of cognitive impairment and Alzheimer’s disease
title Characterization of Aldh2(-/-) mice as an age-related model of cognitive impairment and Alzheimer’s disease
title_full Characterization of Aldh2(-/-) mice as an age-related model of cognitive impairment and Alzheimer’s disease
title_fullStr Characterization of Aldh2(-/-) mice as an age-related model of cognitive impairment and Alzheimer’s disease
title_full_unstemmed Characterization of Aldh2(-/-) mice as an age-related model of cognitive impairment and Alzheimer’s disease
title_short Characterization of Aldh2(-/-) mice as an age-related model of cognitive impairment and Alzheimer’s disease
title_sort characterization of aldh2(-/-) mice as an age-related model of cognitive impairment and alzheimer’s disease
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409701/
https://www.ncbi.nlm.nih.gov/pubmed/25910195
http://dx.doi.org/10.1186/s13041-015-0117-y
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