Searching for just a few words should be enough to get started. If you need to make more complex queries, use the tips below to guide you.
Article type: Research Article
Authors: Davies, Sean S.a; b; * | Bodine, Chrisa | Matafonova, Elenaa | Pantazides, Brooke G.a | Bernoud-Hubac, Nathaliec | Harrison, Fiona E.d | Olson, Sandra J.e | Montine, Thomas J.f | Amarnath, Venkataramane | Roberts II, L. Jacksona; b
Affiliations: [a] Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA | [b] Department of Pharmacology, Vanderbilt University, Nashville, TN, USA | [c] Department of Metabolic Regulation, Nutrition, and Diabetes, Universite de Lyon, Lyon, France | [d] Department of Diabetes, Endocrinology and Metabolism, Vanderbilt University, Nashville, TN, USA | [e] Department of Pathology, Vanderbilt University, Nashville, TN, USA | [f] Department of Pathology, University of Washington, Seattle, WA, USA
Correspondence: [*] Correspondence to: Sean S. Davies Ph.D., Division of Clinical Pharmacology, Department of Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt University, 506A RRB, 2222 Pierce Ave, Nashville, USA. TN 37232-6602, Tel.: +615-322-5049; E-mail: [email protected].
Abstract: Both inflammation and oxidative injury are features of Alzheimer's disease (AD), but the contribution of these intertwined phenomena to the loss of working memory in this disease is unclear. We tested the hypothesis that highly reactive γ-ketoaldehydes that are formed both by non-enzymatic free radical catalyzed lipid peroxidation and by cyclooxygenases may be causally linked to the development of memory impairment in AD. We found that levels of γ-ketoaldehyde protein adducts were increased in the hippocampus of brains obtained postmortem from patients with AD compared to age-matched controls, but that levels of γ-ketoaldehyde protein adducts in the cerebellum were not different in the two groups. Moreover, immunohistochemistry revealed that adducts localized to hippocampal pyramidal neurons. We tested the effect of an orally available γ-ketoaldehyde scavenger, salicylamine, on the development of spatial working memory deficits in hApoE4 targeted replacement mice, a mouse model of dementia. Long-term salicylamine supplementation did not significantly alter body weight or survival, but protected against the development of age-related deficits in spatial working memory in 12–14 month old ApoE4 mice. These findings suggest that γ-ketoaldehyde adduct formation is associated with damage to hippocampal neurons in patients with AD and can contribute to the pathogenesis of spatial working memory deficits in hApoE4 mice. These data provide a rational basis for future studies exploring whether γ-ketoaldehyde scavengers may mitigate the development of cognitive dysfunction in patients with AD.
Keywords: Aldehydes, Alzheimer's disease, inflammation, isolevuglandin, oxidative stress, salicylamine, working memory
DOI: 10.3233/JAD-2011-102118
Journal: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 49-59, 2011
IOS Press, Inc.
6751 Tepper Drive
Clifton, VA 20124
USA
Tel: +1 703 830 6300
Fax: +1 703 830 2300
[email protected]
For editorial issues, like the status of your submitted paper or proposals, write to [email protected]
IOS Press
Nieuwe Hemweg 6B
1013 BG Amsterdam
The Netherlands
Tel: +31 20 688 3355
Fax: +31 20 687 0091
[email protected]
For editorial issues, permissions, book requests, submissions and proceedings, contact the Amsterdam office [email protected]
Inspirees International (China Office)
Ciyunsi Beili 207(CapitaLand), Bld 1, 7-901
100025, Beijing
China
Free service line: 400 661 8717
Fax: +86 10 8446 7947
[email protected]
For editorial issues, like the status of your submitted paper or proposals, write to [email protected]
如果您在出版方面需要帮助或有任何建, 件至: [email protected]