Treatment with a γ-Ketoaldehyde Scavenger Prevents Working Memory Deficits in hApoE4 Mice

Article type: Research Article

Authors: Davies, Sean S.^{a; b; *} | Bodine, Chris^a | Matafonova, Elena^a | Pantazides, Brooke G.^a | Bernoud-Hubac, Nathalie^c | Harrison, Fiona E.^d | Olson, Sandra J.^e | Montine, Thomas J.^f | Amarnath, Venkataraman^e | Roberts II, L. Jackson^{a; 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