Treatment with a γ-ketoaldehyde scavenger prevents working memory deficits in hApoE4 mice.

Davies SS, Bodine C, Matafonova E, Pantazides BG, Bernoud-Hubac N, Harrison FE, Olson SJ, Montine TJ, Amarnath V, Roberts LJ
J Alzheimers Dis. 2011 27 (1): 49-59

PMID: 21709376 · PMCID: PMC3289064 · DOI:10.3233/JAD-2011-102118

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.

MeSH Terms (24)

Aged Aged, 80 and over Age Factors Aldehydes Alzheimer Disease Analysis of Variance Animals Apolipoprotein E4 Body Weight Cerebellum Disease Models, Animal Female Hippocampus Humans Male Maze Learning Memory, Short-Term Memory Disorders Mice Mice, Inbred C57BL Mice, Transgenic Motor Activity Psychomotor Performance Single-Chain Antibodies

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