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

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

DC isoketal-modified proteins activate T cells and promote hypertension

“…Isoketals adduct to lysine residues on proteins and extensively crosslink proteins, leading to alteration of protein function. Increased formation of isoketal protein adducts has been found in several diseases associated with oxidative stress, including alcohol-induced liver damage, atherosclerosis, Alzheimer's disease, and asthma (14)(15)(16)(17). In the current studies, we show that hypertension causes isoketals to accumulate in DCs and that they promote DC cytokine production and immunogenicity.…”

“…Inclusion criteria were as follows: male or female, over 35 years of age, and diagnosis with true resistant hypertension according to American Heart Association Statement (40). We excluded patients with symptomatic ischemic defects in hApoE4 mice (16). Given the emerging recognition of the association between blood pressure and cognitive decline, it is possible that isoketal scavenging will be useful for the constellation of illnesses linked to hypertension.…”

Human apolipoprotein E4 targeted replacement in mice reveals increased susceptibility to sleep disruption and intermittent hypoxia

“…The present study provides evidence on the unique susceptibility of sleep integrity and homeostasis to disruption in hApoE4 mice. However, comparing mice with transgenic human ApoE4 with mice in which a human ApoE3 would be expressed would definitely provide a more suitable control, even if such comparisons have been already reported (9).…”

“…To further examine these issues, we hypothesized that both of these working hypotheses coexist, and therefore that the presence of components of a sleep disorder such as sleep apnea (i.e., IH, SF, or both) would lead to a more pronounced disruption of sleep integrity in a murine model of AD, and that the homeostatic sleep recovery processes to such perturbations would be reduced in the AD mice.Since hApoE4 mice start to develop aberrant pathophysiological responses at around 4 mo of age (9,67), and since C57BL/6 mice have been previously used as controls (9), we chose to study these strains at the age 6 mo.…”

Macrophages come to mind as keys to cognitive decline

“…The length of treatment and timing of therapy may be important considerations. Newer agents, such as NOX inhibitors or scavengers of oxidative products, might also be effective (19). The effect of drugs like these on the PVM is now an important focus of future research.…”