Abstract
BackgroundThe 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.ResultsChanges 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.ConclusionsWe 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 materialThe online version of this article (doi:10.1186/s13041-015-0117-y) contains supplementary material, which is available to authorized users.
Highlights
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
Behavioural analyses Using the open field novel object recognition (NOR) test and spontaneous alternations in the Y-maze, Aldh2-/mice showed a progressive decrease in performance in both memory tasks compared to no change in performance in their wildtype littermates (Figures 1 and 2)
In the Morris Water Maze (MWM) task, there was a significant difference in escape latency for Aldh2-/- mice compared to wildtype mice in all trial blocks in which the platform was hidden (Figure 4A, trial blocks 4-8)
Summary
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. 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. 4-hydroxynonenal (HNE) is an important lipid peroxidation product formed during periods of oxidative stress Both free HNE and HNE protein adducts accumulate in the brains of AD patients [9,10,11,12,13,14,15,16] and in certain transgenic mouse models of AD [5,17]. HNE alters the function and disposition of Aβ, through changes in Aβ formation, aggregation, catabolism and clearance [19,20,21,22,23,24,25,26,27]
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