Characterization of Aldh2 -/- mice as an age-related model of cognitive impairment and Alzheimer’s disease

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.

Deuterium‐reinforced polyunsaturated fatty acids improve cognition in a mouse model of sporadic Alzheimer's disease

“…Thus, the D‐PUFA diet prevented the loss in spacial reference memory performance that would otherwise occur in the Aldh2 − / − mice. Furthermore, the differences in performance in all three memory tasks between mice fed the D‐PUFA and H‐PUFA diets for 18 weeks, were very similar to the differences between wild‐type and Aldh2 − / − mice of a comparable age , indicating that D‐PUFAs essentially reset the performance of Aldh2 − / − mice to that of wild‐type mice.…”

In vivoimaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome

“…Three‐month‐old HNE mice (17), 2‐mo‐old 5xFAD mice, and 4‐mo‐old AS mice [all on C57BL/6 (B6) backgrounds] were studied; additional age‐matched B6 mice were purchased as needed (The Jackson Laboratory, Bar Harbor, ME, USA). In all cases, a baseline T 1 data set was collected and mice were allowed to recover from the isoflurane anesthesia.…”

Mitophagy and Alzheimer’s Disease: Cellular and Molecular Mechanisms

“…These rats develop synaptic loss and mitochondrial abnormalities at 4 months of age, pTau at 3 months of age, but an increase in Aβ 1 - 42 levels only at 15–25 months of age [108]. Other important models that may be relevant to sporadic AD are the senescence-accelerated mouse prone 8 strain (SAMP8) [109] and aldehyde-dehydrogenase knockout mice [110]. Such animal models will be useful for research into age-related abnormalities of mitophagy that may predispose the brain to late-onset AD.…”