Aldehyde Dehydrogenase 2 Knockout Mice as a Potential Model of Vascular Cognitive Impairment and Alzheimer's Disease
MetadataShow full item record
Oxidative stress causes tissue damage in several models of vascular cognitive impairment (VCI) and in age-related Alzheimer’s disease (AD). We have developed a novel oxidative stress-based mouse model of age-related cognitive impairment based on gene deletion of aldehyde dehydrogenase 2 (ALDH2). ALDH2 is important for the detoxification of endogenous aldehydes such as 4-hydroxynonenal (HNE), a lipid peroxidation product formed during oxidative stress that can form protein adducts, altering cell function. These mice exhibit age-related decreases in performance in recognition and spatial memory tasks beginning at 3 months of age and maximal at 6-7 months as well as changes in anxiety-like behavior. These changes are not a result of confounding changes in motor function or physical phenotype. Executive dysfunction, an early impairment seen in VCI, has also been exhibited in Aldh2-/- mice as demonstrated by a lack of reversal learning in the Morris Water Maze task and impairments in the attentional set shifting task. With respect to vascular pathologies, previous studies found that 9-12-month-old Aldh2-/- mice exhibit aortic endothelial dysfunction, and arterial hypercontractility, HNE adduct formation and age-related amyloid-β (Aβ) deposition in cerebral microvessels. Echocardiographic analysis and radiotelemetry indicated diastolic dysfunction, and elevated systolic, diastolic and mean arterial pressure at 12 months of age in male Aldh2-/- mice. Finally, we have shown that cognitive impairment can be mitigated using three novel therapeutic strategies: an HNE scavenger (AG-01), deuterated polyunsaturated fatty acids (PUFAs) to slow the lipid peroxidation chain reaction, and 4-methyl-5-(2-(nitrooxy) ethyl) thiazol-3-ium chloride (NMZ) to activate CREB signalling. A validated, oxidative stress-based animal model of cognitive impairment and age-related AD and VCI will allow greater insight into the pathogenesis and molecular/cellular mechanisms of these neurological conditions.
URI for this recordhttp://hdl.handle.net/1974/25659
Request an alternative formatIf you require this document in an alternate, accessible format, please contact the Queen's Adaptive Technology Centre
The following license files are associated with this item: