NEURONAL OXIDATIVE STRESS AND DENDRITIC TRIMMING IN A MOUSE MODEL OF LATE ONSET ALZHEIMER`S DISEASE
The study of late-onset (sporadic) Alzheimer`s Disease (LOAD) has lacked animal models where the impairments develop with aging. Oxidative stress promotes LOAD, so we have developed an oxidative stress-based model of age-related cognitive impairment based on gene deletion of aldehyde dehydrogenase 2 (Aldh2). This enzyme is important for the detoxification of endogenous aldehydes, such as 4-hydroxynonenal, arising from lipid peroxidation. Previous work showed that the knockout (KO) mice exhibit a progressive decline in spatial and recognition memory compared to wildtype (WT) mice. Therefore, we searched for an underlying morphological substrate. First, morphometric analyses of pyramidal neurons using Golgi-Cox staining were performed in dorsal and ventral hippocampal CA1 (dCA1 and vCA1) as well as in overlying the primary sensory cortex in 12 month-old KO vs WT mice (Chapter 2). In 12-month old mice, the morphological results of dCA1 neurons revealed significant dendritic reductions in length, intersections, ends, and nodes in KO vs WT. Spine density along the apical dendrites is significantly reduced. In contrast the arborization in vCA1 and primary sensory cortex of KO mice showed comparatively minor reductions in branching and spine density. This specific lesion to the dorsal hippocampus helps explain spatial memory deficits in KO mice, whereas ventral hippocampal lesions cause impairments in stress and emotion. Our second study (Chapter 3) focused on the dCA1 to determine the time course of dendritic trimming over the 12 months and if it was associated with oxidative stress. No reduction in dendritic branching was detected at 3 months in KO vs WT, but by 6 months, dCA1 pyramidal arbors were dramatically cut back and remained so through 9 and 12 months. Immunostaining pyramidal cell bodies for HNE protein adducts (a marker for damage due to oxidative stress) showed small increases within dCA1 at 3 months, progressively increasing through 12 months. As with dendritic cutback, this increase was specific to dCA1, not vCA1 and only in KO mice. These findings are all in keeping with oxidative stress-associated dendritic cutback specific to our KO mice contributing to dorsal (but not ventral) hippocampal dysfunction, promoting cognitive impairment.