Behavioral and neuropathological consequences of transient global ischemia in APP/PS1 Alzheimer model mice

Alzheimer's disease (AD) typically manifests in elderly people with several co-morbidities, especially cardiovascular, whereas transgenic mouse models of this disease usually employ middle-aged animals that have a good general health status. To assess the combined effect of compromised cerebral blood circulation and brain amyloid pathology we induced transient (17min) global ischemia (TGI) to young adult APPswe/PS1dE9 (APdE9) mice modeling AD amyloid pathology, and assessed the outcome on behavior two weeks and on histopathology five weeks after the ischemic insult. Ischemic injury resulted in reduced motor coordination and impaired spatial learning and memory. Neuropathological examination revealed circumscribed sites of neuronal loss in ischemic mice, including hippocampal CA2, lateral CA3 and medial CA1 pyramidal cell layer, and superficial layers of cortical patches. Notably, Fluoro-Jade staining revealed dying neurons as late as five weeks after the initial insult, and staining for active microglia and astrocytes confirmed the presence of inflammatory reaction. The extent of neuronal loss in CA2 and CA1 correlated significantly with impairment in spatial memory. There was no genotype difference in either behavioral or neuropathological consequences of TGI. However, the post-operative survival of transgenic animals was greatly reduced compared to wild type animals. APdE9 mice at a pre-plaque age appear to be more sensitive than wild-type mice to TGI in terms of post-operative recovery but the surviving APdE9 mice do not display more severe neurological deficits than wild-type mice.