-amyloid (A), derived form the -amyloid precursor protein (APP), is important for the pathogenesis of Alzheimer's disease (AD), which is characterized by progressive decline of cognitive functions, formation of A plaques and neurofibrillary tangles, and loss of neurons. However, introducing a human wild-type or mutant APP gene to rodent models of AD does not result in clear neurodegeneration, suggesting that contributory factors lowering the threshold of neuronal death may be present in AD. Because brain ischemia has recently been recognized to contribute to the pathogenesis of AD, we studied the effect of focal brain ischemia in 8-and 20-month-old mice overexpressing the 751-amino acid isoform of human APP. We found that APP751 mice have higher activity of p38 mitogen-activated protein kinase (p38 MAPK) in microglia, the main immune effector cells within the brain, and increased vulnerability to brain ischemia when compared with age-matched wild-type mice. These characteristics are associated with enhanced microglial activation and inflammation but not with altered regulation of cerebral blood flow, as assessed by MRI and laser Doppler flowmetry. Suppression of inflammation with aspirin or inhibition of p38 MAPK with a selective inhibitor, SD-282, abolishes the increased neuronal vulnerability in APP751 transgenic mice. SD-282 also suppresses the expression of inducible nitric-oxide synthase and the binding activity of activator protein 1. These findings elucidate molecular mechanisms of neuronal injury in AD and suggest that antiinflammatory compounds preventing activation of p38 MAPK in microglia may reduce neuronal vulnerability in AD.T he -amyloid precursor protein (APP) is a ubiquitous transmembrane glycoprotein and the source of -amyloid peptides (A), which are the principal components of amyloid plaques in the brain of patients with Alzheimer's disease (AD), an age-related neurodegenerative disease associated with progressive decline of cognitive functions (1, 2). Other hallmarks of AD include the formation of neurofibrillary tangles in neurons, loss of synapses, and decreases in cell density in the distinct regions of the brain. These histopathological changes are observed in familial AD, which is caused by mutations in the APP or presenilin genes, in sporadic AD, and in individuals with Down's syndrome, who carry an extra copy of chromosome 21 and overexpress wild-type APP several fold in the brain (3-6).Substantial evidence indicates importance of APP for the pathogenesis of AD, but the mechanism how APP increases neuronal vulnerability in AD is unclear. A large number of epidemiological studies indicate that inflammatory events are involved because antiinflammatory drugs slow the progression of the disease, and reactive microglia and proinflammatory molecules that are secreted by microglia are present at sites of amyloid plaques (7-11). The inflammation hypothesis is further supported by the findings that secreted derivatives of APP (sAPP-␣) and A activate microglial cells resulting in death ...
Memory impairment progressing to dementia is the main clinical symptom of Alzheimer's disease (AD). AD is characterized histologically by the presence of -amyloid (A) plaques and neurofibrillary tangles in specific brain regions. Although A derived from the A precursor protein (-APP) is believed to play a central etiological role in AD, it is not clear whether soluble and͞or fibrillar forms are responsible for the memory deficit. We have generated and previously described mice expressing human wild-type -APP751 isoform in neurons. These transgenic mice recapitulate early histopathological features of AD and form A deposits but no plaques. Here we describe a specific and progressive learning and memory impairment in these animals. In the Morris water maze, a spatial memory task sensitive to hippocampal damage, one pedigree already showed significant differences in acquisition in 3-month-old mice that increased in severity with age and were expressed clearly in 6-month-and 2-year-old animals. The second transgenic pedigree displayed a milder impairment with a later age of onset. Performance deficits significantly decreased during the 6 days of training in young but not in aged transgenic animals. Both pedigrees of the transgenic mice differed from wild-type mice by less expressed increase of escape latencies after the platform position had been changed in the reversal experiment and by failure to prefer the goal quadrant in probe trials. Both pedigrees performed at wild-type level in a number of other tests (open field exploration and passive and active place avoidance). The results suggest that plaque formation is not a necessary condition for the neuronal -APP751 transgene-induced memory impairment, which may be caused by -APP overexpression, isoform misexpression, or elevated soluble A.
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