Alzheimer's disease (AD) is a heterogenous disorder that involves both genetic and non-genetic factors. Several biological risk factors among which include family history, age, head injury, apolipoprotein E (apoE)-epsilon 4/4 genotype, previous history of hypertension and certain vascular factors have been implicated. These may promote pathogenetic processes converging to common abnormalities. Metabolic or oxidative stress secondary to some of these primary factors such as cerebral hypoperfusion or head injury may induce amyloid beta (Abeta) accumulation and other pathological lesions in Alzheimer's disease. Investigation of the molecular and cellular sequelae of metabolic stress induced by ischemic or traumatic injury is one of multiple approaches to understand the pathogenesis of Alzheimer's disease and the associated progressive decline in neuronal populations in concert with aging. Previous studies from our laboratory demonstrated altered expression of the Alzheimer's disease associated amyloid precursor protein (APP) in the peri-infarcted regions of both rats and humans exposed to metabolic stress induced by cerebral ischemia. Here, we propose to examine brain tissue from non-human primates subjected to ischemic injury and evaluate changes in the cellular distribution and temporal expression of APPs and other amyloid associated factors of current interest (non-amyloid component protein, apoE and presenilins) during metabolic stress induced by the ischemic insult. In the first set of experiments, we will determine conditions for optimal expression of key Alzheimer protein following middle cerebral artery occlusion in rats. Using this model to induce metabolic stress, we will evaluate the cellular expression patterns of APP and Abeta in the damaged and non-damaged regions of the baboon (papio anubis) brain. Then we will assess 1) quantify changes in APP fragments and non-amyloid proteins, 2) assess their mRNAs, and 3) study metabolism of APP in cortical slices. Comparisons between the two species is important to determine why APP may be readily cleaved to Abeta to form amyloid deposits in primates but not in rodents. These studies will lead to the understanding of the regulators of APP metabolism during and after metabolic stress induced by brain injury in non-human primates. The proposed experiments will test the hypothesis that sustained metabolic stress induces APP which in turn increases APP cleavage and Abeta accumulation in non-human primate brain, previously shown to accumulate Abeta deposits. Our wide experience in cerebrovascular research in conjunction with ready accessibility to a primate research facility provides an ideal opportunity to accomplish multiple goals. These issues have not been specifically addressed previously and we expect they will have wide implications on mechanisms of neurodegeneration in Alzheimer's disease.
