application) Neuropathological examinations of older control subjects and cases of Alzheimer's disease (AD) from the cohorts of the Baltimore Longitudinal Study of Aging (BLSA) and Alzheimer?s Disease Research Center (ADRC) cohorts has revealed that the lesions of AD precede the onset of dementia by many years, and perhaps decades, and that the onset of cognitive decline is temporally related to the appearance of microglial activation in senile plaques. These preliminary observations, in concert with reports that anti-inflammatory drugs reduce the risk and rate of progression of AD, suggest that inflammation plays a significant role in the pathogenesis of AD. Moreover, neuropathological studies have shown activation of inflammatory cells, complement, and cytokines in senile plaques in AD. However, previous studies have only examined brains in advanced stages of AD. In Project 4, they propose to examine the early development of AD lesions in the brain, focusing on the activation of astrocytes and microglia, perhaps in response to AB deposition, and the production of complement factors and cytokines capable of amplifying an inflammatory reaction and damaging neurons and synapses.
In Specific Aim 1, they will examine the relationships between microglial activation and cortical volume, number of neurons in hippocampus and ERC, and changes in cognition.
Specific Aim 2 focuses on the activation of astrocytes and their production of complement factors and cytokines (interleukin-6 [IL-6], granulocyte macrophage colony-stimulating factor [GM-CSF], and monocyte chemoattractant protein [MCP-1]) that may attract and activate microglia in senile plaques.
Specific Aim 3 examines the hypotheses that the expression of microglial cytokines (IL-1a, IL-1 B, TNF-a) correlates with neuronal and synaptic degeneration in AD as measured by terminal transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) of neurons and levels of synaptophysin.
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