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The role of inflammation and amyloid beta in Alzheimer disease pathology Dickstein, Dara L.

Abstract

Alzheimer disease (AD) is the most common form of dementia. Due to longer life-spans the number of affected individuals is expected to triple over the next few decades. As a consequence, a great deal of research is focused on determining the many processes by which the disease manifests as well as in discovering biomarkers and therapeutics to aid in diagnosis and disease prevention. The neuropathological hallmarks of AD include extracellular deposits of amyloid into senile plaques, accumulation of abnormal Tau filaments into neurofibrillary tangles, extensive neurodegeneration and inflammation. Although significant advances have been made in AD neurodegeneration, there still remain many unanswered and unforeseen aspects to the disease. It has been established that microglia, the immune cells of the brain, become activated in response to amyloid; however, the precise intracellular responses of microglia to amyloid and the relationship between microglia and amyloid deposition or clearance is unresolved. There have been many genes identified whose expression is upregulated in activated microglia and many of them have been proposed to be used as markers for inflammation. It has been demonstrated in humans that serum levels of melanotransferrin (p97), an iron binding molecule, is elevated in individuals affected with AD and that it is the activated, plaque-associated microglia that are responsible for this upregulation. This thesis further investigated the association between microglial activation and p97 gene expression and found that the levels of p97, both mRNA and protein, are increased in activated microglia in culture. The change in gene expression occurred largely in response to amyloid treatment possibly by the regulation of the AP-1 transcription factor downstream of the p38 mitogen-activated protein kinase pathway.

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