Presenilin 1 (PS1) and Presenilin 2 (PS2), both intramembranous aspartyl proteases, function in the catalytic core of the gamma-secretase complex. Gamma-secretase can modulate cell differentiation, cell proliferation, tumor progression and inflammation. The process of inflammation in Alzheimer's Disease (AD) pathogenesis has been suggested by in vivo and in vitro studies. Neuropathological changes characteristic of inflammation such as accumulation of activated microglia are seen in AD. In vitro studies have demonstrated that Abeta activates microglia. Indeed, it has been suggested that neuronal injury in AD occurs not only due to accumulation of Abeta, but also due to the marked inflammatory response to the toxic peptide. It is possible that PS contribute to neuronal dysfunction through perturbed gamma-secretase function. However, mounting evidence reveals that PS also have gamma-secretase independent functions implying that PS dysfunction may cause cellular pathology that is not solely related to gamma-secretase activity.
Our laboratory has found that PS2 protein is more highly expressed in non-neuronal cells from patients with AD compared to age matched controls. Additionally, our preliminary data shows that PS2 protein expression is enhanced cultured microglia cells activated by an inflammatory stimulus. Conditional PS1/PS2 repression leads to upregulation of inflammatory genes, and the PS2 knockout mice develop pulmonary fibrosis, a condition presumed to be a result of chronic inflammation in humans. We propose that PS play a role in the CNS inflammatory response.
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