Session Title: Inflammation
PRESENILIN 2 MODULATES MICROGLIA ACTIVATION
S. Jayadev, A. Case, L. Seaburg, H. Nguyen, G. Garden
Neuroinflammation contributes to neurodegeneration in Alzheimer´s disease (AD) and HIV associated dementia (HAD). Mutations in Presenilin (PS) cause familial AD, though the mechanism of mutation is not fully understood. PS1 and PS2 form the catalytic core of the γ-secretase complex which cleaves substrates, including APP, Notch and ErbB4, that may regulate inflammation, development, and cell fate determination. PS also contribute to cellular processes through non-γ-secretase functions. We tested the hypothesis that PS2 participates in CNS neuroinflammation. In both HAD and AD frontal cortex autopsy tissue we observed enhanced microglia PS2 immunoreactivity compared to age matched controls. Cultured murine microglia demonstrate increased PS2 protein after activation via Interferon-γ (IFNγ) or the HIV coat protein, gp120. Microglia stably expressing shRNA targeted against PS2 have decreased γ-secretase activity compared to controls confirming the functional consequence of PS2 knockdown. We found that PS2 deficiency results in altered microglia activation. PS2 knockdown microglia release more TNFα in response to IFNγ and gp/120 as well as phagocytose fewer apoptotic bodies compared to controls expressing non-target shRNA. To address whether PS2 mediated modulation of microglia activity involves γ-secretase function, primary microglia were exposed to DAPT, a pharmacological γ-secretase inhibitor. DAPT treatment results in augmented release of TNFα in response to inflammatory stimuli and decreased ingestion of apoptotic bodies compared to control. Taken together these data suggest that PS2 and the γ-secretase complex participate in modulation of microglia activation. Further studies into PS and γ-secretase mediated innate immunity pathways may provide therapeutically relevant insights into neurodegeneration pathophysiology.