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P4‐059: Statistical Parametric Mapping Analysis of Magnetization Transfer Ratio in Alzheimer's Disease: Comparison With Volumetric Imaging
Author(s) -
Ridha Basil H.,
Ridgway Ged,
Symms Mark,
Barnes Josephine,
Fox Nick C.
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.08.119
Subject(s) - magnetization transfer , voxel , statistical parametric mapping , nuclear medicine , white matter , partial volume , magnetic resonance imaging , mathematics , medicine , radiology
experiments were performed in microglia made deficient in either PS1 or PS2 using short-hairpin RNA (shRNA) as well as in microglia isolated from PS2 knockout mice. Gamma-secretase activity was measured by a luciferase expression based amyloid precursor protein cleavage assay. Expression of PS protein in microglia of AD patient brain autopsy tissue was evaluated by immunohistochemistry. Results: DAPT augments the release of pro-inflammatory cytokines induced by LPS in microglia. To clarify if both PS participate in the gamma-secretase complex that modulates the microglia inflammatory response, we used shRNA to knockdown specific PS expression. PS1 knockdown leads to both elevated PS2 protein levels and increased gamma-secretase activity. PS2 deficiency in microglia leads to elevated PS1 protein but dramatically decreased gamma-secretase activity. Similar to the impact of DAPT, PS2 deficiency results in exaggerated pro-inflammatory cytokine release whereas PS1 deficiency does not. PS2 protein and gene expression is increased in microglia activated by interferon-gamma and PS2 expression is enhanced in microglia in AD brain. Conclusions: Gamma-secretase inhibition and PS2 deficiency cause exaggerated pro-inflammatory cytokine release in microglia. PS2 is the predominant gamma-secretase in microglia and is upregulated by pro-inflammatory stimuli. We hypothesize PS2 participates in the negative regulation of pro-inflammatory pathways in microglia and is induced in states of CNS inflammation to curb detrimental inflammatory behavior in the brain.