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P2‐174: MODELING CHRONIC INFLAMMATION MEDIATED BY MICROGLIAL TREM2 EXPRESSION
Author(s) -
Miller Cole J.,
Yan Leung Brian Pak,
Doty Kevin R.,
Town Terrence
Publication year - 2018
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.2018.06.861
Subject(s) - trem2 , microglia , innate immune system , neuroinflammation , inflammation , pathogenesis , immunology , neuroscience , immune system , receptor , medicine , biology
Background:Neuroinflammation is one of the hallmark features of Alzheimer’s Disease (AD) along with accumulation of toxic amyloid plaques consisting of Ab peptides and other proteins, such as apoE. Triggering Receptor Expressed on Myeloid 2 (TREM2) is strongly associated with late onset AD. Interestingly, apoE has been described as a ligand for TREM2. TREM2 is expressed on microglia which are key immune cell regulators of the inflammatory response. ADAM10 cleaves TREM2 to produce a soluble isoform (sTREM2). This sTREM2 isoform is elevated in the cerebrospinal fluid of AD patients. However, ADAM10 is low in AD brain. Therefore, a remaining question is whether a general increase in TREM2 gene expression under conditions of low ADAM10 levels can produce increased sTREM2 levels in microglia. The hypothesis of this study was that expression of TREM2 and its ligand, apoE, are upregulated in response to increased Ab, which in turn, facilitates an increase in both TREM2 and sTREM2 levels even without an increase in ADAM10. Specifically, the objective of this study was to determine whether levels of key AD-related proteins; ADAM10, apoE, TREM2 and sTREM2, change in human microglial HMC3 cells upon Ab treatment, compared to untreated HMC3 cells.Methods:HMC3 cells were treated with Ab oligomers (5mM) and changes in protein exrpession for ADAM10, apoE, TREM2 and sTREM2 were evaluated by western blotting. Differences in sTREM2 production was also evaluated using a Luminex based assay. Changes in TREM2 and the microglial marker IBA1 in Ab treated HMC3 cells, compared to untreated cells, were analyzed by immunofluorescence Results:Changes in levels of some of these key AD-related proteins; ADAM10, apoE, TREM2 and sTREM2, were observed upon Ab treatment, compared to untreated HMC3 microglial cells. Conclusions:These results suggest that microglia react to increasing levels of Ab toxicity in the AD microenvironment bymodulating the expression of key immune-related proteins. This study will address the impact of these genes in AD associated neuro-inflammation.