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[P4–440]: CHARACTERIZATION OF BIOFLUID STREM2 USING A NOVEL STREM2 ASSAY
Author(s) -
Wang Hong,
Proctor Nicholas,
Spencer Robert,
Hersley Caroline,
Tingley Francis David,
Raines Sarah E.,
Ryder John,
Kuhstoss Stuart Allen,
McConnell Audrey,
Hayashi Mansuo L.,
Wang Yaming
Publication year - 2017
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.2017.07.600
Subject(s) - trem2 , transmembrane protein , extracellular , chemistry , microglia , microbiology and biotechnology , biology , receptor , biochemistry , immunology , inflammation
Background:Apolipoprotein E (apoE) is a key lipid transport protein in brain and plasma. Humans have three apoE isoforms; namely, apoE2, apoE3 and apoE4. Of the three isoforms, apoE4 is strongly associated with late-onset and sporadic forms of Alzheimer’s disease (AD). In addition to its role in neuronal repair, synaptogenesis, and clearance of toxic Aß fragments from brain, apoE has been suggested to play a critical role in inflammation in the brain. Using pan LXR agonists as a tool compound for increasing brain and astrocytic apoE levels, we sought to investigate the effect of increasing astrocytic apoE on brain inflammation induced by lipopolysaccharide (LPS) both in vitro and in vivo. Methods:Using primary mouse microglia and astrocytes and C57/bl6 wild type mice as our model system, we evaluated the effect of increasing apoE protein levels using T0901317 (pan LXR agonist) on LPS induced inflammation. We used RT-qPCR to evaluate the mRNA levels of apoE and apoE lipidating genes and MSD assays to evaluate cytokine protein levels in cell media and brain homogenates. Results: TO901317 treatment led to an increase in brain apoE levels in vivo in wild type mice and in vitro, in both primary murine astrocytes and microglia. This increase in apoE was accompanied by an increase in apoE lipidating genes (Abca1 and Abcg1). Treatment with LPS led to a significant inflammatory response as seen by an increase in pro-inflammatory cytokines, TNFa and IL6. However, TO901317 treatment led to a significant reduction in the levels of the pro-inflammatory cytokines both in vitro (astrocytes and microglia) and in vivo in the brain. Conclusions:Our results indicate that increasing brain and gial apoE using a pan LXR agonist attenuates LPS induced inflammation. Our data suggests that apoE could play an important role in promoting antiinflammatory effects in the brain. Given the strong association of apoE with AD, increasing lipidated apoE in the brain could have multi-prong benefits including anti-inflammatory effects.