Abstract Details

Title Microglial RAGE Accelerates Mortality and Neuronal Dysfunction in a Murine Model of Familial Amyotrophic Lateral Sclerosis

Topic Anterior Horn

Presentation(s) P02 - (-)

Poster/Presentation
Number 173

Objective

Background BACKGROUND: RAGE (Receptor for AGE), a multi-ligand receptor of the immunoglobulin superfamily expressed in multiple cells including microglia/mononuclear phagocytes and neurons, is implicated in oxidant stress and inflammation. Our previous studies demonstrated that neuronal RAGE contributes to neuronal degeneration in Amyotrophic Lateral Sclerosis (ALS).

Design/Methods DESIGN/METHODS: we bred familial ALS (FALS) mice carrying the Superoxide Dismutase-1 mutation G93A with mice overexpressing full length human RAGE in microglia driven by the scavenger receptor type A promoter. Multiple aspects were studied and analysized at function, survival and molecular levels.

Results RESULTS: Double transgenic(tg) mice (FALS/SR RAGE)displayed reduced survival (127.29 days ± 3.51) vs single FALS mice(143 days ± 2.04); p < 0.001. A functional score was employed to test the extent of neurological impairment (normal: score 5). Double tg mice at age 4 months displayed reduced functional score 2.05±0.55 [n=8], compared to single FALS, 3.57±0.89 [n=16]; or SR RAGE mice, 5±0 [n=8] (p<0.01). Real time PCR was employed to assess mRNA transcripts for RAGE, its ligand amphoterin, and inflammatory mediators in spinal cord. Significantly increased mRNA transcripts for RAGE, amphoterin and inducible (i)NOS were observed between FALS and negative littermates at age 4 months; p<0.05. At age 3 months, double tg mice displayed significantly increased RAGE and iNOS transcripts compared to wild type (WT) mice(p<0.05), however, at this age, no significant increase in transcripts for these molecules were observed between single FALS vs WT mice. Compared to single FALS, double tg mice displayed even greater enhancement of mRNA transcripts for TNF-alpha, MCP-1 and IL-6 vs WT mice; p<0.05.

Conclusions CONCLUSIONS: We conclude that RAGE-dependent inflammatory mechanisms in microglia contribute to neuronal dysfunction at early stages of ALS.

Authors/Disclosures
Ling Ling Rong, MD (Corewell Health West, Michigan State University) PRESENTER	Dr. Rong has nothing to disclose.
	No disclosure on file
Clifton L. Gooch, MD, FAAN (University of South Florida)	Dr. Gooch has received publishing royalties from a publication relating to health care. Dr. Gooch has received publishing royalties from a publication relating to health care.
Sheryl Martin-Schild, MD, PhD, FAAN (Dr. Brain, Inc.)	No disclosure on file
	No disclosure on file

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