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[P‐018]: The effects of gender on the relationship between body mass index and CSF AB42 and tau levels
Author(s) -
Carlsson Cynthia M.,
Gleason Carey E.,
Arnold Kimberly,
Ohrt Tracy,
Koscik Rebecca,
Slattery Angela,
Meade Sarah,
Sager Mark,
Asthana Sanjay
Publication year - 2005
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.2005.06.080
Subject(s) - body mass index , medicine , overweight , triglyceride , endocrinology , blood pressure , metabolic syndrome , cerebrospinal fluid , obesity , high density lipoprotein , cholesterol , lipoprotein , blood lipids
the M-CSF receptor (M-CSFR). We previously showed that increasing expression of the M-CSFR on cultured microglia dramatically upregulates microglia M-CSF and IL-1 expression. Objectives: To determine if knockdown of microglial interleukin-1 and M-CSF expression affects NMDA-induced neurotoxicity in a co-culture system. Methods: We used a co-culture model consisting of microglia overexpressing the M-CSFR and hippocampal organotypic cultures treated with the neurotoxin NMDA. To test the importance of microglial IL-1 and M-CSF on neuronal survival, we used an shRNA gene-targeted approach in which we selectively and without toxicity deleted microglial IL-1 or M-CSF expression prior to co-culture assembly. Transfections were performed with the hairpin RNA expression plasmid pGSU6-GFP-shRNA. To quantify neuronal injury, we used propidium iodide as well as FluoroJade staining. Results: We found that when microglia overexpressing the M-CSFR were cocultured with organotypic slices, there was complete protection of neurons from NMDA-induced injury. However, after knockdown of either microglial IL-1 or M-CSF, neuroprotection was abolished. Using TaqMan real-time RT-PCR, we confirmed that the shRNA constructs resulted in a 75% knockdown of cytokine expression. Both M-CSF and IL-1 were necessary for microglial proliferation, but only IL-1 removal also suppressed chemotactic migration of microglia toward the NMDA-injured organotypic culture. Conclusions: These results demonstrate that IL-1 and M-CSF are essential for M-CSFR-induced microglial neuroprotection in a microglial-organotypic hippocampal co-culture system. In AD, increased IL-1 and M-CSF expression by M-CSFR-activated microglia could actually serve to protect, rather than harm neurons. It may be that some inflammatory factors expressed early in AD could be beneficial, so that suppressing inflammation might accelerate rather than prevent disease progression. (Supported by an Alzheimer’s Association New Investigator Award to O.M. and NIH award MH57833).