Alzheimers Dement 2018 06 19;14(6):787-796. Epub 2018 Jan 19.
Douglas Mental Health University Institute, Montréal, Québec, Canada; Centre for the Studies in the Prevention of Alzheimer's Disease, Montréal, Québec, Canada; McGill University, Montréal, Québec, Canada. Electronic address:
Neurobiol Aging 2018 06 9;66:180.e1-180.e9. Epub 2018 Feb 9.
Centre for Studies on the Prevention of Alzheimer's Disease, Douglas Mental Health University Institute, Montreal, Quebec, Canada; Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. Electronic address:
One important aspect in Alzheimer's disease pathology is the presence of chronic inflammation. Considering its role as a key receptor in the microglial innate immune system, TLR4 was shown to regulate the binding and phagocytosis of amyloid plaques by microglia in several mouse models of amyloidosis, as well as the production of pro-inflammatory cytokines. To our knowledge, TLR4 and its association with cytokines have not been thoroughly examined in the brains of subjects affected with Alzheimer's disease. Using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in postmortem human brains, we observed increased expression for the TLR4 and TNF genes (p = 0.001 and p = 0.025, respectively), as well as a trend for higher IL6 gene expression in the frontal cortex of AD subjects when compared to age-matched controls. Similarly, using a mouse model of hippocampal deafferentation without amyloidosis, (i.e., the entorhinal cortex lesioned mouse), we observed significant increases in the expression of both the Tlr4 (p = 0.0367 and p = 0.0193 compared to sham-lesioned mice or to the contralateral side, respectively) and Il1b (p = 0.0055 and p = 0.0066 compared to sham-lesioned mice or to the contralateral side, respectively) genes in the deafferentation phase, but not during the ensuing reinnervation process. In conclusion, we suggest that the modulation of cytokines by TLR4 is differentially regulated whether by the presence of amyloid plaques or by the ongoing deafferentation process.
Centre for Studies on the Prevention of Alzheimer's disease, Verdun, Quebec, Canada; Molecular Neurobiology Unit, Douglas Mental Health University Institute, Research Centre, Verdun, Quebec, Canada; Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
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