TLR4 Gene Expression and Pro-Inflammatory Cytokines in Alzheimer’s Disease and in Response to Hippocampal Deafferentation in Rodents

Abstract

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.

Impact of HMGB1, RAGE, and TLR4 in Alzheimer’s Disease (AD): From Risk Factors to Therapeutic Targeting

“…Similarly, in a mouse model of hippocampal differentiation (at 7 days post-lesion) without amyloidosis (i.e., the entorhinal cortex lesioned mouse), hippocampal TLR4 and IL-1β mRNA expression levels were significantly elevated compared to sham-lesioned mice. However, during reinnervation phase (at 21 days post-lesion) there was no significant difference at the TLR4, IL-1β, IL-6, and TNF-α mRNA levels compared to sham-lesioned mice [21]. This finding suggests that the contribution of TLR4 in neuroinflammatory process during AD is not only triggered by amyloidosis, but also by an amyloid independent differentiation process that occurs in the early phases of the disease [21].…”

“…However, during reinnervation phase (at 21 days post-lesion) there was no significant difference at the TLR4, IL-1β, IL-6, and TNF-α mRNA levels compared to sham-lesioned mice [21]. This finding suggests that the contribution of TLR4 in neuroinflammatory process during AD is not only triggered by amyloidosis, but also by an amyloid independent differentiation process that occurs in the early phases of the disease [21].…”

“…In a clinical study of post-mortem human brains, an upregulation of the TLR4, IL-6, and TNF-α mRNA levels was observed at the frontal cortex of AD subjects as compared to age-matched controls [21]. Similarly, in a mouse model of hippocampal differentiation (at 7 days post-lesion) without amyloidosis (i.e., the entorhinal cortex lesioned mouse), hippocampal TLR4 and IL-1β mRNA expression levels were significantly elevated compared to sham-lesioned mice.…”

“…Accumulative evidence highlights the pathogenic role of HMGB1, RAGE, and TLR4 signaling in AD onset. Upregulation of HMGB1, RAGE, and TLR4 protein levels has been detected in AD peripheral samples [19][20][21]. Moreover, elevated HMGB1 expression was detected in hippocampal neuronal cells of the Aβ 25-35 -induced AD-related model of neuroinflammation and has been correlated with AD progression [18].…”

Open Science Datasets from PREVENT-AD, a Longitudinal Cohort of Pre-symptomatic Alzheimer’s Disease

“…As indicated, allelic variants of six genes associated with AD were determined using pyrosequencing (PyroMArk96). [22][23][24][25] From the 425 participants who underwent baseline visits, 385 were confirmed as appropriate for final data analysis. Among the 40 exclusions, 31 were judged unsuitable for continued participation because of cognitive deficits that had escaped detection but became apparent upon more detailed testing at baseline.…”