TLR4 mutation reduces microglial activation, increases Aβ deposits and exacerbates cognitive deficits in a mouse model of Alzheimer's disease

Background: Amyloid plaques, a pathological hallmark of Alzheimer's disease (AD), are accompanied by activated microglia. The role of activated microglia in the pathogenesis of AD remains controversial: either clearing A beta deposits by phagocytosis or releasing proinflammatory cytokines and cytotoxic substances. Microglia can be activated via toll-like receptors (TLRs), a class of pattern-recognition receptors in the innate immune system. We previously demonstrated that an AD mouse model homozygous for a loss-of-function mutation of TLR4 had increases in A beta deposits and buffer-soluble A beta in the brain as compared with a TLR4 wild-type AD mouse model at 14-16 months of age. However, it is unknown if TLR4 signaling is involved in initiation of A beta deposition as well as activation and recruitment of microglia at the early stage of AD. Here, we investigated the role of TLR4 signaling and microglial activation in early stages using 5-month-old AD mouse models when Ab deposits start. Methods: Microglial activation and amyloid deposition in the brain were determined by immunohistochemistry in the AD models. Levels of cerebral soluble A beta were determined by ELISA. mRNA levels of cytokines and chemokines in the brain and A beta-stimulated monocytes were quantified by real-time PCR. Cognitive functions were assessed by the Morris water maze. Results: While no difference was found in cerebral A beta load between AD mouse models at 5 months with and without TLR4 mutation, microglial activation in a TLR4 mutant AD model (TLR4M Tg) was less than that in a TLR4 wild-type AD model (TLR4W Tg). At 9 months, TLR4M Tg mice had increased A beta deposition and soluble A beta 42 in the brain, which were associated with decrements in cognitive functions and expression levels of IL-1 beta, CCL3, and CCL4 in the hippocampus compared to TLR4W Tg mice. TLR4 mutation diminished A beta-induced IL-1 beta, CCL3, and CCL4 expression in monocytes. Conclusion: This is the first demonstration of TLR4-dependent activation of microglia at the early stage of beta-amyloidosis. Our results indicate that TLR4 is not involved in the initiation of A beta deposition and that, as A beta deposits start, microglia are activated via TLR4 signaling to reduce A beta deposits and preserve cognitive functions from A beta-mediated neurotoxicity.