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Repeated exposure to toll-like receptor 4 (TLR4) ligands, such as lipopolysaccharide (LPS), reduces responses of monocytes/macrophages to LPS (LPS/endotoxin tolerance). Microglial exposure to Aβ deposits, a TLR4 ligand, may cause "Aβ/LPS tolerance," leading to decreased Aβ clearance. We demonstrated that microglial activation by LPS is diminished in Aβ deposit-bearing 12-month-old model mice of Alzheimer's disease (AD), compared with non-AD mice and Aβ deposit-free 2-month-old AD mice. Because miR-146a plays a predominant role in inducing TLR tolerance in macrophages and because miR-146a in extracellular vesicles (EVs) shed by inflammatory macrophages increases in circulation, we investigated potential roles of miR-146a and inflammatory EVs in inducing TLR tolerance in microglia and in altering expression of inflammatory AD risk genes. We found that miR-146a upregulation induces TLR tolerance and alters expression of inflammatory AD risk genes in response to LPS treatment in BV2 microglia. LPS brain injection altered expression of the AD risk genes in 12-month-old AD mice but not in non-AD littermates. EVs from inflammatory macrophages polarize BV2 microglia to M1 phenotype and induce TLR tolerance. Microglia exposed to Aβ in the brain show reduced cytokine responses to systemic inflammation due to peripheral LPS injection, indicating TLR/Aβ tolerance in microglia. Our results suggest that increased miR-146a induces microglial Aβ/LPS tolerance and that circulating EVs shed by inflammatory macrophages contribute to microglial Aβ/LPS tolerance, leading to reduced Aβ clearance. Our study also suggests that altered expression of inflammatory AD risk genes may contribute to AD development via the same molecular mechanism underlying LPS tolerance.

Let Z be the ring of integers and let K(Z,2n) denote the Eilenberg-MacLane space of type (Z,2n) for n ? 1. In this article, we prove that the graded group Am := Aut(??2mn+1(?K(Z,2n))=torsions) of automorphisms of the graded quasi-Lie algebras ?? 2mn+1(?K(Z,2n)) modulo torsions that preserve the Whitehead products is a finite group for m ? 2 and an infinite group for m ? 3, and that the group Aut(?*(K(Z,2n))=torsions) is non-abelian. We extend and apply those results to techniques in localization (or rationalization) theory.

Hydrogen sulfide (Hsub2/subS) plays important roles in brain pathophysiology. However, nuclear imaging probes for the in vivo detection of brain Hsub2/subS in living animals have not been developed. Here, we report the first nuclear imaging probe that enables in vivo imaging of endogenous Hsub2/subS in the brain of live mice.Utilizing a bis(thiosemicarbazone) backbone, a fluorescent ATSM-FITC conjugate was synthesized. Its copper complex, Cu(ATSM-FITC) was thoroughly tested as a biosensor for Hsub2/subS. The same ATSM-FITC ligand was quantitatively labeled with [sup64/supCu]CuClsub2/subto obtain a radioactive [sup64/supCu][Cu(ATSM-FITC)] imaging probe. Biodistribution and positron emission tomography (PET) imaging studies were performed in healthy mice and neuroinflammation models.The Cu(ATSM-FITC) complex reacts instantly with Hsub2/subS to release CuS and becomes fluorescent. It showed excellent reactivity, sensitivity, and selectivity to Hsub2/subS. Endogenous Hsub2/subS levels in living cells were successfully detected by fluorescence microscopy. Exceptionally high brain uptake of [sup64/supCu][Cu(ATSM-FITC)] (gt; 9% ID/g) was observed in biodistribution and PET imaging studies. Subtle changes in brain Hsub2/subS concentrations in live mice were accurately detected by quantitative PET imaging. Due to its dual modality feature, increased Hsub2/subS levels in neuroinflammation models were characterized at the subcellular level by fluorescence imaging and at the whole-body scale by PET imaging.Our biosensor can be readily utilized to study brain Hsub2/subS function in live animal models and shows great potential as a novel imaging agent for diagnosing brain diseases.

In the current study, we explore digital homology modules, and investigate their fundamental properties on (pointed) digital images as one of the developments of symmetries. We also examine pointed digital Hopf spaces and base point preserving digital Hopf functions between pointed digital Hopf spaces with suitable digital multiplications, and explore the digital primitive homology classes, digital Pontryagin algebras on digital Hopf spaces as a symmetric phenomenon in mathematics and computer science.

Accumulation of amyloid beta-peptide (Aβ) in the brain is hypothesized to be a causal event leading to dementia in Alzheimer's disease (AD). Aβ vaccination removes Aβ deposits from the brain. Aβ immunotherapy, however, may cause T cell- and/or Fc-receptor-mediated brain inflammation and relocate parenchymal Aβ deposits to blood vessels leading to cerebral hemorrhages. Because catalytic antibodies do not form stable immune complexes and Aβ fragments produced by catalytic antibodies are less likely to form aggregates, Aβ-specific catalytic antibodies may have safer therapeutic profiles than reversibly-binding anti-Aβ antibodies. Additionally, catalytic antibodies may remove Aβ more efficiently than binding antibodies because a single catalytic antibody can hydrolyze thousands of Aβ molecules. We previously isolated Aβ-specific catalytic antibody, IgVL5D3, with strong Aβ-hydrolyzing activity. Here, we evaluated the prophylactic and therapeutic efficacy of brain-targeted IgVL5D3 gene delivery via recombinant adeno-associated virus serotype 9 (rAAV9) in an AD mouse model. One single injection of rAAV9-IgVL5D3 into the right ventricle of AD model mice yielded widespread, high expression of IgVL5D3 in the unilateral hemisphere. IgVL5D3 expression was readily detectable in the contralateral hemisphere but to a much lesser extent. IgVL5D3 expression was also confirmed in the cerebrospinal fluid. Prophylactic and therapeutic injection of rAAV9-IgVL5D3 reduced Aβ load in the ipsilateral hippocampus of AD model mice. No evidence of hemorrhages, increased vascular amyloid deposits, increased proinflammatory cytokines, or infiltrating T-cells in the brains was found in the experimental animals. AAV9-mediated anti-Aβ catalytic antibody brain delivery can be prophylactic and therapeutic options for AD.

Objectives: The purpose of the study was to investigate the effect of the position of the ankle joint on the isokinetic muscular strength of the knee joint. Methods/Statistical Analysis: The subjects of this study were 20 young and healthy adult females who were applied at random ankle joint positions and underwent the flexion and extension of the knee joint. Isokinetic muscle strength was measured for each process at an angle speed of 60°/sec with CSMI. The comparison of knee muscle strength for each ankle position was conducted by a one-way ANOVA. Post hoc tests utilized LSD. Findings: When the knee joint was extension at a 40° plantar flexion, it showed a significant difference regarding the neutral position and the position of the 20° dorsiflexion (p .05). The muscle strength rate of the knee joint showed a significant difference for the neutral position and the position of the 20° dorsiflexion at the position of a 40° plantar flexion (p

Microglia-mediated clearance of amyloid beta-protein (Aβ) via Toll-like receptor 4 (TLR4) signaling may play an important role in the pathogenesis of Alzheimer's disease (AD). However, as the disease progresses, activated microglia appear to become incapable of clearing Aβ deposits. Because repeated exposure to a TLR4 ligand leads to a diminished response of monocytes/macrophages to lipopolysaccharide (LPS) and because aggregated Aβ is a TLR4 ligand, we hypothesize that chronic exposure of microglia to Aβ deposits may induce a state of Toll-like receptor (TLR) signaling dysfunction, leading to decreased Aβ clearance and accelerated disease progression. LPS or phosphate-buffered saline (PBS) was injected into the hippocampus of AD-model (TgAPP/PS1) and wild-type (non-Tg) mice before and after the onset of Aβ deposition, at age 2 and 12 months, respectively. Brain specimens were collected 7 days post-injection and analyzed for microglial activation and Aβ load. While LPS-injected 2-month-old non-Tg mice showed 48-fold and 11-fold greater Iba1 immunoreactivity in the neocortex and hippocampus, respectively, compared with PBS-injected mice, LPS-injected 2-month-old TgAPP/PS1 mice had 61-fold and 13-fold increases in the neocortex and hippocampus, respectively. LPS injection activated microglia more strongly in TgAPP/PS1 mice than in non-Tg mice at 2 months of age. In contrast, at 12 months of age, Iba1 immunoreactivity of microglia was increased 541-fold and 38-fold in the neocortex and hippocampus, respectively, in LPS-injected non-Tg mice and 2.7-fold and 3.3-fold in the neocortex and hippocampus, respectively, in LPS-injected TgAPP/PS1 mice. Surprisingly, LPS injection decreased CD45 immunoreactivity in TgAPP/PS1 mice but increased it in non-Tg mice at 12 months. Although microglia in 12-month-old non-Tg mice showed stronger response to LPS than 2-month-old non-Tg mice, microglia in TgAPP/PS1 mice exhibited diminished immune response to LPS during aging. Our data indicate that microglial TLR4 signaling is altered in an AD mouse model and suggest that altered TLR4 signaling may contribute to Aβ accumulation in the brain.

Toll-like receptors (TLRs) are a family of pattern-recognition receptors in innate immunity and provide a first line defense against pathogens and tissue injuries. In addition to important roles in infection, inflammation, and immune diseases, recent studies show that TLR signaling is involved in modulation of learning, memory, mood, and neurogenesis. Because MyD88 is essential for the downstream signaling of all TLRs, except TLR3, we investigated the effects of MyD88 deficiency (MyD88-/-) on behavioral functions in mice. Additionally, we recently demonstrated that a mouse model of Alzheimer's disease (AD) deficient for MyD88 had decreases in Aβ deposits and soluble Aβ in the brain as compared with MyD88 sufficient AD mouse models. Because accumulation of Aβ in the brain is postulated to be a causal event leading to cognitive deficits in AD, we investigated the effects of MyD88 deficiency on behavioral functions in the AD mouse model at 10 months of age. MyD88 deficient mice showed more anxiety in the elevated plus-maze. In the motor coordination tests, MyD88 deficient mice remained on a beam and a bar for a longer time, but with slower initial movement on the bar. In the Morris water maze test, MyD88 deficiency appeared to improve spatial learning irrespective of the transgene. Our findings suggest that the MyD88-dependent pathway contributes to behavioral functions in an AD mouse model and its control group.

Having the merits of conceptual simplicity, high-output-power capacity, and wide tuning characteristics, the vircator (virtual cathode oscillator) has been investigated as a high-power microwave (HPM) generator. In axial vircator, the power, frequency, and pulsewidth are all sensitive to the cathode shape, and the frequency depends strongly on the anode-cathode gap distance. The efficiency of the vircator is reported to only a few percent. Therefore, we devised the new type cathode to enhance the output power. The new type cathode is adding the ring to the cathode with velvet, so-called cathode-wing. The electron beam is only emitted from cathode with velvet, while a cathode-wing forms the electric fields to prevent the backstream electrons due to virtual cathode from leaking to the diode chamber wall. We investigated the axial vircator with the cathode-wing by the HPM generator ldquoChundoongrdquo (max 600 kV, 88 kA, 60 ns). It is found that the cathode-wing contributes to enhancement of the output microwave power efficiency to 7% in comparison with 3% for a conventional axial vircator without cathode-wing.

Interleukin-17A (IL-17A) is generally considered as one of the pathogenic factors involved in multiple sclerosis (MS). Indirect evidence for this is that IL-17A-producing T helper 17 (Th17) cells preferentially accumulate in lesions of MS and experimental autoimmune encephalomyelitis (EAE). However, a direct involvement of IL-17A in MS pathogenesis is still an open question. In this study, we overexpressed IL-17A in the brains of mice (IL-17A-in-Brain mice) via recombinant adeno-associated virus serotype 5 (rAAV5)-mediated gene delivery. In spite of high levels of IL-17A expression in the brain and blood, IL-17A-in-Brain mice exhibit no inflammatory responses and no abnormalities in motor coordination and spatial orientation. Unexpectedly, IL-17A-in-Brain mice show decreases in body weight and adipose tissue mass and an improvement in glucose tolerance and insulin sensitivity. IL-17A enhances glucose uptake in PC12 cells by activation of AKT. Our results provide direct evidence for the first time that IL-17A overexpression in the central nervous system does not cause physical and learning disabilities and neuroinflammation and suggest that IL-17A may regulate glucose metabolism through the AKT signaling pathway.

Numerical simulation studies of a coaxial virtual cathode oscillator with and without a bar reflector have been performed by the three-dimensional particle-in-cell (PIC) code, MAGIC. Also, the experimental studies are performed in our high-power microwave pulser, "Chundoong" to compare with numerical results. It consists of a cylindrical anode-mesh, a coaxial type cathode, and a bar reflector. Results show that the output microwave mode without a reflector is shown to be a mixture of TE and TM modes and the output microwave frequency has a narrow bandwidth and a main frequency is about 3.38 GHz from a coaxial vircator without a bar reflector. But the TM01 mode with its frequency of 3.34 GHz is shown to be dominant for the coaxial vircator with a bar reflector. It is found in this experiment that the output microwave power sensitively depends upon the position of a bar reflector

An insertion/deletion polymorphism in the SERT linked promoter region (SERTLPR), previously reported to regulate mRNA expression in vitro, has been associated with mental disorders and response to psychotropic drugs. Contradictory evidence, however, has raised questions about the role of SERTLPR in regulating mRNA expression in vivo. We have used analysis of allelic expression imbalance (AEI) of SERT mRNA to assess quantitatively the contribution of SERTLPR to mRNA expression in human post-mortem pons tissue sections containing serotonergic neurons of the dorsal and median raphe nuclei. Any difference in the expression of one allele over the other indicates the presence of cis-acting elements that differentially affect transcription and/or mRNA processing and turnover. Using a marker SNP in the 3' untranslated region of SERT mRNA, statistically significant differences in allelic mRNA levels were detected in nine out of 29 samples heterozygous for the marker SNP. While the allelic expression differences were relatively small (15-25%), they could nevertheless be physiologically relevant. Although previous results had suggested that the long form of SERTLPR yields higher mRNA levels than the short form, we did not observe a correlation between SERTLPR and allelic expression ratios. Also in contrast to previous results, we found no correlation between SERTLPR and allelic expression ratios or SERT mRNA levels in B-lymphocytes. This study demonstrates that regulation of SERT mRNA is independent of SERTLPR, but could be associated with polymorphisms in partial linkage disequilibrium with SERTLPR.

A numerical simulation study of the high-power microwave generation from the vircator (virtual cathode oscillator) is carried out for coaxial diode structure by using a three-dimensional particle-in-cell (PIC) code called MAGIC. The coaxial vircator has a centered annular cathode body, cathode ring and cylindrical meshed-anode in order to enlarge the active interaction region in the virtual cathode space. In order to enhance a conversion efficiency of the output microwave power, ring-type reflector was installed to coaxial-type diode structure. The simulation results show that the output microwave frequency has a narrow bandwidth and its output microwave power sensitively depends upon the position and width of ring-type reflector. The maximum output microwave power is obtained by adopting a ring-type reflector 10 mm in width and 40 mm in the distance from the intense relativistic electron beam to the ring-type reflector. The output microwave mode without a ring-type reflector is a mixture of TM and TE mode. However, the TM/sub 01/ mode with its resonance frequency of 2.2 GHz is dominant for the ring-type reflector.

We have investigated the influence of anode-cathode (A-K) gap distance on the output characteristics of high-power microwave from coaxial virtual cathode oscillator (vircator). This high-power microwave generator is powered by the "Chundoong" (Max 600 kV, 88 kA, 60 ns), which is an intense relativistic electron beam-pulse generator. In this experiment, it was observed that the microwave power has been strongly dependent upon the A-K gap distance, where the A-K gap has been varied from 4 to 8 mm. The maximum microwave power is observed to be 244 MW, whose efficiency is about 2.75% at the A-K gap distance 4 mm. Also the microwave frequencies are measured to be 5.1/spl les/f/spl les/5.9 GHz from the combination of a coupled line band pass filter with a 1-GHz bandwidth and dispersive delay line method. It is noted that measured output microwave frequency is in good agreement with that of simulation. It is also found that the dominant mode of output microwave is a TM/sub 01/ in this simulation result.

We evaluated the therapeutic efficacy of combined treatment of Aβ-immunization with simvastatin in an Alzheimer mouse model at age 22 months. DNA prime-adenovirus boost immunization induced modest anti-Aβ titers and simvastatin increased the seropositive rate. Aβ-KLH was additionally administered to boost the titers. Irrespective of simvastatin, the immunization did not decrease cerebral Aβ deposits but increased soluble Aβ and tended to exacerbate amyloid angiopathy in the hippocampus. The immunization increased cerebral invasion of leukocytes and simvastatin counteracted the increase. Thus, modest anti-Aβ titers can increase soluble Aβ and simvastatin may reduce inflammation associated with vaccination in aged Alzheimer mouse models.

The accumulation of β-amyloid protein (Aβ) in the brain is thought to be a primary etiologic event in Alzheimer's disease (AD). Fibrillar Aβ plaques, a hallmark of AD abnormality, are closely associated with activated microglia. Activated microglia have contradictory roles in the pathogenesis of AD, being either neuroprotective (by clearing harmful Aβ and repairing damaged tissues) or neurotoxic (by producing proinflammatory cytokines and reactive oxygen species). Aβ aggregates can activate microglia by interacting with multiple toll-like receptors (TLRs), the pattern-recognition receptors of the innate immune system. Because the adapter protein MyD88 is essential for the downstream signaling of all TLRs, except TLR3, we investigated the effects of MyD88 deficiency (MyD88(-/-)) on Aβ accumulation and microglial activation in an AD mouse model. MyD88 deficiency decreased Aβ load and microglial activation in the brain. The decrease in Aβ load in an MyD88(-/-) AD mouse model was associated with increased and decreased protein expression of apolipoprotein E (apoE) and CX3CR1, respectively, compared with that in an MyD88 wild-type AD mouse model. These results suggest that MyD88 deficiency may reduce Aβ load by enhancing the phagocytic capability of microglia through fractalkine (the ligand of CX3CR1) signaling and by promoting apoE-mediated clearance of Aβ from the brain. These findings also suggest that chronic inflammatory responses induced by Aβ accumulation via the MyD88-dependent signaling pathway exacerbate β-amyloidosis in AD.

Accumulation of amyloid-β protein (Aβ) in the brain is thought to be a causal event in Alzheimer's disease (AD). Immunotherapy targeting Aβ holds great promise for reducing Aβ in the brain. Here, we evaluated the efficacy and safety of anti-Aβ single-chain antibody (scFv59) delivery via recombinant adeno-associated virus (rAAV) on reducing Aβ deposits in an AD mouse model (TgAβPPswe/PS1dE9). First, delivery of scFv59 to the brain was optimized by injecting rAAV serotypes 1, 2, and 5 into the right lateral ventricle. Symmetrical high expression of scFv59 was found throughout the hippocampus and partly in the neocortex in both hemispheres via rAAV1 or rAAV5, while scFv59 expression via rAAV2 was mostly limited to one hemisphere. rAAV1, however, induced apoptosis and microglial activation but rAAV5 did not. Therefore, rAAV5 was selected for therapeutic scFv59 delivery in TgAβPPswe/PS1dE9 mice. rAAV5 was similarly injected into the ventricle of 10-month-old TgAβPPswe/PS1dE9 mice and 5 months later its efficacy and safety were evaluated. Immunoreactive Aβ deposits reduced in the hippocampus. Aβ42 levels in cerebrospinal fluid (CSF) tended to increase and the Aβ40 : 42 ratio decreased in CSF, suggesting that Aβ42 was relocated from the parenchyma to CSF. Hemorrhages associated with a focal increase in blood vessel amyloid were found in the brain. While immunotherapy has great potential for clearing cerebral Aβ, caution for cerebrovascular effects should be exercised when rAAV-mediated anti-Aβ immunotherapy is applied.

Background Genetic variation in mRNA expression plays a critical role in human phenotypic diversity, but it has proven difficult to detect regulatory polymorphisms - mostly single nucleotide polymorphisms (rSNPs). Additionally, variants in the transcribed region, termed here 'structural RNA SNPs' (srSNPs), can affect mRNA processing and turnover. Both rSNPs and srSNPs cause allelic mRNA expression imbalance (AEI) in heterozygous individuals. We have used AEI to discover and characterize regulatory polymorphisms in OPRM1, TPH2, MDR1, DRD2, and VKORC1. The objective of this study was to use AEI to determine the extent of cis-regulatory factors in pharmacogenetic genes. Methods We applied a rapid and accurate AEI methodology for testing 42 genes implicated in cardiovascular and central nervous system diseases, and affecting drug metabolism and transport. Each gene was analyzed in physiologically relevant human autopsy tissues, including brain, heart, liver, intestines, and lymphocytes. Results Substantial AEI was observed in approximately 55% of the surveyed genes. Focusing on cardiovascular candidate genes in human hearts, AEI analysis revealed frequent cis-acting regulatory factors in ACE and SOD2 mRNA expression, having potential clinical significance. SNP scanning to locate regulatory polymorphisms in a number of genes failed to support several previously proposed promoter SNPs discovered with use of reporter gene assays in heterologous tissues, while srSNPs appear more frequent than expected. Computational analysis of mRNA folding indicates that approximately 90% of srSNPs affect mRNA folding, and hence potentially function. Conclusion Our results indicate that both rSNPs and srSNPs represent a still largely untapped reservoir of variants that contribute to human phenotypic diversity.

Tryptophan hydroxylase isoform 2 (TPH2) is expressed in serotonergic neurons in the raphe nuclei, where it catalyzes the rate-limiting step in the synthesis of the neurotransmitter serotonin. In search for functional polymorphisms within the TPH2 gene locus, we measured allele-specific expression of TPH2 mRNA in sections of human pons containing the dorsal and median raphe nuclei. Differences in allelic mRNA expression--referred to as allelic expression imbalance (AEI)--are a measure of cis-acting regulation of gene expression and mRNA processing. Two marker SNPs, located in exons 7 and 9 of TPH2 (rs7305115 and rs4290270, respectively), served for quantitative allelic mRNA measurements in pons RNA samples from 27 individuals heterozygous for one or both SNPs. Significant AEI (ranging from 1.2- to 2.5-fold) was detected in 19 out of the 27 samples, implying the presence of cis-acting polymorphisms that differentially affect TPH2 mRNA levels in pons. For individuals heterozygous for both marker SNPs, the results correlated well (r=0.93), validating the AEI analysis. AEI is tightly associated with the exon 7 marker SNP, in 17 of 18 subjects. Remarkably, expression from the minor allele exceeded that of the major allele in each case, possibly representing a gain-of-function. Genotyping of 20 additional TPH2 SNPs identified a haplotype block of five tightly linked SNPs for which heterozygosity is highly correlated with AEI and overall expression of TPH2 mRNA. These results reveal the presence of a functional cis-acting polymorphism, with high frequency in normal human subjects, resulting in increased TPH2 expression levels. The SNPs that correlate with AEI are closely linked to TPH2 SNPs previously shown to associate with major depression and suicide.

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 Aβ 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 Aβ deposits and buffer-soluble Aβ 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 Aβ 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 Aβ deposits start. Methods Microglial activation and amyloid deposition in the brain were determined by immunohistochemistry in the AD models. Levels of cerebral soluble Aβ were determined by ELISA. mRNA levels of cytokines and chemokines in the brain and Aβ-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 Aβ 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 Aβ deposition and soluble Aβ42 in the brain, which were associated with decrements in cognitive functions and expression levels of IL-1β, CCL3, and CCL4 in the hippocampus compared to TLR4W Tg mice. TLR4 mutation diminished Aβ-induced IL-1β, CCL3, and CCL4 expression in monocytes. Conclusion This is the first demonstration of TLR4-dependent activation of microglia at the early stage of β-amyloidosis. Our results indicate that TLR4 is not involved in the initiation of Aβ deposition and that, as Aβ deposits start, microglia are activated via TLR4 signaling to reduce Aβ deposits and preserve cognitive functions from Aβ-mediated neurotoxicity.