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Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease.

The spreading of pathology within and between brain areas is a hallmark of neurodegenerative disorders. In patients with Alzheimers disease, deposition of amyloid- is accompanied by activation of the innate immune system and involves inflammasome-dependent formation of ASC specks in microglia. ASC specks released by microglia bind rapidly to amyloid- and increase the formation of amyloid- oligomers and aggregates, acting as an inflammation-driven cross-seed for amyloid- pathology. Here we show that intrahippocampal injection of ASC specks resulted in spreading of amyloid- pathology in transgenic double-mutant APP[sub.Swe]PSEN1[sub.dE9] mice. By contrast, homogenates from brains of APP[sub.Swe]PSEN1[sub.dE9] mice failed to induce seeding and spreading of amyloid- pathology in ASC-deficient APP[sub.Swe]PSEN1[sub.dE9] mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloid- pathology in APP[sub.Swe]PSEN1[sub.dE9] mice. These findings support the concept that inflammasome activation is connected to seeding and spreading of amyloid- pathology in patients with Alzheimers disease., Author(s): Carmen Venegas [1]; Sathish Kumar [2]; Bernardo S. Franklin [3]; Tobias Dierkes [1, 3]; Rebecca Brinkschulte [3]; Dario Tejera [1]; Ana Vieira-Saecker [1]; Stephanie Schwartz [1]; Francesco Santarelli [1]; [...]

Chemokines are important modulators of neuroinflammation and neurodegeneration. In the brains of Alzheimer's disease (AD) patients and in AD animal models, the chemokine CXCL10 is found in high concentrations, suggesting a pathogenic role for this chemokine and its receptor, CXCR3. Recent studies aimed at addressing the role of CXCR3 in neurological diseases indicate potent, but diverse, functions for CXCR3. Here, we examined the impact of CXCR3 in the amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD. We found that, compared with control APP/ PSI animals, plaque burden and Aβ levels were strongly reduced in CXCR3- deficient APP/PS1 mice. Analysis of microglial phagocytosis in vitro and in vivo demonstrated that CXCR3 deficiency increased the microglial uptake of Aβ. Application of a CXCR3 antagonist increased microglial Aβ phagocytosis, which was associated with reduced TNF-α secretion. Moreover, in CXCR3-deficient APP/PS1 mice, microglia exhibited morphological activation and reduced plaque association, and brain tissue from APP/PS1 animals lacking CXCR3 had reduced concentrations of proinflammatory cytokines compared with controls. Further, loss of CXCR3 attenuated the behavioral deficits observed in APP/PS1 mice. Together, our data indicate that CXCR3 signaling mediates development of AD-like pathology in APP/PS1 mice and suggest that CXCR3 has potential as a therapeutic target for AD., Introduction Alzheimer's disease (AD) is a neurodegenerative brain disorder characterized by the formation of β-amyloid plaques, predominantly in hippocampal and cortical regions (1, 2). Periplaque activation of microglia and astrocytes [...]

Alzheimer's disease is the world's most common dementing illness. Deposition of amyloid-β peptide drives cerebral neuroinflammation by activating microglia (1,2). Indeed, amyloid-β activation of the NLRP3 inflammasome in microglia is [...]

Abstract Microglial activation plays an integral role in the development and course of neurodegeneration. Although neuropeptides such as bradykinin (BK), somatostatin (SST), and endothelin (ET) are known to be important mediators of inflammation in the periphery, evidence of a similar function in brain is scarce. Using immunocytochemistry, we demonstrate the expression of receptors for BK (B1, B2 subtypes), ET (ETA, ETB subtypes) and SST (SST 2, 3, 4 subtypes) in primary microglia and microglial cell lines. Exposure of BV2 and N9, as well as primary microglial cells to BK or SST increased Aβ uptake in a concentration-dependent manner, whereas endothelin decreased Aβ uptake. This was caused by increased phagocytosis of Aβ since the rate of intracellular Aβ degradation remained unaffected. All neuropeptides increased chemotactic activity of microglia. In addition, BK reduced Aβ-induced expression of proinflammatory genes including iNOS and COX-2. ET decreased the Aβ-induced expression of monocyte chemoattractant protein 1 and interleukin-6. These results suggest that neuropeptides play an important role in chemotaxis and Aβ clearance and modulate the brain's response to neuroinflammatory processes.

Abstract Background Septic encephalopathy is a severe brain dysfunction caused by systemic inflammation in the absence of direct brain infection. Changes in cerebral blood flow, release of inflammatory molecules and metabolic alterations contribute to neuronal dysfunction and cell death. Methods To investigate the relation of electrophysiological, metabolic and morphological changes caused by SE, we simultaneously assessed systemic circulation, regional cerebral blood flow and cortical electroencephalography in rats exposed to bacterial lipopolysaccharide. Additionally, cerebral glucose uptake, astro- and microglial activation as well as changes of inflammatory gene transcription were examined by small animal PET using [18F]FDG, immunohistochemistry, and real time PCR. Results While the systemic hemodynamic did not change significantly, regional cerebral blood flow was decreased in the cortex paralleled by a decrease of alpha activity of the electroencephalography. Cerebral glucose uptake was reduced in all analyzed neocortical areas, but preserved in the caudate nucleus, the hippocampus and the thalamus. Sepsis enhanced the transcription of several pro- and anti-inflammatory cytokines and chemokines including tumor necrosis factor alpha, interleukin-1 beta, transforming growth factor beta, and monocot chemoattractant protein 1 in the cerebrum. Regional analysis of different brain regions revealed an increase in ED1-positive microglia in the cortex, while total and neuronal cell counts decreased in the cortex and the hippocampus. Conclusion Together, the present study highlights the complexity of sepsis induced early impairment of neuronal metabolism and activity. Since our model uses techniques that determine parameters relevant to the clinical setting, it might be a useful tool to develop brain specific therapeutic strategies for human septic encephalopathy.

Background: In Alzheimer's disease (AD) progression, amyloid beta load uniformly increases across the brain cortex, while neurofibrillary tangles progressively spread in a stereotypical pattern from entorhinal to visual cortex. AD is known to have a strong genetic link to microglia and recently, expression profiling at single cell resolution has identified disease‐associated microglia populations with differential amyloid‐beta vs. tau pathology association in human AD brain. However, prior human studies focusing on microglia included a limited number of donors and/or cells per donor, and how microglial transcriptomes change with progression of tau pathology remains largely unknown. Method: Using single nuclei RNA sequencing, we profiled 337,512 microglia from 32 donors across 4 pathology groups (no to severe pathology) and five brain regions along the tau spreading pathway (entorhinal cortex, Brodmann Area 20, Brodmann Area 46, secondary visual cortex, and primary visual cortex) to investigate their cellular heterogeneity as a function of disease progression. Phospho‐Tau231 and HT7‐HT7 aggregated tau levels of adjacent tissue were assessed for quantification of tau pathology. Result: We confirmed previously described microglial populations across all profiled regions and identified cluster associations with tau levels, which mirrored the expected stereotypical progression across brain regions. Integrative analysis showed high similarity of microglia subtypes across regions, but interestingly also revealed entorhinal cortex and late tau pathology enriched clusters. Genes upregulated in early vs. late tau‐affected regions at severe pathology stage, but not in healthy brain, were found to be enriched in DNA repair and replication processes as well as immune response activation, while downregulated genes corresponded to glial cell differentiation and gliogenesis. Conclusion: This study constitutes a high‐quality resource of microglia phenotypes in a previously unmet sample size with regard to both donors and cells per donor, well characterized by quantitative readouts for tau pathology association across tau spreading regions. We foresee this study will contribute to a better understanding of how microglial phenotypes can be targeted during the progression of tau pathology in AD, while further work is required to distinguish causality from consequence. [ABSTRACT FROM AUTHOR]