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      CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice


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          Microglia have been implicated in amyloid beta-induced neuropathology, but their role in tau-induced neurodegeneration remains unclear. Mancuso et al. report that blockade of microglial proliferation by CSF1R inhibitor JNJ-40346527 modifies brain inflammation and ameliorates disease progression in P301S tauopathy mice. CSF1R inhibition may have therapeutic potential in tau-mediated neurodegenerative diseases.


          Neuroinflammation and microglial activation are significant processes in Alzheimer’s disease pathology. Recent genome-wide association studies have highlighted multiple immune-related genes in association with Alzheimer’s disease, and experimental data have demonstrated microglial proliferation as a significant component of the neuropathology. In this study, we tested the efficacy of the selective CSF1R inhibitor JNJ-40346527 (JNJ-527) in the P301S mouse tauopathy model. We first demonstrated the anti-proliferative effects of JNJ-527 on microglia in the ME7 prion model, and its impact on the inflammatory profile, and provided potential CNS biomarkers for clinical investigation with the compound, including pharmacokinetic/pharmacodynamics and efficacy assessment by TSPO autoradiography and CSF proteomics. Then, we showed for the first time that blockade of microglial proliferation and modification of microglial phenotype leads to an attenuation of tau-induced neurodegeneration and results in functional improvement in P301S mice. Overall, this work strongly supports the potential for inhibition of CSF1R as a target for the treatment of Alzheimer’s disease and other tau-mediated neurodegenerative diseases.

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          Most cited references39

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          Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy.

          Immune-regulated pathways influence multiple aspects of cancer development. In this article we demonstrate that both macrophage abundance and T-cell abundance in breast cancer represent prognostic indicators for recurrence-free and overall survival. We provide evidence that response to chemotherapy is in part regulated by these leukocytes; cytotoxic therapies induce mammary epithelial cells to produce monocyte/macrophage recruitment factors, including colony stimulating factor 1 (CSF1) and interleukin-34, which together enhance CSF1 receptor (CSF1R)-dependent macrophage infiltration. Blockade of macrophage recruitment with CSF1R-signaling antagonists, in combination with paclitaxel, improved survival of mammary tumor-bearing mice by slowing primary tumor development and reducing pulmonary metastasis. These improved aspects of mammary carcinogenesis were accompanied by decreased vessel density and appearance of antitumor immune programs fostering tumor suppression in a CD8+ T-cell-dependent manner. These data provide a rationale for targeting macrophage recruitment/response pathways, notably CSF1R, in combination with cytotoxic therapy, and identification of a breast cancer population likely to benefit from this novel therapeutic approach. These findings reveal that response to chemotherapy is in part regulated by the tumor immune microenvironment and that common cytotoxic drugs induce neoplastic cells to produce monocyte/macrophage recruitment factors, which in turn enhance macrophage infiltration into mammary adenocarcinomas. Blockade of pathways mediating macrophage recruitment, in combination with chemotherapy, significantly decreases primary tumor progression, reduces metastasis, and improves survival by CD8+ T-cell-dependent mechanisms, thus indicating that the immune microenvironment of tumors can be reprogrammed to instead foster antitumor immunity and improve response to cytotoxic therapy.
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            Inflammation and Alzheimer's disease.

            Inflammation clearly occurs in pathologically vulnerable regions of the Alzheimer's disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insoluble amyloid beta peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Because these stimuli are discrete, microlocalized, and present from early preclinical to terminal stages of AD, local upregulation of complement, cytokines, acute phase reactants, and other inflammatory mediators is also discrete, microlocalized, and chronic. Cumulated over many years, direct and bystander damage from AD inflammatory mechanisms is likely to significantly exacerbate the very pathogenic processes that gave rise to it. Thus, animal models and clinical studies, although still in their infancy, strongly suggest that AD inflammation significantly contributes to AD pathogenesis. By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.
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              Alzheimer disease in the US population: prevalence estimates using the 2000 census.

              Current and future estimates of Alzheimer disease (AD) are essential for public health planning. To provide prevalence estimates of AD for the US population from 2000 through 2050. Alzheimer disease incidence estimates from a population-based, biracial, urban study, using a stratified random sampling design, were converted to prevalence estimates and applied to US Census Bureau estimates of US population growth. A geographically defined community of 3 adjacent neighborhoods in Chicago, Ill, applied to the US population. Alzheimer disease incidence was measured in 3838 persons free of AD at baseline; 835 persons were evaluated for disease incidence. Main Outcome Measure Current and future estimates of prevalence of clinically diagnosed AD in the US population. In 2000, there were 4.5 million persons with AD in the US population. By 2050, this number will increase by almost 3-fold, to 13.2 million. Owing to the rapid growth of the oldest age groups of the US population, the number who are 85 years and older will more than quadruple to 8.0 million. The number who are 75 to 84 years old will double to 4.8 million, while the number who are 65 to 74 years old will remain fairly constant at 0.3 to 0.5 million. The number of persons with AD in the US population will continue to increase unless new discoveries facilitate prevention of the disease.

                Author and article information

                Oxford University Press
                October 2019
                26 August 2019
                26 August 2019
                : 142
                : 10
                : 3243-3264
                [1 ] Biological Sciences, University of Southampton, Southampton General Hospital , Southampton, UK
                [2 ] Department of Physiology Anatomy and Genetics, University of Oxford, Sherrington Building , Parks Road, Oxford OX1 3PT, UK
                [3 ] UK Dementia Research Institute, Cardiff University, Hadyn Ellis Building , Maindy Road, Cardiff, CF24 4HQ, UK
                [4 ] Janssen Research and Development, Turnhoutseweg 30 , box 270, 2340 Beerse 1, Belgium
                [5 ] Janssen Neuroscience Research and Development, Janssen Pharmaceutical Companies of Johnson and Johnson , Turnhoutseweg 30, 2340, Beerse, Belgium
                [6 ] Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King’s College London , London, UK
                [7 ] Experimental Medicine Imaging, GlaxoSmithKline, Gunnels Wood Road, Stevenage , SG1 2NY, UK
                [8 ] Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Stevenage , UK
                [9 ] Janssen Neuroscience External Innovation, Johnson and Johnson Innovation Centre , One Chapel Place, London, W1G 0BG, UK
                [10 ] Oxford Health NHS Foundation Trust , Oxford, UK
                Author notes
                Correspondence to: Renzo Mancuso Biological Sciences, University of Southampton, Southampton General Hospital Southampton, UK E-mail: renzo.mancuso@ 123456kuleuven.vib.be

                Appendix 1.

                © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                : 21 February 2019
                : 11 June 2019
                : 14 June 2019
                Page count
                Pages: 22
                Funded by: Wellcome Trust 10.13039/100010269
                Award ID: 104025/Z/14/Z
                Funded by: NIHR Oxford Health Biomedical Research Centre
                Original Articles

                alzheimer’s disease,microglia,neuroinflammation,tau,csf1r
                alzheimer’s disease, microglia, neuroinflammation, tau, csf1r


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