pexidartinib and Tauopathies

Chronic activation of brain innate immunity is a prominent feature of Alzheimer's disease (AD) and primary tauopathies. However, to what degree innate immunity contributes to neurodegeneration as compared with pathological protein-induced neurotoxicity, and the requirement of a particular glial cell type in neurodegeneration, are still unclear. Here we demonstrate that microglia-mediated damage, rather than pathological tau-induced direct neurotoxicity, is the leading force driving neurodegeneration in a tauopathy mouse model. Importantly, the progression of ptau pathology is also driven by microglia. In addition, we found that

Topics: Alzheimer Disease; Aminopyridines; Animals; Apolipoproteins E; Brain; Dietary Supplements; Disease Models, Animal; Humans; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microglia; Neurodegenerative Diseases; Pyrroles; tau Proteins; Tauopathies

Activation of inflammation pathways in the brain occurs in Alzheimer's disease and may contribute to the accumulation and spread of pathological proteins including tau. The goal of this study was to identify how changes in microglia, a key inflammatory cell type, may contribute to tau protein accumulation and pathology-associated changes in immune and non-immune cell processes such as neuronal degeneration, astrocyte physiology, cytokine expression, and blood vessel morphology.. We used PLX3397 (290 mg/kg), a colony-stimulating factor receptor 1 (CSF1R) inhibitor, to reduce the number of microglia in the brains of a tau-overexpressing mouse model. Mice were fed PLX3397 in chow or a control diet for 3 months beginning at 12 months of age and then were subsequently analyzed for changes in blood vessel morphology by in vivo two-photon microscopy and tissues were collected for biochemistry and histology.. PLX3397 reduced microglial numbers by 30% regardless of genotype compared to control diet-treated mice. No change in tau burden, cortical atrophy, blood vessels, or astrocyte activation was detected. All Tg4510 mice were observed to have an increased in "disease-associated" microglial gene expression, but PLX3397 treatment did not reduce expression of these genes. Surprisingly, PLX3397 treatment resulted in upregulation of CD68 and Tgf1β.. Manipulating microglial activity may not be an effective strategy to combat tau pathological lesions. Higher doses of PLX3397 may be required or earlier intervention in the disease course. Overall, this indicates a need for a better understanding of specific microglial changes and their relation to the disease process.

Topics: Aging; Aminopyridines; Animals; Blood Vessels; Calcium-Binding Proteins; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cytokines; Disease Models, Animal; Gene Expression Regulation; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microfilament Proteins; Microglia; Mutation; Pyrroles; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; RNA, Messenger; tau Proteins; Tauopathies