Abstract
BackgroundActivation 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.MethodsWe 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.ResultsPLX3397 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.ConclusionsManipulating 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.
Highlights
An increase in the number of reactive microglia is a key feature of Alzheimer’s disease (AD, [35]), with data from multiple genome-wide association studies confirming these cells are important to disease pathogenesis [9, 40]
In aged 3xTg mice which develop both amyloid β (Aβ) plaques and tangles, microglial depletion appeared to have a minimal effect on measures of Aβ plaque pathology and no effect on tau pathology assessed by either total tau or AT8 phosphorylation [8]
Reduction of microglia in Tg4510 mice after CSF-1r blockade Beginning at 12 months of age, Tg4510 mice and littermate wild-type controls were fed chow containing PLX3397 (290 mg/kg, PLX3397) or control diet (Fig. 1a–c) for 3 months
Summary
An increase in the number of reactive microglia is a key feature of Alzheimer’s disease (AD, [35]), with data from multiple genome-wide association studies confirming these cells are important to disease pathogenesis [9, 40]. In aged 3xTg mice which develop both Aβ plaques and tangles, microglial depletion appeared to have a minimal effect on measures of Aβ plaque pathology and no effect on tau pathology assessed by either total tau or AT8 phosphorylation [8]. In another AD mouse model, such as the 5XFAD line which only develops plaque pathology, early microglia depletion reduces pathological accumulation of Aβ [37] but later depletion does not, and only has a modest protective effect on neurons [38]. The goal of this study was to identify how changes in microglia, a key inflammatory cell type, may contribute to tau protein accumulation and pathologyassociated changes in immune and non-immune cell processes such as neuronal degeneration, astrocyte physiology, cytokine expression, and blood vessel morphology
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