Genome-wide association studies have identified genes modulating microglia and inflammation to be associated with an enhanced risk for Alzheimer’s disease (AD). Furthermore, increased microglial activation has been associated with the progression of AD. In the rTg4510 tau transgenic AD model, we consistently observed an age-dependent elevation in the microglia marker IBA-1, while gene expression profiling in rTg4510 brain tissues also revealed a robust age-dependent increase in microglia activation-related markers, and a moderate increase in microglia cell- and proliferation-related markers, in comparison to wild-type littermates. Notably, the increase in microglia markers correlated with the accumulation in tau pathology. Consistent with our observations, previous findings in the literature demonstrated that inhibition of colony-stimulating factor-1 receptor (CSF-1R) depleted microglia and reduced tau pathology in multiple tau models.
CSF-1R, a membrane-bound receptor tyrosine kinase, is known for its important role in the proliferation and survival of microglia. CSF-1R has two ligands, CSF-1 and IL-34. We became interested in IL-34, because of its selective activity in the brain. IL-34 knockout removes about half of microglia in mouse brain, while minimally affecting macrophages/monocytes in the periphery. It is unknown to what extent IL-34 inhibition will impact tau pathology. We therefore set out to test this with a high-affinity murine antibody raised against IL-34.
In a prevention paradigm, young rTg4510 mice were treated with an IgG1 control mAb (50 mg/kg), or dose-dependently with an anti-IL-34 mAb (5-, 15-, or 50- mg/kg), or a high dose of a CSF-1R inhibitor (PLX3397) as a positive control. The anti-IL-34 mAb significantly reduced microglia dose-dependently and the expression of proinflammatory cytokine markers. At the highest dose, anti-IL-34 mAb reduced microglia by ~50%, phenocopying the magnitude of microglia reduction in IL-34 knockout mice. Surprisingly, anti-IL-34 mAb demonstrated a robust reduction of tau pathology, with a magnitude comparable to PLX3397, which elicited a much stronger reduction of microglia (~95%). In addition, some brain regions showed evidence for the slowing of neurodegeneration. Our data suggested that partial reduction of microglia is sufficient to robustly reduce tau pathology in rTg4510 mice, and supported the anti-IL-34 mAb as a novel therapy to treat tauopathies and AD.
3/30/22 9:23 am
Great talk, Theresa!