VISUALIZATION OF MICROGLIAL RESPONSE TO TAU-INDUCED NEURODEGENERATION IN A MODEL OF TAUOPATHY

Abstract

Accumulation of intracellular neurofibrillary tangles (NFTs) consisting of microtubule-associated protein tau is a major hallmark of tau-mediated neurodegenerative diseases referred to as tauopathies. Activation of glial cells, both astrocytes and microglia, has been documented as an early event in the pathogenesis of protein misfolding diseases. However, an alteration between NFT formation and microglial activation was not clearly understood. To investigate the temporospatial relationship between pathological tau accumulation and microglial activation, noninvasive in vivo brain imaging studies on a mouse model of tauopathy was conducted. Furthermore, microglial activation status was examined by cell morphology and immunoreactivity of microglial markers. The rTg4510 transgenic mice expressing P301L mutated tau were examined for volumetric MRI and PET imaging from 2 to 13M of age. PET probes, [11C]PBB3 and [11C]AC-5216 were used for visualizing tau pathology and TSPO (the 18-kDa translocator protein, a neuroinflammation marker), respectively. Tau pathology and microglial activation were subsequently analyzed by immunohistochemistry using postmortem mouse brains. Longitudinal imaging studies revealed age-dependent cortical and hippocampal volume reduction, PBB3 and TSPO accumulations. Retentions of tau and TSPO radioligands in these regions were inversely correlated to forebrain volume. Immunohistochemically, both Iba1 and TSPO signals were increased with aging while immunoreactivity of P2Y12, a marker for visualizing microglia in the ramified state, was significantly reduced in cerebral cortex and hippocampus of rTg4510 mice as early as 2 months of age. Our results indicate that mutant tau deposition accompanied with both TSPO accumulation and forebrain atrophy in the rTg4510 mice. Decrease of a ramified morphology in young rTg4510 mice strongly suggests the microglial response to tau-induced neurodegeneration at an early stage of NFT formation. Further examinations are ongoing to validate whether microglial activation in this mouse model is detrimental or beneficial to protecting neurons.