Differential Microglial activation and Astrocyte reactivity in Alzheimer’s trajectory

Abstract

AbstractBackgroundMicroglial activation and astrocyte activation plays a significant role in the pathogenesis of AD. Here, we evaluate microglial activation, the interrelationship between microglial activation, amyloid and tau pathologies, and the impact of microglial activation in Alzheimer’s disease trajectory. We specifically focus on microglia as a major player in neuroinflammation and evaluate the spatial and temporal variation of microglial activation in the disease trajectory. Additionally, we evaluate astroglial activation using novel astrocyte marker and evaluate the relationship between amyloid, MRI volume changes and glucose metabolism in Alzheimer’s trajectory.MethodWe evaluated AD, MCI and cognitively normal subjects using amyloid PET, tau PET and neuroinflammation using TSPO PET scans. A separate group of AD, MCI and control subjects were evaluated using novel astrocyte marker [11C]BU99008 PET along with [18F]FDG PET and amyloid PET. [11C]PBR28 and [11C]BU99008 PET scans were analysed using two tissue compartmental model, while [18F]Flutemetamol was analysed using target to cerebellar ratio. [18F]FDG PET was analysed using pons as a reference region. We performed regional and voxel wise analysis for all the tracers.ResultMicroglial activation was elevated in different cortical regions in both AD and MCI subjects. Microglial activation was associated with lower grey matter density in later stages of the disease, while higher grey matter volume was associated with increased microglial activation in early mild cognitive impairment subjects. There were areas of increased astrocyte activation in both AD and MCI. Higher microglial activation was associated with increased tau formation and neuronal damage in later stages of the disease. Interestingly, there was increased astrocyte reactivity in the early stages of the disease.ConclusionWhile microglial activation in the late phase of the disease is associated with neuronal damage, however, in the early stages microglial activation was associated with higher grey matter volume. Microglial activation demonstrated a biphasic pattern of activation. In contrast to microglial activation, astrocyte activation was prominent in the early stage of the disease and may be associated with neuroprotection. This suggests that in targeting glial activation as a therapeutic strategy, we must target astrocyte and microglia separately and in different stages of the disease.