Preferential clustering of microglia and astrocytes around neuritic plaques during progression of Alzheimer's disease neuropathological changes

Neuroinflammation plays an important role in the pathological cascade of Alzheimer's disease (AD) along with aggregation of extracellular amyloid-β (Aβ) plaques and intracellular aggregates of tau protein. In animal models of amyloidosis, local immune activation is centered around Aβ plaques, which are usually of uniform morphology, dependent on the transgenic model used. In postmortem human brains a diversity of Aβ plaque morphologies is seen including diffuse plaques (non-neuritic plaques, non-NP), dense-core plaques, cotton-wool plaques, and NP. In a recent study, we demonstrated that during the progression of Alzheimer's disease neuropathologic changes (ADNC), a transformation of non-NP into NP occurs which is tightly linked to the emergence of cortical, but not hippocampal neurofibrillary tangle (NFT) pathology. This highlights the central role of NP in AD pathogenesis as well as brain region-specific differences in NP formation. In order to correlate the transformation of plaque types with local immune activation, we quantified the clustering and phenotype of microglia and accumulation of astrocytes around non-NP and NP during the progression of ADNC. We hypothesize that glial clustering occurs in response to formation of neuritic dystrophy around NP. First, we show that Iba1-positive microglia preferentially cluster around NP. Utilizing microglia phenotypic markers, we furthermore demonstrate that CD68-positive phagocytic microglia show a strong preference to cluster around NP in both the hippocampus and frontal cortex. A similar preferential clustering is observed for CD11c and ferritin-positive microglia in the frontal cortex, while this preference is less pronounced in the hippocampus, highlighting differences between hippocampal and cortical Aβ plaques. Glial fibrillary acidic protein-positive astrocytes showed a clear preference for clustering around NP in both the frontal cortex and hippocampus. These data support the notion that NP are intimately associated with the neuroimmune response in AD and underscore the importance of the interplay of protein deposits and the immune system in the pathophysiology of AD.