Microglia modulate Aβ-dependent astrocyte reactivity in Alzheimer’s disease

Experimental evidence suggests that activated microglia induce astrocyte reactivity in neurodegenerative disorders, such as Alzheimer’s disease (AD). Here, we investigated the association between microglial activation and amyloid-β (Aβ) with reactive astrogliosis in the living AD human brain. We studied 101 individuals across the AD spectrum with positron emission tomography (PET) for Aβ aggregation ([ ¹⁸ F]AZD4694) and translocator protein (TSPO) microglial activation ([ ¹¹ C]PBR28), along with the plasma biomarker for astrocyte reactivity glial fibrillary acidic protein (GFAP). We further assessed tau phosphorylation by plasma phosphorylated tau at threonine 217 (p-tau217) and tau aggregation using [ ¹⁸ F]MK-6240 PET. We found that Aβ pathology was associated with increased astrocyte reactivity across cortical brain regions only in the presence of elevated levels of microglial activation. Importantly, the microglia-dependent effects of Aβ on astrocyte reactivity were further related to cognitive impairment through tau phosphorylation and aggregation. Postmortem data from the Allen Human Brain Atlas revealed that TSPO mRNA expression patterns reflected the in-vivo Aβ-glia relationships, indicating that the interplay between AD pathophysiology and glial reactivity might be regulated at the gene expression level. Altogether, our results provide biomarker-based clinical evidence that microglial activation plays a key role in Aβ-related astrocyte reactivity, which, in turn, contributes to downstream pathological features of AD. These findings shed light on the intricate crosstalk between microglia and astrocytes in the AD brain, offering insights for the development of glia-targeting therapies.