How Reactivity of Astrocytes and Microglia Relates to Amyloid and Tau Proteopathy
Microglia and astrocytes tend towards greater reactivity in the aging brain, entering a more inflammatory state. This sustained inflammation is maladaptive and contributes to the development of neurodegenerative conditions. In the research noted here, the data indicates significant differences in the mechanisms that provoke astrocytes versus microglia into reactivity. Other evidence already links microglial inflammation with amyloid-β and tau protein pathology. The earlier stages of Alzheimer's disease may be inflammatory because of the presence of amyloid-β and its effects on microglia, while the later stages have more of the appearance of an accelerating feedback loop between inflammatory signaling and the presence of pathologically altered tau, both of which generate the other.
Previous studies have shown that glial and neuronal changes may trigger synaptic dysfunction in Alzheimer's disease (AD). However, the link between glial and neuronal markers and synaptic abnormalities in the living brain is poorly understood. Here, we investigated the association between biomarkers of astrocyte and microglial reactivity and synaptic dysfunction in 478 individuals across the aging and AD spectrum from two cohorts with available cerebrospinal fluid (CSF) measures of amyloid-β (Aβ), phosphorylated tau(pTau181), astrocyte reactivity (GFAP), microglial activation (sTREM2), and synaptic biomarkers (GAP43 and neurogranin).
Elevated CSF GFAP levels were linked to presynaptic and postsynaptic dysfunction, regardless of cognitive status or Aβ presence. CSF sTREM2 levels were associated with presynaptic biomarkers in cognitively unimpaired and impaired Aβ+ individuals and postsynaptic biomarkers in cognitively impaired Aβ+ individuals. Notably, CSF pTau181 levels mediated all associations between GFAP or sTREM2 levels and synaptic dysfunction biomarkers. These results suggest that neuronal-related synaptic biomarkers could be used in clinical trials targeting glial reactivity in AD.
In conclusion, our findings support a link between glial reactivity and synaptic dysfunction in living humans, which appears to be explained by pathological phosphorylation of tau. While astrocyte reactivity seems to be a partially independent phenomenon leading to synaptic dysfunction in aging and AD, the effects of microglial activation on synaptic function are determined by the emergence of Aβ pathology. These results suggest that synaptic biomarkers hold potential as secondary endpoints for clinical trials targeting glial reactivity in aging and AD.