Neuroinflammation and Tauopathies

Alzheimer's disease (AD) and related Tauopathies are neurodegenerative disorders characterized by the accumulation of hyperphosphorylated Tau protein in neurofibrillary tangles and frequently accompanied by amyloid-β (Aβ) pathology.¹ While Tau aggregation has long been considered a primary driver of neurodegeneration, growing evidence highlights neuroinflammation as a central and early contributor to disease onset and progression. This review combines current knowledge on the molecular and cellular mechanisms linking Tau pathology to chronic neuroinflammatory signaling, with a particular focus on microglia- and astrocyte-mediated responses. We discuss how dysregulated kinase-phosphatase balance, impaired proteostasis, and oxidative stress promote Tau hyperphosphorylation and aggregation, and how these processes are amplified by innate immune pathways, including TREM2-DAP12, toll-like receptors, GPCR signaling, the PI3K-Akt/PTEN axis, Wnt/β-catenin signaling, and the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. Special emphasis is placed on the transition from early protective glial responses to chronic inflammation, which fosters prion-like propagation of Tau and accelerates synaptic dysfunction and neuronal loss. Finally, we evaluate emerging therapeutic strategies aimed at modulating neuroinflammatory pathways and restoring signaling homeostasis, highlighting their potential to slow or halt disease progression. Collectively, this review positions neuroinflammation as a critical mechanistic link between Tau pathology and neurodegeneration, underscoring its relevance as a therapeutic target in AD and other Tauopathies.