摘要：SummaryThe microtubule-associated tau protein forms pathological inclusions that accumulate in an age-dependent manner in tauopathies including Alzheimer's disease (AD). Since age is the major risk factor for AD, we examined endogenous tau species that evolve during aging in physiological and diseased conditions. In aged mouse brain, we found tau-immunoreactive clusters embedded within structures that are reminiscent of periodic acid-Schiff (PAS) granules. We showed that PAS granules harbor distinct tau species that are more prominent in 3xTg-AD mice. Epitope profiling revealed hypo-phosphorylated rather than hyper-phosphorylated tau commonly observed in tauopathies. High-resolution imaging and 3D reconstruction suggest a link between tau clusters, reactive astrocytes, and microglia, indicating that early tau accumulation may promote neuroinflammation during aging. Using postmortem human brain, we identified tau as a component of corpora amylacea (CA), age-related structures that are functionally analogous to PAS granules. Overall, our study supports neuroimmune dysfunction as a precipitating event in tau pathogenesis.Graphical AbstractDisplay OmittedHighlights•Tau is present in mouse hippocampal granules and human corpora amylacea•Tau accumulates with age in hippocampal granules and is accelerated in 3xTg-AD mice•Tau immunoreactive corpora amylacea are present in Alzheimer's disease brain•Age-related tau deposits are associated with reactive astrocytesNeuroscience; Molecular Neuroscience; Cellular Neuroscience
