Properties of Alzheimer’s disease brain-derived tau aggregates define tau processing by human astrocytes

The templated misfolding of tau proteins accounts for tau pathology spread in Alzheimer’s disease (AD). Post-translational modifications, including phosphorylation at specific residues, are closely linked with tau seeding ability and clinical disease progression. This study investigates the role of astrocytes in tau spread, demonstrating that tau aggregates from post-mortem AD brain are internalized and processed by human astrocytes. Differences in tau internalization, clearance, and seeding were observed, potentially reflecting the molecular properties of tau. A direct relationship between tau handling by astrocytes and astrocyte responses was noted in transcriptomic data, highlighting dysregulated genes linked to pathological tau clearance pathways. To explore these differences, mass spectrometry was performed on both control and AD brain extracts, providing insights into the complex interplay between tau diversity and astrocyte responses in AD.