Alzheimer’s disease brain-derived tau extracts show differential processing and transcriptional effects in human astrocytes

TL;DR

This study shows how human astrocytes handle tau aggregates from Alzheimer's brains and how this affects gene activity.

Contribution

The study reveals how astrocytes process and respond to different tau aggregates from Alzheimer’s disease brains.

Findings

Human astrocytes can internalize tau aggregates from Alzheimer’s brain extracts.

Tau handling by astrocytes correlates with molecular properties of the aggregates and affects gene expression.

Astrocyte responses include both clearance of tau and seeding of further aggregation.

Abstract

Post-translational modifications of tau, including phosphorylation at specific residues, are closely linked with tau seeding ability and clinical disease progression. While most previous evidence has focused on neuronal tau spread, evidence supports a similar role for astrocytes. Here, we demonstrate that well characterized tau aggregates isolated from postmortem Alzheimer’s disease brain are internalized and processed by control human–induced pluripotent stem cell-derived astrocytes. Differences in the efficiency of tau internalization, clearance and/or seeding were noted, which reflect molecular properties of tau and/or co-factors in brain extracts. We observed a direct relationship between tau handling by astrocytes and astrocyte transcriptomic changes. Dysregulated genes include several previously identified as upregulated in reactive astrocytes in Alzheimer’s brain, as well as those implicated in pathological tau clearance by autophagy and other pathways. The study provides insights into the complex interplay between tau molecular diversity and astrocyte responses in Alzheimer’s disease.

•Human iPSC-derived astrocytes express efficiently internalize tau aggregates•The internalized tau can be cleared from astrocytes or seed further aggregation•Tau handling profiles are linked to molecular properties of tau or the extracts•Differences in tau handling are reflected in astrocyte transcriptional changes

Human iPSC-derived astrocytes express efficiently internalize tau aggregates

The internalized tau can be cleared from astrocytes or seed further aggregation

Tau handling profiles are linked to molecular properties of tau or the extracts

Differences in tau handling are reflected in astrocyte transcriptional changes

Cell biology; Cellular neuroscience; Neuroscience; Omics

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