Moesin is an effector of tau-induced actin overstabilization, cell cycle activation, and neurotoxicity in Alzheimer’s disease

Summary

In Alzheimer’s disease, neurons acquire phenotypes that are also present in various cancers, including aberrant activation of the cell cycle. Unlike cancer, cell cycle activation in post-mitotic neurons is sufficient to induce cell death. Multiple lines of evidence suggest that abortive cell cycle activation is a consequence of pathogenic forms of tau, a protein that drives neurodegeneration in Alzheimer’s disease and related “tauopathies.” Here we combine network analyses of human Alzheimer’s disease and mouse models of Alzheimer’s disease and primary tauopathy with studies in Drosophila to discover that pathogenic forms of tau drive cell cycle activation by disrupting a cellular program involved in cancer and the epithelial-mesenchymal transition (EMT). Moesin, an EMT driver, is elevated in cells harboring disease-associated phosphotau, over-stabilized actin, and ectopic cell cycle activation. We further find that genetic manipulation of Moesin mediates tau-induced neurodegeneration. Taken together, our study identifies novel parallels between tauopathy and cancer.

Graphical abstract

Highlights

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  Network analyses reveal hub gene Moesin in a cancer-related module in tauopathy

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  Tau-induced Moesin elevation drives actin stabilization and cell cycle activation

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  Epithelial-mesenchymal transition features are present in tau transgenic Drosophila

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  Tau-induced Moesin elevation may disrupt neuronal identity

Abstract

Pathophysiology; Cellular physiology; Gene network