New publication! Novel insights into tau-induced disruption of terminal neuronal differentiation.
We think that pathogenic forms of tau disrupt the cellular program that maintains terminal differentiation of neurons. We have a new publication related to this idea – this project was led by our first PhD student, Adrian Beckmann:
Adrian discovered that tau-induced aberrant activation of Moesin, a crosslinker of the plasma membrane and actin cytoskeleton that is known for its role in cancer and the epithelial-mesenchymal transition (EMT), drives cell cycle activation and consequent neurodegeneration. The idea that pathogenic forms of tau disrupt neuronal identity is based on studies from ourselves and others reporting that neurons in Alzheimer's disease and other tauopathies acquire phenotypes that are also present in various cancers: cytoskeletal over-stabilization, nuclear pleomorphisms, decondensation of constitutive heterochromatin, transposable element activation, and aberrant, abortive activation of the cell cycle. While cell cycle activation drives tumor formation in the context of cancer, activation of the cell cycle in post-mitotic neurons is sufficient to induce neurodegeneration.
If tau disrupts a cellular program that keeps mature neurons neuronal, this should be reflected in the transcriptional signature of patients with tauopathies. Indeed, Rusty Gage and colleagues have previously reported that the mature neuronal fate is unstable in induced neurons from patients with Alzheimer’s disease: https://pubmed.ncbi.nlm.nih.gov/33910058/. In line with the idea that tau disrupts neuronal identity, Adrian identified a large coexpression module related to cancer and the cytoskeleton that was upregulated in brains of patients with Alzheimer’s disease. Moesin was a hub gene within this module. Adrian found that the Moesin module was conserved in tau transgenic (but not APP transgenic) mice, suggesting that the module is driven by pathogenic forms of tau.
Adrian next moved into Drosophila for mechanistic studies into tau-induced Moesin activation. He found that Moesin elevation was coincident with an over-stabilized cytoskeleton and aberrant cell cycle activation in tau transgenic Drosophila, and that tau transgenic flies harbor additional features of EMT along with depletion of neuronal adhesion proteins. Panneuronal depletion of Moesin significantly suppressed tau-induced actin overstabilization, abortive cell cycle activation, and neurodegeneration.
While we haven’t 100% nailed down the big hypothesis that pathogenic forms of tau kill cells by driving (shall I say it??) neuronal dedifferentiation and consequent neuronal death, I think this study gets us one step closer to the idea. Our findings converge with the NIA’s AMP-AD consortium @ampadportal, who have nominated Moesin as a drug target for Alzheimer’s disease based on proteomic data from human Alzheimer’s disease samples: https://agora.adknowledgeportal.org/genes/ENSG00000147065. Moesin elevation has also previously been reported in endothelial cells and microglia of human brains affected by Alzheimer’s disease: https://alz-journals.onlinelibrary.wiley.com/doi/abs/10.1002/alz.045915
This study was made possible by contributions from Dr. Jim Ray, publicly available data from the NIH Accelerating Medicines Partnership Program for AD generated by Dr. Nilufer Ertekin-Taner, and funding from NIA and NINDS.