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

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.

A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation.

Pervasive neuroinflammation occurs in many neurodegenerative diseases, including Alzheimer's disease (AD). SPI1/PU.1 is a transcription factor located at a genome-wide significant AD-risk locus and its reduced expression is associated with delayed onset of AD. We analyzed single-cell transcriptomic datasets from microglia of human AD patients and found an enrichment of PU.1-binding motifs in the differentially expressed genes. In hippocampal tissues from transgenic mice with neurodegeneration, we found vastly increased genomic PU.1 binding. We then screened for PU.1 inhibitors using a PU.1 reporter cell line and discovered A11, a molecule with anti-inflammatory efficacy and nanomolar potency. A11 regulated genes putatively by recruiting a repressive complex containing MECP2, HDAC1, SIN3A, and DNMT3A to PU.1 motifs, thus representing a novel mechanism and class of molecules. In mouse models of AD, A11 ameliorated neuroinflammation, loss of neuronal integrity, AD pathology, and improved cognitive performance. This study uncovers a novel class of anti-inflammatory molecules with therapeutic potential for neurodegenerative disorders.

Pathogenic tau accelerates aging-associated activation of transposable elements in the mouse central nervous system.

Transposable elements comprise almost half of the mammalian genome. A growing body of evidence suggests that transposable element dysregulation accompanies brain aging and neurodegenerative disorders, and that transposable element activation is neurotoxic. Recent studies have identified links between pathogenic forms of tau, a protein that accumulates in Alzheimer's disease and related "tauopathies," and transposable element-induced neurotoxicity. Starting with transcriptomic analyses, we find that age- and tau-induced transposable element activation occurs in the mouse brain. Among transposable elements that are activated at the RNA level in the context of brain aging and tauopathy, we find that the endogenous retrovirus (ERV) class of retrotransposons is particularly enriched. We show that protein encoded by Intracisternal A-particle, a highly active mouse ERV, is elevated in brains of tau transgenic mice. Using two complementary approaches, we find that brains of tau transgenic mice contain increased DNA copy number of transposable elements, raising the possibility that these elements actively retrotranspose in the context of tauopathy. Taken together, our study lays the groundwork for future mechanistic studies focused on transposable element regulation in the aging mouse brain and in mouse models of tauopathy and provides support for ongoing therapeutic efforts targeting transposable element activation in patients with Alzheimer's disease.

Pathogenic Tau Causes a Toxic Depletion of Nuclear Calcium.

Synaptic activity-induced calcium (Ca2+) influx and subsequent propagation into the nucleus is a major way in which synapses communicate with the nucleus to regulate transcriptional programs important for activity-dependent survival and memory formation. Nuclear Ca2+ shapes the transcriptome by regulating cyclic AMP (cAMP) response element-binding protein (CREB). Here, we utilize a Drosophila model of tauopathy and induced pluripotent stem cell (iPSC)-derived neurons from humans with Alzheimer's disease to study the effects of pathogenic tau, a pathological hallmark of Alzheimer's disease and related tauopathies, on nuclear Ca2+. We find that pathogenic tau depletes nuclear Ca2+ and CREB to drive neuronal death, that CREB-regulated genes are over-represented among differentially expressed genes in tau transgenic Drosophila, and that activation of big potassium (BK) channels elevates nuclear Ca2+ and suppresses tau-induced neurotoxicity. Our studies identify nuclear Ca2+ depletion as a mechanism contributing to tau-induced neurotoxicity, adding an important dimension to the calcium hypothesis of Alzheimer's disease.