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Tau protein is involved in various cellular processes, including having a canonical role in binding and stabilization of microtubules in neurons. Tauopathies are neurodegenerative diseases marked by the abnormal accumulation of tau protein aggregates in neurons, as seen, for example, in conditions such as frontotemporal dementia and Alzheimer disease. Mutations in tau coding regions or that disrupt tau mRNA splicing, tau post-translational modifications and cellular stress factors (such as oxidative stress and inflammation) increase the tendency of tau to aggregate and interfere with its clearance. Pathological tau is strongly implicated in the progression of neurodegenerative diseases, and the propagation of tau aggregates is associated with disease severity. Recent technological advancements, including cryo-electron microscopy and disease models derived from human induced pluripotent stem cells, have increased our understanding of tau-related pathology in neurodegenerative conditions. Substantial progress has been made in deciphering tau aggregate structures and the molecular mechanisms that underlie protein aggregation and toxicity. In this Review, we discuss recent insights into the diverse cellular functions of tau and the pathology of tau inclusions and explore the potential for therapeutic interventions.Tau is a microtubule-binding protein that is expressed primarily in neurons. The abnormal accumulation of tau aggregates in neurons is associated with neurodegenerative diseases, known as tauopathies, such as Alzheimer disease and frontotemporal dementia. This Review discusses recent insights into the diverse cellular functions of tau, the pathology of tau aggregates and the potential for therapeutic interventions.

Background Tau is aberrantly acetylated in various neurodegenerative conditions, including Alzheimer’s disease, frontotemporal lobar degeneration (FTLD), and traumatic brain injury (TBI). Previously, we reported that reducing acetylated tau by pharmacologically inhibiting p300-mediated tau acetylation at lysine 174 reduces tau pathology and improves cognitive function in animal models. Methods We investigated the therapeutic efficacy of two different antibodies that specifically target acetylated lysine 174 on tau (ac-tauK174). We treated PS19 mice, which harbor the P301S tauopathy mutation that causes FTLD, with anti-ac-tauK174 and measured effects on tau pathology, neurodegeneration, and neurobehavioral outcomes. Furthermore, PS19 mice received treatment post-TBI to evaluate the ability of the immunotherapy to prevent TBI-induced exacerbation of tauopathy phenotypes. Ac-tauK174 measurements in human plasma following TBI were also collected to establish a link between trauma and acetylated tau levels, and single nuclei RNA-sequencing of post-TBI brain tissues from treated mice provided insights into the molecular mechanisms underlying the observed treatment effects. Results Anti-ac-tauK174 treatment mitigates neurobehavioral impairment and reduces tau pathology in PS19 mice. Ac-tauK174 increases significantly in human plasma 24 h after TBI, and anti-ac-tauK174 treatment of PS19 mice blocked TBI-induced neurodegeneration and preserved memory functions. Anti-ac-tauK174 treatment rescues alterations of microglial and oligodendrocyte transcriptomic states following TBI in PS19 mice. Conclusions The ability of anti-ac-tauK174 treatment to rescue neurobehavioral impairment, reduce tau pathology, and rescue glial responses demonstrates that targeting tau acetylation at K174 is a promising neuroprotective therapeutic approach to human tauopathies resulting from TBI or genetic disease.

Aggregation of the protein tau defines tauopathies, which include Alzheimer's disease and frontotemporal dementia. Specific neuronal subtypes are selectively vulnerable to tau aggregation and subsequent dysfunction and death, but the underlying mechanisms are unknown. To systematically uncover the cellular factors controlling the accumulation of tau aggregates in human neurons, we conducted a genome-wide CRISPRi-based modifier screen in iPSC-derived neurons. The screen uncovered expected pathways, including autophagy, but also unexpected pathways, including UFMylation and GPI anchor synthesis. We discover that the E3 ubiquitin ligase CUL5 is a potent modifier of tau levels in human neurons, ubiquitinates tau, and is a correlated with vulnerability to tauopathies in mouse and human. Disruption of mitochondrial function promotes proteasomal misprocessing of tau, which generates tau proteolytic fragments like those in disease and changes tau aggregation . These results reveal new principles of tau proteostasis in human neurons and pinpoint potential therapeutic targets for tauopathies.

Tauopathies, characterized by accumulation of tau aggregates, are a heterogeneous group of neurodegenerative diseases. These include Alzheimer’s disease (AD), the most common tauopathy, as well as subtypes of frontotemporal lobar degeneration with tau pathology (FTLD-Tau) such as Pick’s disease (PiD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and several others. Tau is encoded by a single gene (MAPT) and gives rise to six isoforms, including those with three (3R) or four (4R) microtubule-binding repeats due to alternative splicing of exon 10. Tauopathies are classified as 3R, 4R, and 3R/4R mixed subtypes, each exhibiting distinct tau filament structures revealed by cryogenic electron microscopy (cryo-EM). Tau filaments in AD (3R/4R), PiD (3R), CBD (4R), and PSP (4R) are structurally distinct. Many familial FTLD-Tau-causing MAPT mutations alter the 3R-4R ratio, with several, including P301S/L, located in exon 10 and thus 4R-specific.Human induced pluripotent stem cell (hiPSC)-derived neurons are invaluable for modeling neurological diseases, including but not limited to tauopathies. Combined with CRISPR-Cas9 technology, these enable isogenic controls for precise disease modeling and functional genomics to identify disease modifiers. However, iPSC-derived neurons express very low levels of 4R Tau, even after extended culture, making them unsuitable for modeling 4R tauopathies such as PSP or familial FTLD-Tau mutations in exon 10. Moreover, robust tau aggregation has been difficult to recapitulate in iPSC neurons. No insoluble tau aggregates were observed in MAPT-P301L or MAPT-IVS10 + 16 iPSC-derived neurons, and only limited tau inclusions appeared in neuronal processes after 120 days. A key contributing factor could be the lack of 4R tau expression.In the current study, we report the establishment of a robust and scalable human iPSC 4R tauopathy model. We engineered hiPSC lines to express 4R tau and 4R tau carrying the P301S MAPT mutation (4R-P301S) when differentiated into neurons. Upon seeding with tau fibrils, we showed that 4R-P301S neurons develop a progressive spread of tau aggregation, aberrant neuronal activity, and endolysosomal pathway dysfunction. Using CRISPR interference (CRISPRi)-based functional genomic screening, we identified novel genetic modifiers and pathways and established a robust platform to discover potential therapeutic strategies for 4R tauopathy.

Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to lack of appropriate human models. Current human induced pluripotent stem cell (hiPSC)-derived neurons express very low levels of 4-repeat (4R)-tau isoforms that are normally expressed in adult brain. Here, we engineered new iPSC lines to express 4R-tau and 4R-tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes, including shared transcriptomic signatures, autophagic body accumulation, and impaired neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of Tau-seeding-induced Tau propagation, including retromer VPS29 and the UFMylation cascade as top modifiers. In AD brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade suppressed seeding-induced Tau propagation. This model provides a powerful platform to identify novel therapeutic strategies for 4R tauopathy.Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to lack of appropriate human models. Current human induced pluripotent stem cell (hiPSC)-derived neurons express very low levels of 4-repeat (4R)-tau isoforms that are normally expressed in adult brain. Here, we engineered new iPSC lines to express 4R-tau and 4R-tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes, including shared transcriptomic signatures, autophagic body accumulation, and impaired neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of Tau-seeding-induced Tau propagation, including retromer VPS29 and the UFMylation cascade as top modifiers. In AD brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade suppressed seeding-induced Tau propagation. This model provides a powerful platform to identify novel therapeutic strategies for 4R tauopathy.