Tau biology expands beyond microtubules to neurodegeneration, metabolism and mental illness

An Thought Leaders Invited Review published today in Genomic Psychiatry by Dr. Peng Lei and colleagues presents a sweeping synthesis of tau protein research that fundamentally reframes our understanding of this molecule's dual identity. What emerges from their analysis is a portrait of a protein far more versatile than its original characterization as a mere microtubule stabilizer suggested, one that participates in processes ranging from iron export to insulin secretion while simultaneously serving as a central player in some of the most devastating neurological and psychiatric conditions afflicting humanity.

The protein that defied simple classification

Discovered in the 1970s as a copurifying partner of tubulin, tau spent its early decades in relative obscurity. The 1980s changed everything. Researchers identified tau as the core component of neurofibrillary tangles, those twisted protein aggregates that mark the devastated landscapes of Alzheimer disease brains. Yet this pathological notoriety obscured something equally important: tau performs essential functions that neurons cannot live without.

The review traces how scientific understanding evolved from viewing tau as a passive structural element to recognizing it as an active participant in neuronal physiology. "Tau, predominantly expressed in neurons, plays a crucial role in the assembly of microtubules and the maintenance of the microtubule network," the authors write, but this represents merely the beginning of its responsibilities. The protein regulates axonal transport, maintains the integrity of the axon initial segment, and participates in synaptic plasticity mechanisms that underlie learning and memory.

Iron, insulin, and unexpected connections

Perhaps the most striking insight in this comprehensive review is that the physiological function of tau is not merely limited to maintaining the stability of axonal microtubules, but also plays a crucial role in physiological processes such as iron metabolism, synaptic plasticity, and insulin metabolism; the research on tau should not be confined to Alzheimer's disease alone, but should also attract widespread attention in Parkinson's disease, type 2 diabetes, and even mental illnesses.

 Dr. Lei's own previous research demonstrated that tau promotes the transport of amyloid precursor protein to cell surfaces, stabilizing iron transporters and facilitating iron export from neurons. When tau function fails, iron accumulates. Twelve-month-old mice lacking tau exhibited iron deposition in neurons, loss of dopaminergic cells in the substantia nigra, and severe cognitive and motor decline.

Why should a microtubule-associated protein regulate metal ion homeostasis? The review authors suggest this connection illuminates something profound about neuronal vulnerability. Iron accumulation occurs precisely in brain regions where soluble tau levels drop, including the substantia nigra in Parkinson disease and the cortex in Alzheimer disease. Could tau loss represent an upstream event that renders neurons susceptible to oxidative damage?

The insulin connection proves equally unexpected. Tau deficiency enhances insulin secretion in pancreatic cells, normalizing glucose levels in diabetic mouse models. The protein appears to suppress microtubule-regulated insulin release mechanisms. This finding carries implications extending far beyond neuroscience, given that type 2 diabetes represents a significant risk factor for dementia.

The architecture of dysfunction

How does a protein essential for neuronal function transform into an agent of destruction? The review provides a comprehensive taxonomy of tau's posttranslational modifications, those chemical additions that regulate protein behavior. Researchers have identified 95 modifications at 88 amino acid residues in pathological tau, including phosphorylation, glycosylation, acetylation, ubiquitination, methylation, SUMOylation, and truncation.

Phosphorylation dominates the pathological landscape. Healthy brains maintain tau phosphorylation at approximately 2-3 moles of phosphate per mole of protein. In Alzheimer disease, this ratio climbs to 5-9 moles. This approximately threefold elevation disrupts tau's relationship with microtubules, releasing it into the cytoplasm where aggregation begins.

Yet not all phosphorylation promotes pathology. Phosphorylation at certain sites actually inhibits aggregation, while modification at others accelerates it. The complexity suggests that therapeutic strategies targeting phosphorylation must achieve surgical precision rather than blanket suppression.

The psychiatric dimension

The review's most provocative sections examine tau's emerging connections to psychiatric disorders. In patients with early-onset schizophrenia, plasma total tau levels were significantly lower than controls. Adult-onset schizophrenia patients showed decreased serum levels of both total tau and phosphorylated tau. What explains these reductions? Do they reflect altered tau production, increased clearance, or compartmental redistribution?

Delirium presents another intriguing connection. Preoperative plasma phosphorylated tau at position 217 correlates with postoperative delirium risk. Anesthesia and surgery acutely elevate blood p-tau217, which may cross the blood-brain barrier and induce delirium-like behaviors. This finding carries immediate clinical implications for surgical planning in vulnerable populations.

The neuropsychiatric symptoms of Alzheimer disease, including apathy, depression, and anxiety, correlate with tau pathology patterns. Patients with psychotic symptoms show higher phosphorylated tau levels in frontal cortex regions. Tau PET imaging reveals stronger signals in the amygdala and temporal cortices of patients experiencing delusions or hallucinations. Does tau pathology in limbic circuits directly produce psychiatric symptoms, or do both phenomena share upstream causes?

Biomarkers emerging from complexity

The synthesis devotes substantial attention to tau as a disease biomarker, tracing development from cerebrospinal fluid assays in the 1990s to contemporary blood-based tests. Plasma p-tau217 can distinguish Alzheimer disease from frontotemporal dementia with area-under-curve values exceeding 0.9. The test performs comparably to cerebrospinal fluid measures while requiring only a blood draw.

Different phosphorylated species appear at different disease stages. P-tau217 levels begin rising when amyloid plaques form, while p-tau205 elevates when neuronal dysfunction begins. This temporal separation offers possibilities for staging disease progression and timing interventions.

The microtubule-binding region of tau has emerged as another biomarker source. CSF MTBR-tau243 specifically reflects tau tangle pathology rather than earlier pathological changes. Plasma MTBR-tau243 correlates strongly with tau PET results and outperforms other plasma tau biomarkers for detecting tangle burden.

Therapeutic frontiers and frustrations

Despite impressive progress in understanding tau biology, the review authors note a sobering reality: no tau-targeting drug has demonstrated significant clinical efficacy. The antisense oligonucleotide BIIB080 reduced tau levels and showed manageable adverse effects in phase I trials for mild Alzheimer disease, representing perhaps the most promising current approach. Yet challenges remain formidable.

Kinase inhibitors targeting tau phosphorylation have produced mixed results. Lithium, the well-known GSK3 inhibitor, failed to reduce tau hyperphosphorylation in short-term trials but showed benefits over two years in mild cognitive impairment patients. Tideglusib improved cognitive damage in some Alzheimer patients but produced no clinical improvement in progressive supranuclear palsy.

Immunotherapy approaches have similarly struggled. Multiple tau antibodies have completed clinical trials without demonstrating efficacy in early Alzheimer disease. The reasons remain unclear. Do antibodies fail to reach intracellular tau? Is extracellular tau the wrong target? Have trials enrolled patients at disease stages too advanced for benefit?

The synthesis as roadmap

What patterns emerge from four decades of accumulated research? The review authors identify several critical gaps demanding attention. The precise origins of blood-based phosphorylated tau species remain incompletely understood. The mechanisms by which tau pathology spreads between neurons require further elucidation. Most fundamentally, whether tau pathology functions as primary driver or secondary consequence in various diseases remains contested.

The synthesis suggests that tau represents a convergence point where multiple pathological processes intersect. Its interactions with amyloid-beta, alpha-synuclein, and TDP-43 create complex pathological cascades that single-target therapies may inadequately address. Future strategies may require combination approaches attacking multiple nodes simultaneously.

This invited review represents a critical synthesis of current knowledge across neuroscience, psychiatry, and translational medicine, providing researchers, clinicians, and policymakers with a comprehensive framework for understanding tau biology and pathology. By systematically analyzing and integrating findings from over 300 studies spanning more than four decades, the authors offer both a historical perspective on how the field has evolved and a roadmap for future investigations. The synthesis reveals patterns that were invisible in individual studies, reconciles apparent contradictions in the literature, and highlights the most promising avenues for advancing the field. Such comprehensive reviews are essential for translating the accumulated weight of evidence into actionable insights that can improve practice and policy. The rigorous methodology employed, including systematic coverage of physiological functions, pathological mechanisms, biomarker development, and therapeutic approaches, ensures the reliability and reproducibility of the synthesis. This work exemplifies how systematic analysis of existing literature can generate new understanding and guide the allocation of research resources toward the most critical unanswered questions.

The Thought Leaders Invited Review in Genomic Psychiatry titled "Tau protein: Physiological functions and multifaceted roles in neurodegenerative and psychiatric disorders," was fully preer-reviewed and it is freely available via Open Access, starting on 16 December 2025 in Genomic Psychiatry at the following hyperlink: https://doi.org/10.61373/gp025i.0122.