Tau and neurodegenerative disease: the story so far

Journal name:
Nature Reviews Neurology
Year published:
Published online


In 1975, tau protein was isolated as a microtubule-associated factor from the porcine brain. In the previous year, a paired helical filament (PHF) protein had been identified in neurofibrillary tangles in the brains of individuals with Alzheimer disease (AD), but it was not until 1986 that the PHF protein and tau were discovered to be one and the same. In the AD brain, tau was found to be abnormally hyperphosphorylated, and it inhibited rather than promoted in vitro microtubule assembly. Almost 80 disease-causing exonic missense and intronic silent mutations in the tau gene have been found in familial cases of frontotemporal dementia but, to date, no such mutation has been found in AD. The first phase I clinical trial of an active tau immunization vaccine in patients with AD was recently completed. Assays for tau levels in cerebrospinal fluid and plasma are now available, and tau radiotracers for PET are under development. In this article, we provide an overview of the pivotal discoveries in the tau research field over the past 40 years. We also review the current status of the field, including disease mechanisms and therapeutic approaches.

At a glance


  1. Timeline of discoveries and advances in the tau research field.
    Figure 1: Timeline of discoveries and advances in the tau research field.

    Pivotal discoveries are shaded blue, and other major advances are shaded grey. These findings substantially enhanced our understanding of the aetiopathogenesis of neurofibrillary degeneration in Alzheimer disease (AD) and other tauopathies, and aided the identification of biomarkers and therapeutic targets. Additional major findings are summarized in Supplementary information S1 (box). CSF, cerebrospinal fluid; FTDP-17, frontotemporal dementia with parkinsonism linked to chromosome 17; I2PP2A, PP2A inhibitor 2; NFT, neurofibrillary tangle; PHF, paired helical filament; PP2A, protein phosphatase 2A; P-tau, hyperphosphorylated tau.

  2. Tau mutations and alternative splicing of the MAPT pre-mRNA in FTD.
    Figure 2: Tau mutations and alternative splicing of the MAPT pre-mRNA in FTD.

    a | Schematic of full-length human tau, tau441, showing, in green, various missense mutations that have been found in inherited cases of frontotemporal dementia (FTD) and, in red, sites that can be phosphorylated, some or all of which render tau abnormally hyperphosphorylated in Alzheimer disease (AD) and other tauopathies. b | In addition to the missense mutations, several silent mutations have been found in FTDs. These silent mutations and some of the missense mutations affect the alternative splicing of MAPT pre-mRNA, giving rise to a change in the usual 1:1 3R:4R ratio. Both missense mutations and mutations that alter this ratio promote abnormal hyperphosphorylation of tau similar to that found in the absence of any mutations in AD. In the presence of compromised protein phosphatase 2A activity, as seen in AD, hyperphosphorylation could induce conformational changes similar to those induced by FTD-associated mutations in MAPT. 3R/4R, three/four microtubule-binding domain repeats.

  3. Tau as a primary and secondary cause of disease.
    Figure 3: Tau as a primary and secondary cause of disease.

    a | Familial frontotemporal dementia (FTD) is caused by missense or silent mutations. Missense mutations make tau a favourable substrate for abnormal hyperphosphorylation. Silent mutations and some missense mutations alter the splicing of MAPT pre-mRNA, thereby changing the 3R:4R tau ratio. A 3R:4R tau imbalance can increase levels of unbound tau — a preferred substrate for protein kinases. b | In sporadic tauopathies, a shift in protein kinase:protein phosphatase balance can result in tau hyperphosphorylation. Brain acidosis following ischaemia and hypoxia — for example, after hyperglycaemia in diabetes, or in chronic traumatic encephalopathy (CTE) or traumatic brain injury (TBI) — can lead to activation and translocation of asparaginyl endopeptidase (AEP) from neuronal lysosomes to the cytoplasm and nucleus. Activated AEP cleaves I2PP2A into I2NTF and I2CTF, both of which inhibit protein phosphatase 2A (PP2A) activity. Guam parkinsonism–dementia complex and sporadic Alzheimer disease (AD) can also be caused by environmental factors such as β-N-methylamino-l-alanine (BMAA). BMAA activates mGluR5, which dissociates the catalytic subunit of PP2A, PP2Ac, from the receptor. Free PP2Ac is phosphorylated by Src kinase, resulting in PP2A inhibition. 3R/4R, three/four microtubule-binding domain repeats; P-tau, hyperphosphorylated tau.

  4. Generation of tau seeds and spread of tau pathology.
    Figure 4: Generation of tau seeds and spread of tau pathology.

    Tau seeds are generated by an imbalance between the activities of tau protein kinases and phosphatases, resulting in sP-tau (P-tau seeds). The sP-tau is either released from a disintegrated tangle-bearing neuron or exocytosed from an affected cell. The sP-tau templates extracellular tau (e-tau). The seeds are either endocytosed in a random fashion by other neurons in the vicinity, or are trans-synaptically taken up by the connected neurons and/or the affected neuron undergoes retrograde degeneration that serves as a distress signal to the connecting neurons. The connecting neurons respond to distress by altering their own protein kinase and phosphatase signalling, which results in hyperphosphorylation of tau. sP-tau, abnormally hyperphosphorylated tau seeds.

  5. Key steps in AD neurofibrillary degeneration, and possible therapeutic approaches.
    Figure 5: Key steps in AD neurofibrillary degeneration, and possible therapeutic approaches.

    Abnormal hyperphosphorylation of tau is the common key step in neurofibrillary degeneration in Alzheimer disease (AD) and other tauopathies. Activity of PP2A, the main regulator of tau phosphorylation, is compromised, at least in AD, Down syndrome and Guam parkinsonism–dementia brains. Nevertheless, both inhibition of tau protein kinase and enhancement of protein phosphatase 2A (PP2A) activity are potential therapeutic approaches. Promotion of O-GlcNAcylation, which negatively regulates hyperphosphorylation of tau, is an alternative strategy. Sequestration of normal microtubule-associated proteins (MAPs) by hyperphosphorylated tau (P-tau) can be prevented by inhibiting tau hyperphosphorylation or neutralizing the binding with a compound. Microtubule-stabilizing compounds can have beneficial therapeutic effects by making stability of the microtubule network independent from tau. Tau pathology can be reduced by inhibiting tau hyperphosphorylation, dissociating tau aggregates, or tau immunization. Finally, pharmacological promotion of neuroregeneration by enhancing neurogenesis and neuronal plasticity has produced not only rescue of cognitive impairment but also reduction of both tau and amyloid-β pathologies in a transgenic mouse model of AD.


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  1. Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Inge Grundke-Iqbal Research Floor, 1050 Forest Hill Road, Staten Island, New York 10314, USA.

    • Khalid Iqbal,
    • Fei Liu &
    • Cheng-Xin Gong


All authors researched data for the article, made substantial contributions to discussions of the content, wrote the article, and reviewed and/or edited the manuscript before submission.

Competing interests statement

K.I. serves on the scientific advisory board of AXON Neuroscience, has received research grants from Ever NeuroPharma and Signum Biosciences, and holds several patents on treatment of Alzheimer disease and related conditions. C.-X.G. serves on the scientific advisory board of Alectos Therapeutics. F.L. declares no competing interests.

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  • Khalid Iqbal

    Khalid Iqbal is Professor and Chairman, Department of Neurochemistry at the New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, USA. His research findings include the bulk isolation of neurofibrillary tangles (NFTs) from Alzheimer disease (AD) brains, and discovery of abnormal hyperphosphorylation of tau (P-tau) and its aggregation as NFTs, templation of normal tau by AD P-tau in a prion-like manner, involvement of protein phosphatase-2A in tau pathology, and various subgroups and mechanisms of sporadic AD. His research group focuses on dissecting out mechanism of sporadic AD with special reference to neurofibrillary pathology, and studying the potential of neuroregeneration as a therapeutic approach to AD and related neurodegenerative conditions.

  • Fei Liu

    Fei Liu has focused on the study of tau pathogenesis in Alzheimer disease (AD) and related neurodegenerative disorders since the beginning of her postdoctoral training in 1999. Since 2011, she has been the Head of the Molecular Neuroscience Laboratory in the Department of Neurochemistry at the New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, USA. Her research group studies dysregulation of tau metabolism and tau pathogenesis in AD.

  • Cheng-Xin Gong

    Cheng-Xin Gong is the Head of Brain Metabolism Laboratory, New York State Institute for Basic Research in Developmental Disabilities, and an Adjunct Professor of the City University of New York, USA. He has been studying tau-mediated molecular mechanisms of neurodegeneration in Alzheimer disease (AD) since 1991. His current research interests include investigating the role of impaired brain insulin signalling and protein O-GlcNAcylation in AD neurodegeneration, and developing novel therapeutic strategies on the basis of these mechanisms.

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