Review

Authors: Jesus Avila, Jose J Lucas, Mar Perez...

The morphology of a neuron is determined by its cytoskeletal scaffolding. Thus proteins that associate with the principal cytoskeletal components such as the microtubules have a strong influence on both the morphology and physiology of neurons. Tau is a microtubule-associated protein that stabilizes neuronal microtubules under normal physiological conditions. However, in certain pathological situations, tau protein may undergo modifications, mainly through phosphorylation, that can result in the generation of aberrant aggregates that are toxic to neurons. This process occurs in a number of neurological disorders collectively known as tauopathies, the most commonly recognized of which is Alzheimer's disease. The purpose of this review is to define the role of tau protein under normal physiological conditions and to highlight the role of the protein in different tauopathies.

Topics: Animals; Disease Models, Animal; Humans; Microtubules; Neurons; Protein Processing, Post-Translational; Tauopathies; tau Proteins

PubMed: 15044677
DOI: 10.1152/physrev.00024.2003

Review

Authors: Denisa Floriana Vasilica Pîrşcoveanu, Ionica Pirici, Valerica Tudorică...

The study of rare, inherited forms of different diseases resulted in the discovery of gene defects that cause inherited variants of the respective diseases. The defective genes were found to encode major molecular players leading to the neuropathological lesions or factors that characterize these diseases. The exact role of the tau protein in the neurodegenerative process is still under debate. It is very important to understand the normal biological roles of tau and the specific events that induce tau to become neurotoxic. Tau is the major microtubule-associated protein (MAP) of a mature neuron. The other neuronal MAPs are MAP1 and MAP2. These three MAPs perform similar function, promoting assembly and stability of microtubules. Tau protein was isolated as a microtubule-associated factor in the porcine brain. It was isolated as a protein that co-purified with tubulin and had the ability to promote microtubule assembly in vitro. Normal adult human brain tau contains 2-3 moles phosphate÷mole of tau protein. Hyperphosphorylation of tau depress this biological activity of tau. Almost 80 diseases caused by missense mutations and intronic mutations in the tau gene have been found in familial cases of frontotemporal dementia (FTD). In Alzheimer's disease (AD), there are intraneuronal neurofibrillary tangles composed of the microtubule-associated protein tau (MAPT). In other neurodegenerative diseases, there are similar deposits of tau, in the absence of extracellular deposits (progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, etc.). Tau pathology is also often seen in some forms of Parkinson's disease (PD) and prion diseases. In genetic forms of FTD, mutations in tau implicate abnormal tau as the initiation of neurodegeneration. In FTD, there are deposits especially in temporal and frontal lobes, regions that are very important for behavior and executive function. It is critical to understand how tau becomes pathogenic, in order to consider developing any strategies for treatment.

Topics: Humans; Neurodegenerative Diseases; tau Proteins

PubMed: 29556602
DOI: No ID Found

Authors: Yang Shi, Wenjuan Zhang, Yang Yang...

The ordered assembly of tau protein into filaments characterizes several neurodegenerative diseases, which are called tauopathies. It was previously reported that, by cryo-electron microscopy, the structures of tau filaments from Alzheimer's disease, Pick's disease, chronic traumatic encephalopathy and corticobasal degeneration are distinct. Here we show that the structures of tau filaments from progressive supranuclear palsy (PSP) define a new three-layered fold. Moreover, the structures of tau filaments from globular glial tauopathy are similar to those from PSP. The tau filament fold of argyrophilic grain disease (AGD) differs, instead resembling the four-layered fold of corticobasal degeneration. The AGD fold is also observed in ageing-related tau astrogliopathy. Tau protofilament structures from inherited cases of mutations at positions +3 or +16 in intron 10 of MAPT (the microtubule-associated protein tau gene) are also identical to those from AGD, suggesting that relative overproduction of four-repeat tau can give rise to the AGD fold. Finally, the structures of tau filaments from cases of familial British dementia and familial Danish dementia are the same as those from cases of Alzheimer's disease and primary age-related tauopathy. These findings suggest a hierarchical classification of tauopathies on the basis of their filament folds, which complements clinical diagnosis and neuropathology and also allows the identification of new entities-as we show for a case diagnosed as PSP, but with filament structures that are intermediate between those of globular glial tauopathy and PSP.

Topics: Aged; Aged, 80 and over; Amino Acid Sequence; Cryoelectron Microscopy; Dementia; Denmark; Female; Humans; Introns; Male; Middle Aged; Models, Molecular; Mutation; Protein Folding; Protein Isoforms; Supranuclear Palsy, Progressive; Tauopathies; United Kingdom; tau Proteins

PubMed: 34588692
DOI: 10.1038/s41586-021-03911-7

Review

Authors: Huiting Zheng, Huimin Sun, Qixu Cai...

Tau protein misfolding and aggregation are pathological hallmarks of Alzheimer's disease and over twenty neurodegenerative disorders. However, the molecular mechanisms of tau aggregation in vivo remain incompletely understood. There are two types of tau aggregates in the brain: soluble aggregates (oligomers and protofibrils) and insoluble filaments (fibrils). Compared to filamentous aggregates, soluble aggregates are more toxic and exhibit prion-like transmission, providing seeds for templated misfolding. Curiously, in its native state, tau is a highly soluble, heat-stable protein that does not form fibrils by itself, not even when hyperphosphorylated. In vitro studies have found that negatively charged molecules such as heparin, RNA, or arachidonic acid are generally required to induce tau aggregation. Two recent breakthroughs have provided new insights into tau aggregation mechanisms. First, as an intrinsically disordered protein, tau is found to undergo liquid-liquid phase separation (LLPS) both in vitro and inside cells. Second, cryo-electron microscopy has revealed diverse fibrillar tau conformations associated with different neurodegenerative disorders. Nonetheless, only the fibrillar core is structurally resolved, and the remainder of the protein appears as a "fuzzy coat". From this review, it appears that further studies are required (1) to clarify the role of LLPS in tau aggregation; (2) to unveil the structural features of soluble tau aggregates; (3) to understand the involvement of fuzzy coat regions in oligomer and fibril formation.

Topics: tau Proteins; Humans; Protein Aggregation, Pathological; Animals; Alzheimer Disease; Protein Aggregates

PubMed: 38732197
DOI: 10.3390/ijms25094969

Review

Authors: Chanung Wang, David M Holtzman

As we age, we experience changes in our nighttime sleep and daytime wakefulness. Individuals afflicted with Alzheimer's disease (AD) can develop sleep problems even before memory and other cognitive deficits are reported. As the disease progresses and cognitive changes ensue, sleep disturbances become even more debilitating. Thus, it is imperative to gain a better understanding of the relationship between sleep and AD pathogenesis. We postulate a bidirectional relationship between sleep and the neuropathological hallmarks of AD; in particular, the accumulation of amyloid-β (Aβ) and tau. Our research group has shown that extracellular levels of both Aβ and tau fluctuate during the normal sleep-wake cycle. Disturbed sleep and increased wakefulness acutely lead to increased Aβ production and decreased Aβ clearance, whereas Aβ aggregation and deposition is enhanced by chronic increased wakefulness in animal models. Once Aβ accumulates, there is evidence in both mice and humans that this results in disturbed sleep. New findings from our group reveal that acute sleep deprivation increases levels of tau in mouse brain interstitial fluid (ISF) and human cerebrospinal fluid (CSF) and chronic sleep deprivation accelerates the spread of tau protein aggregates in neural networks. Finally, recent evidence also suggests that accumulation of tau aggregates in the brain correlates with decreased nonrapid eye movement (NREM) sleep slow wave activity. In this review, we first provide a brief overview of the AD and sleep literature and then highlight recent advances in the understanding of the relationship between sleep and AD pathogenesis. Importantly, the effects of the bidirectional relationship between the sleep-wake cycle and tau have not been previously discussed in other reviews on this topic. Lastly, we provide possible directions for future studies on the role of sleep in AD.

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; Humans; Sleep; Sleep Wake Disorders; tau Proteins

PubMed: 31408876
DOI: 10.1038/s41386-019-0478-5

Review

Authors: Kevin H Strang, Todd E Golde, Benoit I Giasson...

In multiple neurodegenerative diseases, including Alzheimer's disease (AD), a prominent pathological feature is the aberrant aggregation and inclusion formation of the microtubule-associated protein tau. Because of the pathological association, these disorders are often referred to as tauopathies. Mutations in the MAPT gene that encodes tau can cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), providing the clearest evidence that tauopathy plays a causal role in neurodegeneration. However, large gaps in our knowledge remain regarding how various FTDP-17-linked tau mutations promote tau aggregation and neurodegeneration, and, more generally, how the tauopathy is linked to neurodegeneration. Herein, we review what is known about how FTDP-17-linked pathogenic MAPT mutations cause disease, with a major focus on the prion-like properties of wild-type and mutant tau proteins. The hypothesized mechanisms by which mutations in the MAPT gene promote tauopathy are quite varied and may not provide definitive insights into how tauopathy arises in the absence of mutation. Further, differences in the ability of tau and mutant tau proteins to support prion-like propagation in various model systems raise questions about the generalizability of this mechanism in various tauopathies. Notably, understanding the mechanisms of tauopathy induction and spread and tau-induced neurodegeneration has important implications for tau-targeting therapeutics.

Topics: Animals; Humans; Microtubules; Mutation; Parkinsonian Disorders; Protein Aggregation, Pathological; Protein Processing, Post-Translational; Protein Splicing; Tauopathies; tau Proteins

PubMed: 30742061
DOI: 10.1038/s41374-019-0197-x

Review

Authors: Che-Wei Chang, Eric Shao, Lennart Mucke...

Several lines of evidence implicate the protein tau in the pathogenesis of multiple brain disorders, including Alzheimer's disease, other neurodegenerative conditions, autism, and epilepsy. Tau is abundant in neurons and interacts with microtubules, but its main functions in the brain remain to be defined. These functions may involve the regulation of signaling pathways relevant to diverse biological processes. Informative disease models have revealed a plethora of abnormal tau species and mechanisms that might contribute to neuronal dysfunction and loss, but the relative importance of their respective contributions is uncertain. This knowledge gap poses major obstacles to the development of truly impactful therapeutic strategies. The current expansion and intensification of efforts to translate mechanistic insights into tau-related therapeutics should address this issue and could deliver better treatments for a host of devastating conditions.

Topics: Animals; Brain; Brain Diseases; Humans; Microtubules; Neurons; Tauopathies; tau Proteins

PubMed: 33632820
DOI: 10.1126/science.abb8255

Authors: Eleanor Drummond, Geoffrey Pires, Claire MacMurray...

Accumulation of phosphorylated tau is a key pathological feature of Alzheimer's disease. Phosphorylated tau accumulation causes synaptic impairment, neuronal dysfunction and formation of neurofibrillary tangles. The pathological actions of phosphorylated tau are mediated by surrounding neuronal proteins; however, a comprehensive understanding of the proteins that phosphorylated tau interacts with in Alzheimer's disease is surprisingly limited. Therefore, the aim of this study was to determine the phosphorylated tau interactome. To this end, we used two complementary proteomics approaches: (i) quantitative proteomics was performed on neurofibrillary tangles microdissected from patients with advanced Alzheimer's disease; and (ii) affinity purification-mass spectrometry was used to identify which of these proteins specifically bound to phosphorylated tau. We identified 542 proteins in neurofibrillary tangles. This included the abundant detection of many proteins known to be present in neurofibrillary tangles such as tau, ubiquitin, neurofilament proteins and apolipoprotein E. Affinity purification-mass spectrometry confirmed that 75 proteins present in neurofibrillary tangles interacted with PHF1-immunoreactive phosphorylated tau. Twenty-nine of these proteins have been previously associated with phosphorylated tau, therefore validating our proteomic approach. More importantly, 34 proteins had previously been associated with total tau, but not yet linked directly to phosphorylated tau (e.g. synaptic protein VAMP2, vacuolar-ATPase subunit ATP6V0D1); therefore, we provide new evidence that they directly interact with phosphorylated tau in Alzheimer's disease. In addition, we also identified 12 novel proteins, not previously known to be physiologically or pathologically associated with tau (e.g. RNA binding protein HNRNPA1). Network analysis showed that the phosphorylated tau interactome was enriched in proteins involved in the protein ubiquitination pathway and phagosome maturation. Importantly, we were able to pinpoint specific proteins that phosphorylated tau interacts with in these pathways for the first time, therefore providing novel potential pathogenic mechanisms that can be explored in future studies. Combined, our results reveal new potential drug targets for the treatment of tauopathies and provide insight into how phosphorylated tau mediates its toxicity in Alzheimer's disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Chromatography, Liquid; Female; Humans; Male; Middle Aged; Phosphorylation; Proteomics; Tandem Mass Spectrometry; tau Proteins

PubMed: 32812023
DOI: 10.1093/brain/awaa223

Randomized Controlled Trial

Authors: Nicolas R Barthélemy, Haiyan Liu, William Lu...

Tau hyperphosphorylation is an early step in tau-mediated neurodegeneration and is associated with intracellular aggregation of tau as neurofibrillary tangles, neuronal and synaptic loss, and eventual cognitive dysfunction in Alzheimer disease. Sleep loss increases the cerebrospinal fluid concentration of amyloid-β and tau. Using mass spectrometry, we measured tau and phosphorylated tau concentrations in serial samples of cerebrospinal fluid collected from participants who were sleep-deprived, treated with sodium oxybate, or allowed to sleep normally. We found that sleep loss affected phosphorylated tau differently depending on the modified site. These findings suggest a mechanism for sleep loss to increase risk of Alzheimer disease. ANN NEUROL 2020;87:700-709.

Topics: Adult; Female; Humans; Male; Middle Aged; Phosphorylation; Sleep Deprivation; tau Proteins

PubMed: 32057125
DOI: 10.1002/ana.25702

Authors: Kanta Horie, Nicolas R Barthélemy, Chihiro Sato...

Tau is a microtubule associated protein in the brain that aggregates in Alzheimer's disease to form pathological tangles and neurites. Insoluble tau aggregates composed of the microtubule binding region (MTBR) of tau are highly associated with the cognitive and clinical symptoms of Alzheimer's disease. In contrast, levels of soluble forms of tau, such as CSF total tau and phosphorylated tau-181 and tau-217, increase prior to tau aggregation in Alzheimer's disease, but these biomarkers do not measure the MTBR of tau. Thus, how CSF MTBR-tau is altered in Alzheimer's disease remains unclear. In this study, we used sequential immunoprecipitation and chemical extraction methods followed by mass spectrometry to analyse MTBR-tau species in Alzheimer's disease and control CSF. We quantified MTBR-tau-specific regions in the CSF and identified that species containing the region beginning at residue 243 were the most highly correlated with tau PET and cognitive measures. This finding suggests that CSF level of tau species containing the upstream region of MTBR may reflect changes in tau pathology that occur in Alzheimer's disease and could serve as biomarkers to stage Alzheimer's disease and track the development of tau-directed therapeutics.

Topics: Aged; Alzheimer Disease; Binding Sites; Biomarkers; Brain; Cross-Sectional Studies; Female; Humans; Male; tau Proteins

PubMed: 33283854
DOI: 10.1093/brain/awaa373