Tau protein in familial and sporadic diseases

Abnormal protein aggregation is a common characteristic of many neurodegenerative diseases of the brain. Filamentous deposits made of the microtubule-associated protein tau constitute a major defining characteristic of several neurodegenerative diseases known as tauopathies. The role of tau in neurodegeneration has been clarified by the identification of genetic mutations in the tau gene in cases with familial frontotemporal dementia and parkinsonism linked to chromosome 17. Furthermore, some sporadic tauopathies are associated with tau gene polymorphisms. Although it is still debated how tau gene mutations lead to neuronal death, it is clear that different mutations lead to tau pathologies with characteristics similar to those found in sporadic tauopathies. These findings have definitely shown that in tauopathies tau aggregation is directly associated with development of neurodegeneration and neuronal death.     

Frontotemporal dementia with tau pathology

Tau is a microtubule-associated protein involved in microtubule assembly and stabilization. Filamentous deposits made of tau constitute a major defining characteristic of several neurodegenerative diseases known as tauopathies including Alzheimer's disease. The involvement of tau in neurodegeneration has been clarified by the identification of genetic mutations in the tau gene in cases with familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Although the mechanism through which tau mutations lead to neuronal death is still unresolved, it is clear that tau mutations lead to formation of tau filaments that have a different morphology, contain different types of tau isoforms and produce distinct tau deposits. The range of tau pathology identified in FTDP-17 recapitulates the tau pathology present in sporadic tauopathies and indicates that tau dysfunction plays a major role also in these diseases.     

Tau,where are we now?

Tau is a multifunctional protein that was originally identified as a microtubule-associated protein. Tau is primarily a neuronal protein, but it is becoming increasingly evident that tau is present in non-neuronal cells where it also plays important roles. Tau is the primary protein component of the filaments (both paired helical and straight filaments) found in Alzheimer's disease brain. Further there is an ever growing family of neurodegenerative diseases called "tauopathies" where tau pathology is the primary, defining characteristic with little or no Abeta pathology. These findings, along with the fact that mutations in the tau gene cause a group of diseases collectively known as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), clearly demonstrate that tau dysfunction results in neuronal dysfunction and death. This review highlights recent findings concerning the normal metabolism and function of tau, as well as the abnormal processing and function of tau in Alzheimer's disease and in the tauopathies, both sporadic and familial.     

Frontotemporal dementia and tauopathy

The presence of abundant neurofibrillary lesions made of hyperphosphorylated tau proteins is the characteristic neuropathology of a subset of neurodegenerative disorders classified as "tauopathies." The discovery of mutations in the tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) constitutes convincing evidence that tau proteins play a key role in the pathogenesis of neurodegenerative disorders. Moreover, it now is known that the most common form of sporadic frontotemporal dementia (FTD), which is characterized by frontotemporal neuron loss, gliosis, and microvacuolar change, also is a tauopathy caused by a loss of tau protein expression. Thus, these discoveries have begun to change the classification and the neuropathologic diagnosis of FTD and tauopathies, as well as current understanding of the disease mechanisms underlying them. Although transgenic mice expressing wild-type human tau or variants thereof with an FTDP-17 mutation result in tau pathologies and brain degeneration similar to that seen in human tauopathies, the precise mechanisms leading to the onset and progression of neurodegenerative disorders remain incompletely understood. Here, we review current understanding of human neurodegenerative tauopathies and prospects for translative recent insights about these into therapeutic interventions to prevent or ameliorate them.     

Frontotemporal lobar degeneration – tau as a pied piper?

Frontotemporal lobar degeneration (FTLD) is the second most-common form of cortical dementia in the presenium after Alzheimer disease. Clinically three disease entities can be distinguished: frontotemporal dementia, semantic dementia, and primary progressive aphasia. The underlying neuropathology can be classified into disorders with tau pathology (including Pick disease, corticobasal degeneration, progressive supranuclear palsy, and familial frontotemporal dementia with parkinsonism linked to chromosome 17 – FTDP-17), and into disorders that lack tau abnormalities (including dementia lacking distinctive histology and motor neuron disease inclusion dementia). The recent discovery of tau gene mutations in FTDP-17 brought tau to the center stage, but led to the erroneous trend of collectively grouping all forms of FTLD as tauopathies. However, clinicopathological and genetic studies strongly suggest that the majority of sporadic and familial FTLD cases are not associated with tau pathology and/or tau gene mutations. Furthermore, recent studies have linked several autosomal dominantly inherited familial frontotemporal dementia cases to a variety of gene loci on different chromosomes. Thus, this review is intended to summarize our current knowledge about the sporadic and familial FTLD disorders that lack tau pathology, and shall further strengthen the view that FTLD is heterogeneous, both in terms of clinicopathological phenotypes as well as genetic backgrounds. Electronic Publication     

Chronic lithium treatment decreases mutant tau protein aggregation in a transgenic mouse model

Tau protein hyperphosphorylation and aggregation into neurofibrillary tangles are characteristic features of several neurodegenerative disorders referred to as tauopathies. Among them, frontotemporal dementia and Parkinsonism linked to chromosome 17 may be caused by dominant missense mutations in the tau gene. Transgenic mice expressing mutant tau serve as valid model systems to study the ethiopathogenesis of these diseases and assay possible therapeutic interventions. Here we report that chronic lithium treatment of a transgenic mouse strain expressing human tau with three missense mutations results in decreased glycogen synthase kinase-3-dependent-tau phosphorylation and a reduction of filamentous aggregates. These data indicate that lithium, presumably acting through the inhibition of glycogen synthase kinase 3, may be useful to curb neurodegeneration in tauopathies.     

Tau and tauopathies

Tau protein is a neuronal microtubule-associated protein (MAP), which localizes primarily in the axon. It is one of the major and most widely distributed MAPs in the central nervous system. Its biochemistry and molecular pathology is being increasingly studied. Tau is a key component of neurofbrillary tangles in Alzheimer's disease (AD). Disorders with neuronal, oligodendroglial or astrocytic filamentous tau inclusions are now grouped under the common rubric of tauopathies. The discovery of mutations in the tau gene, located on Chromosome 17 and its relationship to frontotemporal dementia with Parkinsonism (FTDP-17) has enhanced the importance of tau protein in cognitive neurology. Aberrant aggregates of tau have been documented in most of the neurodegenerative diseases with filamentous inclusions. The role of cerebrospinal fluid tau in the diagnosis of dementias is being investigated quite extensively. Recently, it has been shown that Abeta immunotherapy leads to the clearance of early tau pathology. It is becoming clearer that understanding tau better will lead to better understanding of many neurodegenerative diseases that may help develop interventional strategies.     

REVIEW: tau protein pathology in Alzheimer's disease and related disorders

Abundant neurofibrillary lesions made of hyperphosphorylated microtubule-associated protein tau constitute one of the defining neuropathological features of Alzheimer's disease. However, tau containing filamentous inclusions in neurones and/or glial cells also define a number of other neurodegenerative disorders clinically characterized by dementia and/or motor syndromes. All these disorders, therefore, are grouped under the generic term of tauopathies. In the first part of this review we outline the morphological and biochemical features of some major tauopathies, e. g. Alzheimer's disease, argyrophilic grain disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration. The impact of the recent finding of tau gene mutations in familial frontotemporal dementia and parkinsonism linked to chromosome 17 on other tauopathies is discussed in the second part. The review closes with a look towards a new understanding of neurodegenerative disorders characterized by filamentous nerve cell inclusions. The recent identification of the major protein component of their respective inclusions led to a surprising convergence of seemingly unrelated disorders. The new findings now allow us to classify neurodegenerative disorders with filamentous nerve cell inclusions into four main categories: (i) the tauopathies; (ii) the alpha-synucleinopathies; (iii) the polyglutamine disorders; and (iv) the iquitin disorders'. Within the proposed classification scheme, tauopathies constitute the most frequent type of disorder.     

Frequency of tau mutations in familial and sporadic frontotemporal dementia and other tauopathies

Abstract. Tau gene mutations with insoluble Tau neuropathology have been identified in pedigrees with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Other neurodegenerative diseases, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), are also characterised by insoluble Tau neuropathology. This study sought to determine the nature and frequency of tau gene mutations in an affected proband cohort of patients within this spectrum of neurodegenerative diseases. Sixty-four individuals with clinical features consistent with FTD and other tauopathies were referred over a three year period. There was neuropathological confirmation of disease in 30%. Individuals were screened for mutations in the coding region and flanking intronic regions of the tau gene by direct sequencing of PCR products. Four confirmed tau gene mutations were identified representing 6.3 % for the total affected proband cohort. Tau gene mutations were found in three of twelve (25%) of the cases with a family history of dominantly inherited frontotemporal dementia, but in only one of 25 cases without a family history (4 %). Although tauopathies have been considered to result from genetic defects, screening for tau gene mutations in sporadic cases is not likely to identify pathogenic mutations.     

Tau-based treatment strategies in neurodegenerative diseases

Neurofibrillary tangles are a characteristic hallmark of Alzheimer’s and other neurodegenerative diseases, such as Pick’s disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). These diseases are summarized as tauopathies, because neurofibrillary tangles are composed of intracellular aggregates of the microtubule-associated protein tau. The molecular mechanisms of tau-mediated neurotoxicity are not well understood; however, pathologic hyperphosphorylation and aggregation of tau play a central role in neurodegeneration and neuronal dysfunction. The present review, therefore, focuses on therapeutic approaches that aim to inhibit tau phosphorylation and aggregation or to dissolve preexisting tau aggregates. Further experimental therapy strategies include the enhancement of tau clearance by activation of proteolytic, proteasomal, or autophagosomal degradation pathways or anti-tau directed immunotherapy. Hyperphosphorylated tau does not bind microtubules, leading to microtubule instability and transport impairment. Pharmacological stabilization of microtubule networks might counteract this effect. In several tauopathies there is a shift toward four-repeat tau isoforms, and interference with the splicing machinery to decrease four-repeat splicing might be another therapeutic option.     

Tau pathology in a family with dementia and a P301L mutation in tau

Familial forms of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) have recently been associated with coding region and intronic mutations in the tau gene. Here we report our findings on 2 affected siblings from a family with early-onset dementia, characterized by extensive tau pathology and a Pro to Leu mutation at codon 301 of tau. The proband, a 55-year-old woman, and her 63-year-old brother died after a progressive dementing illness clinically diagnosed as Alzheimer disease. Their mother, 2 sisters, maternal aunt and uncle, and several cousins were also affected. Autopsy in both cases revealed frontotemporal atrophy and degeneration of basal ganglia and substantia nigra. Sequencing of exon 10 of the tau gene revealed a C to T transition at codon 301, resulting in a Pro to Leu substitution. Widespread neuronal and glial inclusions, neuropil threads, and astrocytic plaques similar to those seen in corticobasal degeneration were labeled with a battery of antibodies to phosphorylation-dependent and phosphorylation-independent epitopes spanning the entire tau sequence. Isolated tau filaments had the morphology of narrow twisted ribbons. Sarkosyl-insoluble tau exhibited 2 major bands of 64 and 68 kDa and a minor 72 kDa band, similar to the pattern seen in a familial tauopathy associated with an intronic tau mutation. These pathological tau bands predominantly contained the subset of tau isoforms with 4 microtubule-binding repeats selectively affected by the P301L missense mutation. Our findings emphasize the phenotypic and genetic heterogeneity of tauopathies and highlight intriguing links between FTDP-17 and other neurodegenerative diseases.     

Animal models of tauopathies]

Accumulation of intraneuronal amyloid comprised of tau proteins occurs in a group of neurodegenerative disorders, collectively termed tauopathies, and pathological alterations of tau proteins alone are sufficient to cause degeneration of neurons, as compellingly evidenced by discovery of tau gene mutations in kindreds of familial tauopathy known as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Mice modeling tauopathies have been generated by overexpression of human tau with FTDP-17 mutations, in order to gain more profound insights into molecular links between tau abnormalities and neurodegeneration. A subset of these mice were reported to exhibit abundant tau amyloid lesions resembling neurofibrillary changes in human tauopathies, and pronounced neuronal loss notable as progressive brain atrophy. Significantly, formation of mature amyloid fibrils is not tightly associated with neuron death, while deposition of microtubule-unbound phosphorylated tau, which conceivably emerges early in tau fibrillogenesis, appears to critically contribute to disruption of neuronal integrity. In addition to such mechanistic elucidation, mouse models of tauopathies are currently being applied to exploitation of imaging agents for visualization of tau pathologies in living brains. This technology would greatly facilitate diagnostic workup of patients with suspected tauopathies when combined with appropriate imaging modalities.     

Prion-like Spreading in Tauopathies

Tau is a microtubule-associated protein that functions in regulating cytoskeleton dynamics, especially in neurons. Misfolded and aggregated forms of tau produce pathological structures in a number of neurodegenerative diseases, including Alzheimer’s disease (AD) and tauopathy dementias. These disorders can present with a sporadic etiology, such as in AD, or a familial etiology, such as in some cases of frontotemporal dementia with parkinsonism. Notably, the pathological features of tau pathology in these diseases can be very distinct. For example, the tau pathology in corticobasal degeneration is distinct from that of an AD patient. A wealth of evidence has emerged within the last decade to suggest that the misfolded tau in tauopathies possesses prion-like features and that such features may explain the diverse characteristics of tauopathies. The prion-like concept for tauopathies arose initially from the observation that the progressive accumulation of tau pathology as the symptoms of AD progress seemed to follow anatomically linked pathways. Subsequent studies in cell and animal models revealed that misfolded tau can propagate from cell to cell and from region to region in the brain through direct neuroanatomical connections. Studies in these cell and mouse models have demonstrated that experimentally propagated forms of misfolded tau can exist as conformationally distinct “strains” with unique biochemical, morphological, and neuropathological characteristics. This review discusses the clinical, pathological, and genetic diversity of tauopathies and the discoveries underlying the emerging view that the unique features of clinically distinct tauopathies may be a reflection of the strain of misfolded tau that propagates in each disease.     

Tau and MAPT genetics in tauopathies and synucleinopathies

MAPT encodes the microtubule-associated protein tau, which is the main component of neurofibrillary tangles (NFTs) and found in other protein aggregates. These aggregates are among the pathological hallmarks of primary tauopathies such as frontotemporal dementia (FTD). Abnormal tau can also be observed in secondary tauopathies such as Alzheimer's disease (AD) and synucleinopathies such as Parkinson's disease (PD). On top of pathological findings, genetic data also links MAPT to these disorders. MAPT variations are a cause or risk factors for many tauopathies and synucleinopathies and are associated with certain clinical and pathological features in affected individuals. In addition to clinical, pathological, and genetic overlap, evidence also suggests that tau and alpha-synuclein may interact on the molecular level, and thus might collaborate in the neurodegenerative process. Understanding the role of MAPT variations in tauopathies and synucleinopathies is therefore essential to elucidate the role of tau in the pathogenesis and phenotype of those disorders, and ultimately to develop targeted therapies. In this review, we describe the role of MAPT genetic variations in tauopathies and synucleinopathies, several genotype-phenotype and pathological features, and discuss their implications for the classification and treatment of those disorders.     

Tau alternative splicing and frontotemporal dementia

A number of neurodegenerative diseases are characterized by the presence of abundant deposits containing Tau protein. Expression of the human tau gene is under complex regulation. Mutations in the tau gene have been identified in patients with frontotemporal lobe dementia. These mutations affect either biochemical/biophysical properties or the delicate balance of different splicing isoforms. In this review, we summarize recent advances in our understanding of genetics and molecular pathogenesis of tauopathies with the focus on frontotemporal lobe dementia. We review published studies on tau pre-mRNA splicing regulation. Understanding molecular mechanisms of tauopathies may help in developing effective therapies for neurodegenerative tauopathies and related disorders, including Alzheimer disease.     

Mutations in MAPT give rise to aneuploidy in animal models of tauopathy

Tau is a major microtubule-associated protein in brain neurons. Its misfolding and accumulation cause neurodegenerative diseases characterized by brain atrophy and dementia, named tauopathies. Genetic forms are caused by mutations of microtubule-associated protein tau gene (MAPT). Tau is expressed also in nonneural tissues such as lymphocytes. Tau has been recently recognized as a multifunctional protein, and in particular, some findings supported a role in genome stability. In fact, peripheral cells of patients affected by frontotemporal dementia carrying different MAPT mutations showed structural and numerical chromosome aberrations. The aim of this study was to assess chromosome stability in peripheral cell from two animal models of genetic tauopathy, JNPL3 and PS19 mouse strains expressing the human tau carrying the P301L and P301S mutations, respectively, to confirm the previous data on humans. After demonstrating the presence of mutated tau in spleen, we performed standard cytogenetic analysis of splenic lymphocytes from homozygous and hemizygous JNPL3, hemizygous PS19, and relevant controls. Losses and gains of chromosomes (aneuploidy) were evaluated. We detected a significantly higher level of aneuploidy in JNPL3 and PS19 than in control mice. Moreover, in JNPL3, the aneuploidy was higher in homozygotes than in hemizygotes, demonstrating a gene dose effect, which appeared also to be age independent. Our results show that mutated tau is associated with chromosome instability. It is conceivable to hypothesize that in genetic tauopathies the aneuploidy may be present also in central nervous system, possibly contributing to neurodegeneration.     

New developments in frontotemporal dementia and parkinsonism linked to chromosome 17

PURPOSE OF REVIEW: The identification of tau mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has revealed invaluable information regarding the role of the tau protein in neurodegenerative disease. Over the past year several new mutations have been identified, and experimental studies have provided further insight into the mechanism of neurodegeneration due to tau mutations and possible interactions with amyloid pathology. RECENT FINDINGS: Extensive clinical and pathological variation is seen in patients with different types of mutation, as well as in patients with the same mutation. Mutations may be found in patients with frontotemporal dementia (FTD), parkinsonism, progressive supranuclear palsy and corticobasal degeneration, justifying mutation analysis in familial cases of these disorders. Genetic heterogeneity exists in frontotemporal dementia, because a number of FTDP-17 families have neither tau mutations nor tau pathology. Genetic linkage has been found in familial FTD (chromosome 3), FTD with amyotrophic lateral sclerosis (9q21-q22), and FTD with inclusion body myopathy (9q13.3-p12). Tau deposits may consist of mainly mutated protein, or of mutated and wild-type protein in equal amounts, depending on the mutation. Recent animal studies show that amyloid-beta deposition may accelerate formation of neurofibrillary tangles. SUMMARY: Hopefully, the identification of responsible genetic defects and associated proteins will be helpful in improving our understanding of the role of the tau protein in the common neurodegenerative process of frontotemporal degeneration.     

Evidence that non-fibrillar tau causes pathology linked to neurodegeneration and behavioral impairments

The discovery that mutations within the tau gene lead to frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) provided direct evidence that tau alterations can lead to neurodegenerative disease. While the presence of tau fibrils and tangles is a common feature of all tauopathies, including Alzheimer's disease (AD), data are emerging from biochemical, cell-based and transgenic mouse studies which suggest that a pre-fibrillar form of pathological tau may play a key role in eliciting central nervous system neurodegeneration and behavioral impairments. Herein we review recent findings that implicate diffusible tau pathology in the onset of neurodegeneration, and discuss the implications of these findings as they relate to tau tangles and possible therapeutic strategies for the treatment of AD and related tauopathies.     

Decrease of the immunophilin FKBP52 accumulation in human brains of Alzheimer's disease and FTDP-17

Human neurodegenerative diseases characterized by abnormal intraneuronal inclusions of the tau protein, or "tauopathies", include Alzheimer's disease (AD), Pick's disease, progressive supranuclear palsy, corticobasal degeneration as well as fronto-temporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Several abnormalities of tau may contribute to the pathological processes, yet the mechanisms involved in tau cellular toxicity remain unclear. Previously, we demonstrated an interaction between various isoforms of tau and the immunophilin FKBP52 (FK506-Binding Protein), suggesting a direct involvement of FKBP52 in tau function. Here we analyze the expression of FKBP52 in human brains of patients with different tauopathies, including AD. Immunohistofluorescence studies carried out on cerebral cortex in different tauopathies reveal that FKBP52 is not sequestered by filamentous tau inclusions while FKBP52 is colocalized with tau in the control case brains. We found that FKBP52 expression level is abnormally low in frontal cortex of AD and FTDP-17 brains, as compared to controls, despite no alteration in the FKBP52 mRNA expression level. The possible involvement of FKBP52 in pathological tau expression/function is discussed.