Tau pathology: a marker of neurodegenerative disorders

Delacourte Andre and Luc Buee

Summary

Tau is not only a basic component of neurofibrillary degeneration, but also an etiological factor, as demonstrated by mutations on tau gene responsible for FTDP-17. Also, polymorphisms on tau gene and the hierarchical invasion of neocortical areas by tau pathology in numerous sporadic neurodegenerative diseases suggest that tau pathology is a primary pathogenic event in non-familial dementing diseases and a lead for solid diagnostic and therapeutic approaches.

I - Introduction

The characterization and classification of numerous neurodegenerative diseases have been dramatically improved following the discovery of molecular markers such as Ab, PrP, Tau, alpha-synuclein. These markers are the basic components of specific brain lesions, respectively amyloid plaques, prion plaques, tangles and Lewy bodies [1]. Tau pathology, or tauopathy, which are the molecular words for neurofibrillary degeneration, is a process affecting cortical and subcortical brain areas and is found among more than 20 different dementing disorders (table I). Recently, numerous familial tauopathies have been characterized. They have in common genetic defects on tau gene, but clinical and neuropathological phenotypes are extremely heterogeneous. Understanding the basic mechanisms of tau pathology will certainly bring new opportunities for the diagnosis and treatment of most dementing disorders.

II - Tau pathology as a marker of neurofibrillary degeneration (NFD)

Tau pathology corresponds to the intraneuronal aggregation of microtubule-associated tau proteins into abnormal filaments [2]. The normal role of tau is to stabilize microtubules, which are the tracks of the intraneuronal transport. There are six tau isoforms in the human brain that exhibit either three (3R) or four microtubule-binding domains (4R) (Fig. 1). The three tau isoforms with 4R are more efficient than 3R-tau isoforms to stabilize microtubules. Conversely, phosphorylation of tau destabilizes microtubules and it is suggested that abnormal phosphorylation, as observed in AD, provokes a collapse of the microtubule network. At the electron microscopic level, the filamentous material of NFD is either helical, twisted or straight, according to the neurodegenerative disorders (Table II) [3]. At the optical level, it accumulates in bundles to constitute the so-called neurofibrillary tangles, neuropile threads, dystrophic neurites of neuritic plaques and Pick bodies. Tau inclusions have different biochemical signatures that are disease-specific. They vary from a major triplet (60, 64, 69 kilodaltons) observed in Alzheimer's disease (AD), as revealed by western blots using phospho-dependent anti-tau antibodies (Class I), to an upper doublet in progressive supranuclear palsy (PSP) (tau 64, 69) and corticobasal degeneration (CBD) (Class II), a lower doublet tau 60, 64 in Pick's disease (Class III) and a major tau 60 band in myotonic dystrophy (Class IV) (table II) [4]. More than 20 different disorders are affected by tau pathology (Table 2). All of them with a neocortical involvement are characterized by cognitive impairment and generally dementia, as recently documented in PSP [5] and in AD ([6], [7], [8]). Conversely, there is no correlation between clinical symptoms and the biochemical signature. For instance, on one hand, British type cerebral angiopathy, is caused by a point mutation at the stop codon of BRI gene [9]. This disease is characterized by a Class I tau pathology [10]. On the other hand, numerous familial frontotemporal dementias including pallido-nigro-luysian degeneration, disinhibition-dementia-parkinsonism-amyotrophy complex, familial multiple system tauopathy, and progressive subcortical gliosis result from pathogenic mutations on tau, whose gene is on chromosome 17. These diseases are now gathered in the group of frontotemporal dementias with parkinsonism linked to chromosome 17 (FTDP-17) and display Class I, II or III tau pathologies, according to the location of the genetic defect on tau gene (see next section).

The natural history of Alzheimer's disease has also been investigated at the molecular level. Several groups have detailed the pathway of tau pathology spreading in the different brain areas, showing that it is sequential, progressive, invariable, hierarchical, predictable ([11], [8]). Generally, cognitive impairment is observed when association brain areas are affected by tau pathology. Surprisingly, in some non-demented cases, huge amounts of lesions can be found ([7], [8], [12]). These findings demonstrate that the degenerating process can be balanced for a while (several years?) by a powerful compensating effect. They suggest that cofactors of AD, such as vascular factors ([13]; [14], [15]), could weigh either on the pathology itself, or on the neuronal reservoir. Together, these observations could mean that neuroprotection can influence greatly the fate of AD, either by slowing down the pathology, and also by sustaining neuronal plasticity.

Since lesion antigens are overabundant at the infraclinical stage of AD, their detection in the CSF could help to set up an early biological diagnosis. The simultaneous significant increase of tau and decrease of Ab 1-42 levels in the CSF in AD is likely to be useful for the clinical diagnosis in the near future ([16].

III. Tau pathology as an etiological agent

Frontotemporal dementia with parkinsonism linked to chr.17 (FTDP-17)

The discovery that Tau mutations are directly involved in numerous FTDP-17 has been dramatically documented. More than 20 different mutations have been spotted. Familial diseases such as familial progressive subcortical gliosis also belong to the FTDP-17 group [2]. Most of the pathogenic mutations are responsible for an increase of 4R tau isoforms, giving a Class II tau pathology (see table 3). 4R tau isoforms, with the additional peptidic sequence of exon 10, have a much stronger affinity towards microtubules than 3R isoforms, and an excess could modify microtubule functions, which will be stiffer and less dynamic. The other mutations are missense mutations that affect also microtubule polymerization and stability by decreasing the tau-microtubule binding and they lead to one of the Class I, II, III tau pathologies (see table 3). The striking feature of these familial tauopathies is the heterogeneity of the phenotype, which results from the different effects on tau (overexpression, loss of function). Early parkinsonism and stronger involvement of the substantia nigra are confined to mutations affecting the 3R to 4R tau isoforms ratio [17]. Indeed, for the same mutation in the same family, different onset and different phenotypes can be observed (table 3), showing that numerous additional factors can bring more heterogeneity to the phenotype.

Also, we note that the neuropathological profile in FTDP-17 is quite different from AD, with a special involvement of astrocytes and cortical white matter, but also with an important heterogeneity for each mutation. Interestingly, but surprisingly, different groups have reported that numerous amyloid deposits were found in the brain of some FTDP-17 young patients [18] , [19]. This is really puzzling and deserves more investigations.

However, not all diseases with a tau pathology have mutations on tau gene. This has been verified for CBD, PSP [20], [21], amyotrophic lateral sclerosis/parkinsonism dementia complex of Guam [22], and AD [23].

Polymorphisms in PSP

Conrad and colleagues identified a polymorphic dinucleotide repeat sequence in a Caucasian population with PSP [24]. This polymorphism, named A0, corresponding to a 11 TG dinucleotide repeat in the intron 9 of tau gene, is found in 95% of the PSP cohort (95.5%), and only in 57 % of normal controls and 50% of patients with AD. Recently, these data were confirmed by several studies and extended to a haplotype including a number of polymorphisms in linkage disequilibrium with A0 and, named H1. This haplotype corresponds to A0 polymorphism, numerous single nucleotide polymorphisms along the entire tau gene and one intronic 238bp deletion flanking exon 10 ([25], [26], [27]; [20]; [28]; [29]; [30]; [31], [32]. These polymorphisms may influence the exon 10 splicing and thus the proportion of 4R/3R tau isoforms, leading to a Class II tau pathology (Hutton et al., 2000 (Ann NY Acad Sci, in press)). It should be noted that these A0 pomlymorphism or H1 haplotype were recently described in other pathologies including CBD and ParkinsonOs disease [33]; [34]). Some other polymorphisms in the tau gene were also described as being associated with risk for AD ([35]; [36]) but these data are still controversial [37].

"Sporadic" AD

Non-autosomic dominant AD represents 99,7% of all AD cases [38]. The first risk factor for "sporadic" AD is age. Genetic risk factors are also important, such as epsilon 4 alleles of apolipoprotein E [38]. It is interesting to note that there is an important and systematic vulnerability of the hippocampal region to tau pathology in aging. Indeed, aggregated tau proteins are always detected in the hippocampal region at the age of 75 years [7], sometimes independently of amyloid deposits [8]. This hippocampal vulnerability is likely a springboard for Alzheimer pathology, namely APP dysfunction, which will exacerbate and extend tau pathology in other brain areas [11], [39]. Together, neuropathological and biochemical data concur to indicate that tau pathology is instrumental in AD. In that respect, it should be pointed out that recent criteria for the neuropathological diagnosis have rehabilitated tau pathology [40], in good agreement with Alo?oes Alzheimer observations and the natural history of AD.

The spreading of tau pathology is also an important feature of other diseases, such as PSP and CBD, but the pathway is different, from subcortical to neocortical, mainly frontal and hippocampal areas [5], [41]. For all tauopathies, either sporadic or familial, the spreading of neurofibrillary degeneration along specific neuronal populations likely relies on factors such as neuronal vulnerability and trophic factors. The characteristics of neuronal populations, and their vulnerability, could be driven in part by the specific sets of tau isoforms that they express. Analyzing the factors that fuel the dynamic of tauopathy spreading in cortical areas will certainly give clues for neuroprotection [39].

IV - Conclusion

Tau pathology is an event occurring in all human brains, at least in the hippocampal region, and systematically after 75 years old. Tau pathology is also observed in many dementing disorders. Some of them, such as AD, have a high prevalence. Tau gene defects are responsible for FTDP-17 and tau gene also displays numerous polymorphisms that may contribute to the development of neurofibrillary degeneration. Therefore, and logically, the interest for tau pathology has increased dramatically these last years. At the present time, we need relevant experimental models to understand this many-sided degenerating process. Tau transgenic mice are already on the bench. Surprisingly, transgenic mice with mutated APP gene, generating a load of Ab 20 fold what is found in the human brain, are reluctant to develop an extensive tau pathology. The explanation could be that the regulation of tau is more complex in the human brain [42], and that age is an important factor (the main risk factor in AD) which cannot be used optimally with short-lived animals.

Table I

Presentation of the different neurodegenerative disorders with a tau pathology, and their different biochemical tau signatures, from Class I to Class IV.

Disease Classes of tau pathology

Aging (hippocampal region, patients over 75 years)         class I

AlzheimerOs disease, familial and sporadic                 class I

Amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam                  class I

Argyrophilic grain dementia

British type amyloid angiopathy                  class I

Corticobasal degeneration                  class II

Dementia pugilistica/autism with self-injury behaviour                  class I

DownOs syndrome                  class I

FTDP-17             classes II, I and III

Gerstmann-Straussler-Scheinker disease (Indiana kindred)                  class I

Hallenvorden-Spatz disease

Inclusion body myositis

Multiple system atrophy

Myotonic dystrophy                  class IV

Niemann-Pick disease type C                  class I

PickOs disease                  class III

Presenile dementia with tangles and calcifications

Prion protein cerebral amyloid angiopathy

Progressive supranuclear palsy                  class II

Post-encephalitic parkinsonism                  class I

Subacute sclerosing panencephalitis

Tangle only dementia

Table II, III

Presentation of the different characteristics of diseases with tauopathies.

The content in tau isoforms found in the different types of tau lesions is indicated. The different profiles of pathological tau observed in Alzheimer's disease (AD) (Class I), in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) (Class II), in Pick's disease (PiD) (Class III) and in myotrophic dystrophy (MyoD) (Class IV) are represented.

The shape of pathological filaments at the electron microscopic level (E.M) are paired helical filaments (PHF), twisted filaments (TF), straight filaments (SF) or random coiled filaments (RCF).

Inclusions at the optical level are neurofibrillary tangles (NFT), neuritic plaques (NP) or Pick bodies.

Cells affected are neurones (N) or glial cells (G) sometimes more specifically found in neocortical layers II, III, V.

N/A: data not available

DDPAC: disinhibition-dementia-parkinsonism-amyotrophy complex; FPDT : Familial form of presenile dementia; HFTD: hereditary fronto-temporal dementia; MSTD: Multiple system tauopathy with presenile dementia; PPND: Pallido-ponto-nigral degeneration; PSG-1: progressive subcortical gliosis.

TABLE II

See figure on biochemical tau signatures

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