Alzheimer tauopathy

The biochemical parameters of tau pathology

Introduction: Tau is an outstanding biochemical marker of neurofibrillary degeneration (NFD), well correlated with clinical manifestations. Tau pathology concerns many familial or sporadic neurodegenerative disorders, such as Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease (PiD), FTDP-17, myotonic dystrophy (MyoD), and many other diseases. Molecular parameters of Tau pathology help to understand the involvement of tau in the physiopathology of these diseases and to set up diagnoses and therapeutic strategies.

Six main features define tau pathology:

1) the quantitative aspects, using western blots ;
2) the different biochemical signatures observed in AD, PSP, CBD, PiD, MyoD (one to four immunodetected electrophoretic bands);
3) the specific tau isoforms content of brain lesions. Indeed, "disease-specific" sets of tau isoforms aggregate to constitute 4 main categories of tau lesions: class 1: AD (all 6 isoforms), class 2: PSP/CBD (3 Exon10+ isoforms), class 3: PiD (3 Exon10- isoforms) and class 4: MyoD (mainly and sometimes exclusively the shortest tau isoform);
4) the different states of phosphorylation of tau, with hyper and abnormal phosphorylation, as well as disease-specific sites of phosphorylation (ex: ser262);
5) the spatiotemporal progression of tau pathology, which is extremely well correlated with cognitive impairment;
6) the genetic aspects, with pathogenic tau mutations in FTDP-17 or characteristic polymorphisms in PSP.

These results emphasize two important physiopathological points:

A) neuronal populations are likely distinguished by the expression of different sets of tau isoforms. A dysregulation in the expression could generate vulnerability and neurodegeneration

B) there is a "dynamic process" that fuels the precise, sequential and hierarchical spreading of tau pathology in brain areas, along corticocortical projections. This process should be a target for neuroprotection.

Together, tau pathology is a many-sided degenerating process that will open diagnostic and therapeutic avenues.

References

The different diseases with a tau pathology

Aging (hippocampal region, 100% > 75y)

Alzheimer's disease (familial, sporadic)

Amyotrophic lateral sclerosis/PD complex of Guam

Argyrophilic grain dementia

British type amyloid angiopathy

Corticobasal degeneration

Dementia pugilistica/autism with self-injury behaviour

DownOs syndrome

FTDP-17

Gerstmann-Straussler-Scheinker disease (rarely)

Hallenvorden-Spatz disease

Inclusion body myositis

Multisystem atophy

Myotonic dystrophy

Niemann-Pick disease type C

Parkinson with dementia of Guadeloupe

Pick's disease

Presenile dementia with tangles and calcifications

Prion protein cerebral amyloid angiopathy

Progressive supranuclear palsy

Post-encephalitic parkinsonism

Subacute sclerosing panencephalitis

Tangle only dementia

Six main features define tau pathology:

1) the quantitative aspects, using western blots ;
2) the different biochemical signatures observed in AD, PSP, CBD, PiD, MyoD
3) the specific tau isoforms content of brain lesions.
4) the different states of phosphorylation of tau, with hyper and abnormal phosphorylation, as well as disease-specific sites of phosphorylation
5) the spatiotemporal progression of tau pathology, which is extremely well correlated with cognitive impairment;
6) the genetic aspects, with pathogenic tau mutations in FTDP-17 or characteristic polymorphisms in PSP.

References

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