EXECUTIVE SUMMARY

The microtubule associated protein Tau

• alternative splicing and posttranslational modifications leads to multiple Tau isoforms

• Tau proteins have major functions in the CNS in axonal transport and possibly in signal transduction

• Tau phosphorylation modulates its activity in the CNS

Tau alterations in neurodegenerative diseases

• MAPT mutations are responsible of rare forms of dementia

• MAPT polymorphims are associated with some dementia like PSP, CBD, PD or AD

• Altered MAPT splicing is observed in genetic forms of dementia and in sporadic Tauopathies. The consequently imbalance of Tau isoforms could be responsible of neuron dysfunction.

• Tau aggregation is a major feature of a class of dementia named Tauopathies.

• Altered Tau conformation is observed in Tauopathies

• Tau abnormal hyperphosphorylation is a main stigmat observed in Tauopathies.

• Loss of Tau protein expression is observed in some types of FTDs.

• Tau protein cleavage is observed in the brain of patients with Tauopathies.

Tau proteins as biomarkers of brain pathology

Immunohistology of Tau inclusions and electrophoretic analysis of Tau aggregates allows a classification of Tauopathies usefull for post-mortem differential diagnosis.

Tau proteins as peripheral biomarkers of neurodegenerative diseases

• CSF total Tau levels has a clear diagnostic value for AD but is insufficient for differential dementia diagnosis

• CSF phospho-Tau levels have an improved diagnostic value for AD compared to total Tau levels and a potential for differential diagnosis depending on phosphorylation sites.

• ApoE has no effect on CSF-tTau and pTau. Kinesin polymorphism is associated with high CSF-pTau levels.

• CSF-pTau levels are altered very early during the disease course of AD and are therefore useful predictive biomarkers.

• CSF-tTau levels has a diagnostic value in AD and CJD and a prognostic value in transient acute neuronal damage syndroms.

• The combination of CSF Tau levels together or with other biomarkers increases sensitivity and specificity of diagnosis.

• Stable levels of CSF tTau and pTau are potentially useful for monitoring novel therapeutic assays.

• The new identified multiple fragments of Tau in brain and CSF are promising candidates for differential diagnosis of Tauopathies.