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tauopathies

Friday 17 October 2003

Definition: The ‘tauopathies’ or ’taupathies’ are a group of neurodegenerative disorders characterized by the presence of filamentous deposits, consisting of hyperphosphorylated tau protein, in neurons and glia. Abnormal tau phosphorylation and deposition in neurones and glial cells is one of the major features in taupathies.

The term tauopathy, which was first used to describe a family with frontotemporal dementia (FTD) and abundant tau deposits (Spillantini et al., 1997), is now used to identify a group of diseases with widespread tau pathology in which tau accumulation appears to be directly
associated with neuronal death and disease development.

Major neurodegenerative tauopathies includes sporadic and hereditary neurodegenerative diseases characterized by filamentous tau deposits in brain and spinal cord.

In prototypical tauopathies, glial and neuronal tau inclusions are the sole or predominant CNS lesions. They includes

- amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS-FTDP)
- argyrophilic grain dementia
- diffuse neurofibrillary tangles with calcification
- frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)
- corticobasal degeneration (CBD)
- Pick disease
- progressive supranuclear palsy (PSP)
- progressive subcortical gliosis (PSG)
- tangle only dementia

By extension, tauopathies caracterize a larger group of diseases in which significant filaments and aggregates of tau protein are found. They includes :

- sporadic/familial Alzheimer disease (AD)
- amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS-FTDP)
- argyrophilic grain dementia
- dementia pugilistica
- diffuse neurofibrillary tangles with calcification
- Down syndrome
- frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)
- Gerstmann-Straussler-Scheinker disease
- Hallervorden-Spatz disease
- inclusion body myositis
- Creutzfeld-Jakob disease (CJD)
- multiple system atrophy
- Niemann-Pick disease type C (NPC)
- Pick disease
- prion protein cerebral amyloid angiopathy
- progressive supranuclear palsy (PSP)
- subacute sclerosing panencephalitis
- tangle-predominant Alzheimer disease
- frontotemporal dementia (FTD)
- corticobasal degeneration (CBD)
- myotonic dystrophy
- non-guanamian motor neuron disease with neurofibrillary tangles
- postencephalitic parkinsonism
- prion protein cerebral amyloid angiopathy
- progressive subcortical gliosis
- subacute sclerosing panencephalitis
- tangle only dementia

Mutations of MAPT gene coding for tau protein are found only in:

- 17q21-linked presenile dementia (MIM.600274)
- 17q21-linked familial frontotemporal dementia (MIM.600274)
- 17q21-linked frontotemporal dementia with parkinsonism (FTDP-17) (MIM.600274)
- 17q21-linked parkinsonism
- 17q21-linked Pick disease (MIM.172700)
- 17q21-linked progressive supranuclear palsy (PSP) (MIM.601104) (rare)
- 17q21-linked atypical progressive supranuclear palsy (atypical PSP) (MIM.260540) (rare)
- fatal respiratory hypoventilation (#14595660#)

Four types of MAPT mutations

- missense mutations
- silent mutations
- deletion mutation
- intronic mutations (afetr exon 10)

Loclaization of Tau filaments

- neurones and glial cells

  • frontotemporal dementia with parkinsonism (FTDP-17)
  • progressive supranuclear palsy (PSP)
  • corticobasal degeneration (CBD)
  • PSG
  • Prion disease (PiD) and Creutzfeld-Jakob disease (CJD)

The term tauopathies also can be extended to other neurodegenerative
diseases where tau pathology is found in conjunction with other abnormal protein lesions, such as Alzheimer disease (AD), or occasionally with other diseases where prion protein, Bri, or α-synuclein (SNCA) are aggregated. Such disorders may be considered secondary
tauopathies, and in these diseases, although tau is probably not the initial pathological factor, tau aggregates contribute to the final degeneration.

Tau deposits can also be found in several other neurodegenerative diseases in which tau pathology is evident in conjunction with other abnormal protein lesions, such as Alzheimer disease (AD). Abundant cytoplasmic inclusions consisting of aggregated hyperphosphorylated protein tau are a characteristic pathological observation in several neurodegenerative disorders such as Alzheimer’s disease, Pick’s disease, frontotemporal dementia, cortico-basal degeneration and progressive supranuclear palsy.

Classification

Tau deposits can also be found in many neurodegenerative diseases in which tau pathology is evident in conjunction with other abnormal protein lesions, such as Alzheimer disease (AD).

Abundant cytoplasmic inclusions consisting of aggregated hyperphosphorylated protein tau are a characteristic pathological observation in several neurodegenerative disorders such as Alzheimer’s disease, Pick’s disease, frontotemporal dementia, cortico-basal degeneration and progressive supranuclear palsy.

- tau protein aggregation and accumulation

  • Alzheimer disease
  • Pick disease
  • frontotemporal dementia (FTD)
  • cortico-basal degeneration (CBD)
  • progressive supranuclear palsy (PSP)

- tau protein mutations

- ch. 17 linked presenile dementia
- ch. 17 linked familial frontotemporal dementia
- ch. 17 linked parkinsonism

Model of tauopathies

Tau is central in the AD–FTD spectrum. A speculative model for tau-mediated neurodegeneration in the genetic AD–FTD spectrum of brain disorders. In addition to tau pathology, APP and typical PSENs mutations lead to Aβ-positive pathology causing vascular damage and hence neuronal death.

By contrast, genetic alterations in MAPT lead to Aβ-independent tau-mediated neuronal death.

Loss of PSENs function might result in Aβ-negative tau-mediated neurodegeneration further emphasizing that tau is the central molecule in the AD-FTD spectrum.

Neurofibrillary tangles (NFTs) and Tau aggregation

In NFTs, Tau proteins are hyperphosphorylated (PHF-tau). They can be full-length or cleaved by CASP6.

Tau aggregation

- phosphorylation
- ubiquitination
- oxidation
- glycation
- co-factors

Therapeutics

- NFTs formation blocking

  • blocking peptides
  • immunotherapy vs phosphorylated tau

- kinase inhibitors

  • lithium blocking GSK3beta

- microtubule stabilization

  • taxol

References

- Dermaut B, Kumar-Singh S, Rademakers R, Theuns J, Cruts M, Van Broeckhoven C. Tau is central in the genetic Alzheimer-frontotemporal dementia spectrum. Trends Genet. 2005 Dec;21(12):664-72. PMID: #16221505#

- Laferla FM, Oddo S. Alzheimer’s disease: Abeta, tau and synaptic dysfunction. Trends Mol Med. 2005 Apr;11(4):170-6. PMID: #15823755#

- D’Souza I, Schellenberg GD. Regulation of tau isoform expression and dementia. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):104-15. PMID: #15615630#

- Goedert M, Jakes R. Mutations causing neurodegenerative tauopathies. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):240-50. PMID: #15615642#

- Iqbal K, Alonso Adel C, Chen S, Chohan MO, El-Akkad E, Gong CX, Khatoon S, Li B, Liu F, Rahman A, Tanimukai H, Grundke-Iqbal I. Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):198-210. PMID: #15615638#

- von Bergen M, Barghorn S, Biernat J, Mandelkow EM, Mandelkow E. Tau aggregation is driven by a transition from random coil to beta sheet structure. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):158-66. Epub 2004 Nov 12. PMID: #15615635#

- Hyman BT, Augustinack JC, Ingelsson M. Transcriptional and conformational changes of the tau molecule in Alzheimer’s disease. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):150-7. PMID: #15615634#

- Gamblin TC. Potential structure/function relationships of predicted secondary structural elements of tau. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):140-9. PMID: #15615633#

- Yancopoulou D, Spillantini MG. Tau protein in familial and sporadic diseases. Neuromolecular Med. 2003;4(1-2):37-48. PMID: #14528051#

- Hutton M, Lewis J, Dickson D, Yen SH, McGowan E. Analysis of tauopathies with transgenic mice. Trends Mol Med. 2001 Oct;7(10):467-70. PMID: #11597522#

- Avila J. Tau aggregation into fibrillar polymers: taupathies. FEBS Lett. 2000 Jun 30;476(1-2):89-92. PMID: #10878257#

- Heutink P. Untangling tau-related dementia. Hum Mol Genet. 2000 Apr 12;9(6):979-86. PMID: #10767321#

Portfolio

  • Model of disease pathways in tauopathies.