microtubule associated protein tau

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Ligands
microtubule associated protein tau (Human)

GtoPdb Ligand ID: 9275

Compound class: Endogenous peptide in human, mouse or rat

Comment: The MAPT gene transcript undergoes complex, regulated alternative splicing. Different splice variants are expressed in different neurons and at different stages of neuronal maturation. The 757 amino acid isoform 1 contains three tau/MAP repeats which mediate tau interaction with tubulin (isoforms with four tau/MAP repeats are also reported).

MAPT gene polymorphisms are reported to predispose to neurodegenerative diseases including Alzheimer's disease (AD), Pick's disease [3-4,7] and frontotemporal dementia [5-6,11]. These types of conditions are known as tauopathies. The neurofibrillary tangles detected in AD brains are made up of pathologic paired helical filaments composed in large part of a truncated 100-amino-acid fragment of tau protein [10].

So far we have annotated three types of target relationships for tau protein:
1) aggregation antagonists/inhibitors (e.g. leucomethylthioninium)
2) imaging reagents for detection (e.g. flortaucipir (18F))
3) anti-tau monoclonal antibodies (e.g. zagotenemab)

In addition to zagotenemab, other clinical stage mAbs that target tau include gosuranemab (BMS-986168/BIIB092; for progressive supranuclear palsy PSP- development terminated, primary endpoint was not met in Phase 2), semorinemab (RO-7105705; for AD), tilavonemab (ABBV-8E12; for PSP and AD) and bepranemab (UCB0107; originally in development for PSP).

Species: Human

References
1. Alam R, Driver D, Wu S, Lozano E, Key SL, Hole JT, Hayashi ML, Lu J. (2017) Preclinical characterization of an antibody [LY3303560] tyargeting aggregated Tau. Alzheimers Dement, 136 (7): P592–P593. DOI: 10.1016/j.jalz.2017.07.227
2. Baddeley TC, McCaffrey J, Storey JM, Cheung JK, Melis V, Horsley D, Harrington CR, Wischik CM. (2015) Complex disposition of methylthioninium redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer's disease. J Pharmacol Exp Ther, 352 (1): 110-8. [PMID:25320049]
3. Neumann M, Schulz-Schaeffer W, Crowther RA, Smith MJ, Spillantini MG, Goedert M, Kretzschmar HA. (2001) Pick's disease associated with the novel Tau gene mutation K369I. Ann Neurol, 50 (4): 503-13. [PMID:11601501]
4. Pickering-Brown S, Baker M, Yen SH, Liu WK, Hasegawa M, Cairns N, Lantos PL, Rossor M, Iwatsubo T, Davies Y et al.. (2000) Pick's disease is associated with mutations in the tau gene. Ann Neurol, 48 (6): 859-67. [PMID:11117542]
5. Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD. (1998) Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol, 43 (6): 815-25. [PMID:9629852]
6. Rizzu P, Van Swieten JC, Joosse M, Hasegawa M, Stevens M, Tibben A, Niermeijer MF, Hillebrand M, Ravid R, Oostra BA et al.. (1999) High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands. Am J Hum Genet, 64 (2): 414-21. [PMID:9973279]
7. Rosso SM, van Herpen E, Deelen W, Kamphorst W, Severijnen LA, Willemsen R, Ravid R, Niermeijer MF, Dooijes D, Smith MJ et al.. (2002) A novel tau mutation, S320F, causes a tauopathy with inclusions similar to those in Pick's disease. Ann Neurol, 51 (3): 373-6. [PMID:11891833]
8. Sander K, Lashley T, Gami P, Gendron T, Lythgoe MF, Rohrer JD, Schott JM, Revesz T, Fox NC, Årstad E. (2016) Characterization of tau positron emission tomography tracer [(18)F]AV-1451 binding to postmortem tissue in Alzheimer's disease, primary tauopathies, and other dementias. Alzheimers Dement, 12 (11): 1116-1124. [PMID:26892233]
9. Silva MC, Ferguson FM, Cai Q, Donovan KA, Nandi G, Patnaik D, Zhang T, Huang HT, Lucente DE, Dickerson BC et al.. (2019) Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models. Elife, 8: e45457. DOI: 10.7554/eLife.45457 [PMID:30907729]
10. Wischik CM, Novak M, Thøgersen HC, Edwards PC, Runswick MJ, Jakes R, Walker JE, Milstein C, Roth M, Klug A. (1988) Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci USA, 85 (12): 4506-10. [PMID:3132715]
11. Yoshida H, Crowther RA, Goedert M. (2002) Functional effects of tau gene mutations deltaN296 and N296H. J Neurochem, 80 (3): 548-51. [PMID:11906000]

References

1. Alam R, Driver D, Wu S, Lozano E, Key SL, Hole JT, Hayashi ML, Lu J. (2017)
Preclinical characterization of an antibody [LY3303560] tyargeting aggregated Tau.
Alzheimers Dement, 136 (7): P592–P593. DOI: 10.1016/j.jalz.2017.07.227

2. Baddeley TC, McCaffrey J, Storey JM, Cheung JK, Melis V, Horsley D, Harrington CR, Wischik CM. (2015)
Complex disposition of methylthioninium redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer's disease.
J Pharmacol Exp Ther, 352 (1): 110-8. [PMID:25320049]

3. Neumann M, Schulz-Schaeffer W, Crowther RA, Smith MJ, Spillantini MG, Goedert M, Kretzschmar HA. (2001)
Pick's disease associated with the novel Tau gene mutation K369I.
Ann Neurol, 50 (4): 503-13. [PMID:11601501]

4. Pickering-Brown S, Baker M, Yen SH, Liu WK, Hasegawa M, Cairns N, Lantos PL, Rossor M, Iwatsubo T, Davies Y et al.. (2000)
Pick's disease is associated with mutations in the tau gene.
Ann Neurol, 48 (6): 859-67. [PMID:11117542]

5. Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD. (1998)
Tau is a candidate gene for chromosome 17 frontotemporal dementia.
Ann Neurol, 43 (6): 815-25. [PMID:9629852]

6. Rizzu P, Van Swieten JC, Joosse M, Hasegawa M, Stevens M, Tibben A, Niermeijer MF, Hillebrand M, Ravid R, Oostra BA et al.. (1999)
High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands.
Am J Hum Genet, 64 (2): 414-21. [PMID:9973279]

7. Rosso SM, van Herpen E, Deelen W, Kamphorst W, Severijnen LA, Willemsen R, Ravid R, Niermeijer MF, Dooijes D, Smith MJ et al.. (2002)
A novel tau mutation, S320F, causes a tauopathy with inclusions similar to those in Pick's disease.
Ann Neurol, 51 (3): 373-6. [PMID:11891833]

8. Sander K, Lashley T, Gami P, Gendron T, Lythgoe MF, Rohrer JD, Schott JM, Revesz T, Fox NC, Årstad E. (2016)
Characterization of tau positron emission tomography tracer [(18)F]AV-1451 binding to postmortem tissue in Alzheimer's disease, primary tauopathies, and other dementias.
Alzheimers Dement, 12 (11): 1116-1124. [PMID:26892233]

9. Silva MC, Ferguson FM, Cai Q, Donovan KA, Nandi G, Patnaik D, Zhang T, Huang HT, Lucente DE, Dickerson BC et al.. (2019)
Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models.
Elife, 8: e45457. DOI: 10.7554/eLife.45457 [PMID:30907729]

10. Wischik CM, Novak M, Thøgersen HC, Edwards PC, Runswick MJ, Jakes R, Walker JE, Milstein C, Roth M, Klug A. (1988)
Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease.
Proc Natl Acad Sci USA, 85 (12): 4506-10. [PMID:3132715]

11. Yoshida H, Crowther RA, Goedert M. (2002)
Functional effects of tau gene mutations deltaN296 and N296H.
J Neurochem, 80 (3): 548-51. [PMID:11906000]