Tau in Alzheimer's Disease: Pathological Alterations and an Attractive Therapeutic Target

Overview

Journal Curr Med Sci

Specialty General Medicine

Date 2021 Jan 11

PMID 33428128

Citations 9

Authors

Jian-Lan Gu

Fei Liu

Affiliations

Soon will be listed here.

Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative disease with two major hallmarks: extracellular amyloid plaques made of amyloid-β (Aβ) and intracellular neurofibrillary tangles (NFTs) of abnormally hyperphosphorylated tau. The number of NFTs correlates positively with the severity of dementia in AD patients. However, there is still no efficient therapy available for AD treatment and prevention so far. A deeper understanding of AD pathogenesis has identified novel strategies for the generation of specific therapies over the past few decades. Several studies have suggested that the prion-like seeding and spreading of tau pathology in the brain may be a key driver of AD. Tau protein is considered as a promising candidate target for the development of therapeutic interventions due to its considerable pathological role in a variety of neurodegenerative disorders. Abnormal tau hyperphosphorylation plays a detrimental pathological role, eventually leading to neurodegeneration. In the present review, we describe the recent research progresses in the pathological mechanisms of tau protein in AD and briefly discuss tau-based therapeutic strategies.

Citing Articles

Unveiling the Interplay: Neurovascular Coupling, Astrocytes and G Protein-Coupled Receptors in Alzheimer's Disease.

Al-Jaf S, Soliman A, El-Yazbi A, Abd-Elrahman K ACS Pharmacol Transl Sci. 2025; 8(2):271-285.

PMID: 39974631 PMC: 11833731. DOI: 10.1021/acsptsci.4c00614.

Aβ induces stress granule formation via PACT/PKR pathway.

Ramasamy V, Nathan A, Choi M, Kim S, Ohn T Sci Rep. 2025; 15(1):5829.

PMID: 39966464 PMC: 11836309. DOI: 10.1038/s41598-025-88380-y.

The potential link between the development of Alzheimer's disease and osteoporosis.

Nasme F, Behera J, Tyagi P, Debnath N, Falcone J, Tyagi N Biogerontology. 2025; 26(1):43.

PMID: 39832071 DOI: 10.1007/s10522-024-10181-z.

New and emerging drug therapies for Alzheimer disease.

Waite L Aust Prescr. 2024; 47(3):75-79.

PMID: 38962384 PMC: 11216914. DOI: 10.18773/austprescr.2024.021.

Real-word application of the AT(N) classification and disease-modifying treatment eligibility in a hospital-based cohort.

Canu E, Rugarli G, Coraglia F, Basaia S, Cecchetti G, Calloni S J Neurol. 2024; 271(5):2716-2729.

PMID: 38381175 DOI: 10.1007/s00415-024-12221-7.

References

Grundke-Iqbal I, Iqbal K, Quinlan M, Tung Y, Zaidi M, Wisniewski H . Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem. 1986; 261(13):6084-9. View

Arriagada P, Growdon J, Hedley-Whyte E, Hyman B . Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology. 1992; 42(3 Pt 1):631-9. DOI: 10.1212/wnl.42.3.631. View

Riley K, Snowdon D, Markesbery W . Alzheimer's neurofibrillary pathology and the spectrum of cognitive function: findings from the Nun Study. Ann Neurol. 2002; 51(5):567-77. DOI: 10.1002/ana.10161. View

Grundke-Iqbal I, Iqbal K, Tung Y, Quinlan M, Wisniewski H, Binder L . Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A. 1986; 83(13):4913-7. PMC: 323854. DOI: 10.1073/pnas.83.13.4913. View

Alonso A, Zaidi T, Grundke-Iqbal I, Iqbal K . Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc Natl Acad Sci U S A. 1994; 91(12):5562-6. PMC: 44036. DOI: 10.1073/pnas.91.12.5562. View

Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K . Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci U S A. 2001; 98(12):6923-8. PMC: 34454. DOI: 10.1073/pnas.121119298. View

Braak H, Del Tredici K . The pathological process underlying Alzheimer's disease in individuals under thirty. Acta Neuropathol. 2010; 121(2):171-81. DOI: 10.1007/s00401-010-0789-4. View

Braak H, Braak E . Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991; 82(4):239-59. DOI: 10.1007/BF00308809. View

Braak H, Braak E . Staging of Alzheimer's disease-related neurofibrillary changes. Neurobiol Aging. 1995; 16(3):271-8; discussion 278-84. DOI: 10.1016/0197-4580(95)00021-6. View

10.

Grober E, Dickson D, Sliwinski M, Buschke H, Katz M, Crystal H . Memory and mental status correlates of modified Braak staging. Neurobiol Aging. 2000; 20(6):573-9. DOI: 10.1016/s0197-4580(99)00063-9. View

11.

Ahmed Z, Cooper J, Murray T, Garn K, McNaughton E, Clarke H . A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity. Acta Neuropathol. 2014; 127(5):667-83. PMC: 4252866. DOI: 10.1007/s00401-014-1254-6. View

12.

Kumar H, Udgaonkar J . Mechanistic approaches to understand the prion-like propagation of aggregates of the human tau protein. Biochim Biophys Acta Proteins Proteom. 2019; 1867(10):922-932. DOI: 10.1016/j.bbapap.2019.04.004. View

13.

Colin M, Dujardin S, Schraen-Maschke S, Meno-Tetang G, Duyckaerts C, Courade J . From the prion-like propagation hypothesis to therapeutic strategies of anti-tau immunotherapy. Acta Neuropathol. 2019; 139(1):3-25. PMC: 6942016. DOI: 10.1007/s00401-019-02087-9. View

14.

Goedert M, Eisenberg D, Crowther R . Propagation of Tau Aggregates and Neurodegeneration. Annu Rev Neurosci. 2017; 40:189-210. DOI: 10.1146/annurev-neuro-072116-031153. View

15.

Goedert M, Spillantini M, Jakes R, Rutherford D, Crowther R . Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron. 1989; 3(4):519-26. DOI: 10.1016/0896-6273(89)90210-9. View

16.

Iqbal K, Alonso A, Chen S, Chohan M, El-Akkad E, Gong C . Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta. 2004; 1739(2-3):198-210. DOI: 10.1016/j.bbadis.2004.09.008. View

17.

Kosik K, Orecchio L, Bakalis S, Neve R . Developmentally regulated expression of specific tau sequences. Neuron. 1989; 2(4):1389-97. DOI: 10.1016/0896-6273(89)90077-9. View

18.

Takuma H, Arawaka S, Mori H . Isoforms changes of tau protein during development in various species. Brain Res Dev Brain Res. 2003; 142(2):121-7. DOI: 10.1016/s0165-3806(03)00056-7. View

19.

Gendron T, Petrucelli L . The role of tau in neurodegeneration. Mol Neurodegener. 2009; 4:13. PMC: 2663562. DOI: 10.1186/1750-1326-4-13. View

20.

Mukrasch M, Bibow S, Korukottu J, Jeganathan S, Biernat J, Griesinger C . Structural polymorphism of 441-residue tau at single residue resolution. PLoS Biol. 2009; 7(2):e34. PMC: 2642882. DOI: 10.1371/journal.pbio.1000034. View