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  • Updated 11.29.2023
  • Released 06.13.2022
  • Expires For CME 11.29.2026

Pathogenesis and pathology of tauopathies



Diseases with pathologic tau protein inclusions in neurons or glia are known as tauopathies. Tau pathology causes several neurodegenerative diseases, including Alzheimer disease, progressive supranuclear palsy, corticobasal degeneration, Pick disease, and chronic traumatic encephalopathy. Misfolded tau is an attractive therapeutic target, and research has advanced our understanding of the pathophysiology of tauopathies. Although successful disease-modifying therapies directly targeting tau remain elusive, 2023 heralded the arrival of lecanemab, an anti-amyloid drug targeting the common and secondary tauopathy, Alzheimer disease.

Key points

• Tau is a protein that stabilizes microtubules to facilitate axonal transport and maintain neuronal integrity.

• Tauopathies are diverse neurodegenerative diseases characterized by inclusions of abnormal tau deposited in different areas or cells of the brain, leading to heterogeneous clinical features.

• Pathologically, abnormal tau causes disease when insoluble filaments aggregate in neurons and astroglial cells and propagate between cells in neural networks in a prion-like fashion.

• Although several drugs targeting tauopathies have failed in clinical trials, promising new therapies continue to emerge.

Historical note and terminology

In 1907, Alois Alzheimer published a short paper describing plaques and tangles in the brain of a patient with presenile dementia. This is the first known description of tau pathology (13; 16). Electron microscopy performed by Michael Kidd in 1963 then identified paired helical filament as the prominent structural component in neurofibrillary tangles (25). In 1975, Weingarten described a “heat stable protein essential for microtubule assembly” and named the protein “tau” (56). Tau was subsequently identified as the major structural component of the neurofibrillary tangles seen in Alzheimer disease in 1986 (17).

In the 1990s, researchers identified autosomal dominant mutations in the MAPT gene associated with a familial syndrome of frontotemporal dementia and parkinsonism. This group of disorders was labeled “frontotemporal dementia and parkinsonism linked to chromosome 17” (FTDP-17). In one of the families studied, the disorder was named “multiple system tauopathy with presenile dementia.” This resulted in the introduction of the term “tauopathy,” a term that now encompasses disorders characterized by pathologic tau protein deposition (12).

Given that the MAPT gene encodes tau, these disorders provided evidence that aberrant tau can cause neurodegenerative disorders (21; 40). Studies of pathologic changes in the brains of Alzheimer patients have further supported the role of pathologic tau in neurodegeneration (43). Furthermore, a study of patients with progressive supranuclear palsy found a correlation between pathologic tau burden and degree of cognitive impairment, particularly executive dysfunction (27). Overall, the presence of pathologic tau correlates well with the degree of clinical impairment.

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