The formation of tau pore-like structures is prevalent and cell specific

Possible implications for the disease phenotypes

Cristian Lasagna Reeves, Urmi Sengupta, Diana Castillo-Carranza, Julia E. Gerson, Marcos Guerrero-Munoz, Juan C. Troncoso, George R. Jackson, Rakez Kayed

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Pathological aggregation of the microtubule-associated protein tau and subsequent accumulation of neurofibrillary tangles (NFTs) or other tau-containing inclusions are defining histopathological features of many neurodegenerative diseases, which are collectively known as tauopathies. Due to conflicting results regarding a correlation between the presence of NFTs and disease progression, the mechanism linking pathological tau aggregation with cell death is poorly understood. An emerging view is that NFTs are not the toxic entity in tauopathies; rather, tau intermediates between monomers and NFTs are pathogenic. Several proteins associated with neurodegenerative diseases, such as Aβ-amyloid (Aβ) and α-synuclein, have the tendency to form pore-like amyloid structures (annular protofibrils, APFs) that mimic the membrane-disrupting properties of pore-forming protein toxins. The present study examined the similarities of tau APFs with other tau amyloid species and showed for the first time the presence of tau APFs in brain tissue from patients with progressive supranuclear palsy (PSP) and dementia with Lewy bodies (DLB), as well as in the P301L mouse model, which overexpresses mutated tau. Furthermore, we found that APFs are preceded by tau oligomers and do not go on to form NFTs, evading fibrillar fate. Collectively, our results demonstrate that in vivo APF formation depends on mutations in tau, phosphorylation levels, and cell type. These findings establish the pathological significance of tau APFs in vivo and highlight their suitability as therapeutic targets for several neurodegenerative tauopathies.

Original languageEnglish (US)
Article number56
JournalActa neuropathologica communications
Volume2
Issue number1
DOIs
StatePublished - Jan 27 2014
Externally publishedYes

Fingerprint

Neurofibrillary Tangles
Tauopathies
Phenotype
Amyloid
Neurodegenerative Diseases
Synucleins
Progressive Supranuclear Palsy
Lewy Body Disease
Porins
Microtubule-Associated Proteins
Poisons
Disease Progression
Cell Death
Phosphorylation
Mutation
Membranes
Brain
Proteins

Keywords

  • Annular protofibrils
  • Oligomers
  • Tau
  • Tauopathies

ASJC Scopus subject areas

  • Medicine(all)

Cite this

The formation of tau pore-like structures is prevalent and cell specific : Possible implications for the disease phenotypes. / Lasagna Reeves, Cristian; Sengupta, Urmi; Castillo-Carranza, Diana; Gerson, Julia E.; Guerrero-Munoz, Marcos; Troncoso, Juan C.; Jackson, George R.; Kayed, Rakez.

In: Acta neuropathologica communications, Vol. 2, No. 1, 56, 27.01.2014.

Research output: Contribution to journalArticle

Lasagna Reeves, Cristian ; Sengupta, Urmi ; Castillo-Carranza, Diana ; Gerson, Julia E. ; Guerrero-Munoz, Marcos ; Troncoso, Juan C. ; Jackson, George R. ; Kayed, Rakez. / The formation of tau pore-like structures is prevalent and cell specific : Possible implications for the disease phenotypes. In: Acta neuropathologica communications. 2014 ; Vol. 2, No. 1.
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