Modeling Prion-Like Processing of Tau Protein in Alzheimer's Disease for Pharmaceutical Development

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Abstract

Following our discovery of a fragment from the repeat domain of tau protein as a structural constituent of the PHF-core in Alzheimer's disease (AD), we developed an assay that captured several key features of the aggregation process. Tau-tau binding through the core tau fragment could be blocked by the same diaminophenothiazines found to dissolve proteolytically stable PHFs isolated from AD brain. We found that the PHF-core tau fragment is inherently capable of auto-catalytic self-propagation in vitro, or "prion-like processing", that has now been demonstrated for several neurodegenerative disorders. Here we review the findings that led to the first clinical trials to test tau aggregation inhibitor therapy in AD as a way to block this cascade. Although further trials are still needed, the results to date suggest that a treatment targeting the prion-like processing of tau protein may have a role in both prevention and treatment of AD.

Original languageEnglish
Pages (from-to)1287-1303
Number of pages16
JournalJournal of Alzheimer's Disease
Volume62
Issue number3
Early online date8 Dec 2017
DOIs
Publication statusPublished - 13 Mar 2018

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Prions
Alzheimer Disease
tau Proteins
Neurodegenerative Diseases
Clinical Trials
Brain
urinary gonadotropin fragment
Therapeutics

Keywords

  • Journal Article
  • Alzheimer’s disease
  • clinical trials
  • paired helical filaments
  • prion-like processing
  • protein aggregation inhibitors
  • tau protein

Cite this

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title = "Modeling Prion-Like Processing of Tau Protein in Alzheimer's Disease for Pharmaceutical Development",
abstract = "Following our discovery of a fragment from the repeat domain of tau protein as a structural constituent of the PHF-core in Alzheimer's disease (AD), we developed an assay that captured several key features of the aggregation process. Tau-tau binding through the core tau fragment could be blocked by the same diaminophenothiazines found to dissolve proteolytically stable PHFs isolated from AD brain. We found that the PHF-core tau fragment is inherently capable of auto-catalytic self-propagation in vitro, or {"}prion-like processing{"}, that has now been demonstrated for several neurodegenerative disorders. Here we review the findings that led to the first clinical trials to test tau aggregation inhibitor therapy in AD as a way to block this cascade. Although further trials are still needed, the results to date suggest that a treatment targeting the prion-like processing of tau protein may have a role in both prevention and treatment of AD.",
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T1 - Modeling Prion-Like Processing of Tau Protein in Alzheimer's Disease for Pharmaceutical Development

AU - Wischik, Claude M

AU - Schelter, Björn O

AU - Wischik, Damon J

AU - Storey, John M D

AU - Harrington, Charles R

PY - 2018/3/13

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N2 - Following our discovery of a fragment from the repeat domain of tau protein as a structural constituent of the PHF-core in Alzheimer's disease (AD), we developed an assay that captured several key features of the aggregation process. Tau-tau binding through the core tau fragment could be blocked by the same diaminophenothiazines found to dissolve proteolytically stable PHFs isolated from AD brain. We found that the PHF-core tau fragment is inherently capable of auto-catalytic self-propagation in vitro, or "prion-like processing", that has now been demonstrated for several neurodegenerative disorders. Here we review the findings that led to the first clinical trials to test tau aggregation inhibitor therapy in AD as a way to block this cascade. Although further trials are still needed, the results to date suggest that a treatment targeting the prion-like processing of tau protein may have a role in both prevention and treatment of AD.

AB - Following our discovery of a fragment from the repeat domain of tau protein as a structural constituent of the PHF-core in Alzheimer's disease (AD), we developed an assay that captured several key features of the aggregation process. Tau-tau binding through the core tau fragment could be blocked by the same diaminophenothiazines found to dissolve proteolytically stable PHFs isolated from AD brain. We found that the PHF-core tau fragment is inherently capable of auto-catalytic self-propagation in vitro, or "prion-like processing", that has now been demonstrated for several neurodegenerative disorders. Here we review the findings that led to the first clinical trials to test tau aggregation inhibitor therapy in AD as a way to block this cascade. Although further trials are still needed, the results to date suggest that a treatment targeting the prion-like processing of tau protein may have a role in both prevention and treatment of AD.

KW - Journal Article

KW - Alzheimer’s disease

KW - clinical trials

KW - paired helical filaments

KW - prion-like processing

KW - protein aggregation inhibitors

KW - tau protein

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