Development of a high throughput drug screening assay for the detection of changes in tau levels - Proof of concept with HSP90 inhibitors

Chad A. Dickey, Jason Eriksen, Adeela Kamal, Francis Burrows, Srinivas Kasibhatla, Christopher B. Eckman, Mike Hutton, Leonard Petrucelli

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Therapeutic development for Alzheimer's disease has largely focused on the removal of beta amyloid because of its suggested role in the primary agent in initiating the disease process. However, with the recent discovery of mutations that result as pathologic buildup of tau in the absence of amyloid pathology, tau is beginning to be recognized as a potential target for drug discovery. We have developed a high-throughput drug screening method that allows for direct intracellular quantitation of tau protein species, enabling the fast, reliable detection of these changes. We have identified a family of small, blood brain barrier penetrant heat shock protein 90 inhibitors that significantly reduce tau protein levels in vitro. Western blot analysis demonstrated a clear inverse correlation between the tau levels and the increase in HSP27, HSP40 and HSP90. Modifications to this assay will further allow the specific analysis of pathologically relevant species. Using this assay, we have demonstrated that a class of HSP90 inhibitors is able to significantly lower intracellular tau levels most likely through induction of a heat shock response.

Original languageEnglish (US)
Pages (from-to)231-238
Number of pages8
JournalCurrent Alzheimer Research
Volume2
Issue number2
DOIs
StatePublished - Apr 2005

Fingerprint

High-Throughput Screening Assays
tau Proteins
Preclinical Drug Evaluations
Amyloid
HSP90 Heat-Shock Proteins
Heat-Shock Response
Drug Discovery
Blood-Brain Barrier
Alzheimer Disease
Western Blotting
Pathology
Mutation
Therapeutics
In Vitro Techniques

ASJC Scopus subject areas

  • Biological Psychiatry
  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health

Cite this

Development of a high throughput drug screening assay for the detection of changes in tau levels - Proof of concept with HSP90 inhibitors. / Dickey, Chad A.; Eriksen, Jason; Kamal, Adeela; Burrows, Francis; Kasibhatla, Srinivas; Eckman, Christopher B.; Hutton, Mike; Petrucelli, Leonard.

In: Current Alzheimer Research, Vol. 2, No. 2, 04.2005, p. 231-238.

Research output: Contribution to journalArticle

Dickey, Chad A. ; Eriksen, Jason ; Kamal, Adeela ; Burrows, Francis ; Kasibhatla, Srinivas ; Eckman, Christopher B. ; Hutton, Mike ; Petrucelli, Leonard. / Development of a high throughput drug screening assay for the detection of changes in tau levels - Proof of concept with HSP90 inhibitors. In: Current Alzheimer Research. 2005 ; Vol. 2, No. 2. pp. 231-238.
@article{fb38699e44f8489db7d9a020fc08d2ae,
title = "Development of a high throughput drug screening assay for the detection of changes in tau levels - Proof of concept with HSP90 inhibitors",
abstract = "Therapeutic development for Alzheimer's disease has largely focused on the removal of beta amyloid because of its suggested role in the primary agent in initiating the disease process. However, with the recent discovery of mutations that result as pathologic buildup of tau in the absence of amyloid pathology, tau is beginning to be recognized as a potential target for drug discovery. We have developed a high-throughput drug screening method that allows for direct intracellular quantitation of tau protein species, enabling the fast, reliable detection of these changes. We have identified a family of small, blood brain barrier penetrant heat shock protein 90 inhibitors that significantly reduce tau protein levels in vitro. Western blot analysis demonstrated a clear inverse correlation between the tau levels and the increase in HSP27, HSP40 and HSP90. Modifications to this assay will further allow the specific analysis of pathologically relevant species. Using this assay, we have demonstrated that a class of HSP90 inhibitors is able to significantly lower intracellular tau levels most likely through induction of a heat shock response.",
author = "Dickey, {Chad A.} and Jason Eriksen and Adeela Kamal and Francis Burrows and Srinivas Kasibhatla and Eckman, {Christopher B.} and Mike Hutton and Leonard Petrucelli",
year = "2005",
month = "4",
doi = "10.2174/1567205053585927",
language = "English (US)",
volume = "2",
pages = "231--238",
journal = "Current Alzheimer Research",
issn = "1567-2050",
publisher = "Bentham Science Publishers B.V.",
number = "2",

}

TY - JOUR

T1 - Development of a high throughput drug screening assay for the detection of changes in tau levels - Proof of concept with HSP90 inhibitors

AU - Dickey, Chad A.

AU - Eriksen, Jason

AU - Kamal, Adeela

AU - Burrows, Francis

AU - Kasibhatla, Srinivas

AU - Eckman, Christopher B.

AU - Hutton, Mike

AU - Petrucelli, Leonard

PY - 2005/4

Y1 - 2005/4

N2 - Therapeutic development for Alzheimer's disease has largely focused on the removal of beta amyloid because of its suggested role in the primary agent in initiating the disease process. However, with the recent discovery of mutations that result as pathologic buildup of tau in the absence of amyloid pathology, tau is beginning to be recognized as a potential target for drug discovery. We have developed a high-throughput drug screening method that allows for direct intracellular quantitation of tau protein species, enabling the fast, reliable detection of these changes. We have identified a family of small, blood brain barrier penetrant heat shock protein 90 inhibitors that significantly reduce tau protein levels in vitro. Western blot analysis demonstrated a clear inverse correlation between the tau levels and the increase in HSP27, HSP40 and HSP90. Modifications to this assay will further allow the specific analysis of pathologically relevant species. Using this assay, we have demonstrated that a class of HSP90 inhibitors is able to significantly lower intracellular tau levels most likely through induction of a heat shock response.

AB - Therapeutic development for Alzheimer's disease has largely focused on the removal of beta amyloid because of its suggested role in the primary agent in initiating the disease process. However, with the recent discovery of mutations that result as pathologic buildup of tau in the absence of amyloid pathology, tau is beginning to be recognized as a potential target for drug discovery. We have developed a high-throughput drug screening method that allows for direct intracellular quantitation of tau protein species, enabling the fast, reliable detection of these changes. We have identified a family of small, blood brain barrier penetrant heat shock protein 90 inhibitors that significantly reduce tau protein levels in vitro. Western blot analysis demonstrated a clear inverse correlation between the tau levels and the increase in HSP27, HSP40 and HSP90. Modifications to this assay will further allow the specific analysis of pathologically relevant species. Using this assay, we have demonstrated that a class of HSP90 inhibitors is able to significantly lower intracellular tau levels most likely through induction of a heat shock response.

UR - http://www.scopus.com/inward/record.url?scp=20844450734&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=20844450734&partnerID=8YFLogxK

U2 - 10.2174/1567205053585927

DO - 10.2174/1567205053585927

M3 - Article

C2 - 15974923

AN - SCOPUS:20844450734

VL - 2

SP - 231

EP - 238

JO - Current Alzheimer Research

JF - Current Alzheimer Research

SN - 1567-2050

IS - 2

ER -