Development of a High Throughput Drug Screening Assay for the Detection of Changes in Tau Levels - Proof of Concept with HSP90 inhibitors

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

Source: Current Alzheimer Research, Volume 2, Number 2, April 2005 , pp. 231-238(8)

Publisher: Bentham Science Publishers

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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.

Keywords: alzheimer’s disease (ad); neurodegeneration; neurofibrillary tangles (nft); nmda receptor antagonist; amyloid precursor protein; tau knockout mice; expression

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1567205053585927

Affiliations: 1: Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville FL, 32224, USA.

Publication date: 2005-04-01

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Current Alzheimer Research publishes peer-reviewed frontier review and research articles on all areas of Alzheimer's disease. This multidisciplinary journal will help in understanding the neurobiology, genetics, pathogenesis, and treatment strategies of Alzheimer's disease. The journal publishes objective reviews written by experts and leaders actively engaged in research using cellular, molecular, and animal models. The journal also covers original articles on recent research in fast emerging areas of molecular diagnostics, brain imaging, drug development and discovery, and clinical aspects of Alzheimer's disease. Manuscripts are encouraged that relate to the synergistic mechanism of Alzheimer's disease with other dementia and neurodegenerative disorders. Book reviews, meeting reports and letters-to-the-editor are also published. The journal is essential reading for researchers, educators and physicians with interest in age-related dementia and Alzheimer's disease. Current Alzheimer Research provides a comprehensive 'bird's-eye view' of the current state of Alzheimer's research for neuroscientists, clinicians, health science planners, granting, caregivers and families of this devastating disease.

Development of a High Throughput Drug Screening Assay for the Detection of Changes in Tau Levels - Proof of Concept with HSP90 inhibitors

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