“Alzheimer's disease therapeutics and risk factors identification through the control of hyperphosphorylated tau”

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Date: November 12, 2020
Time: 11:00 a.m. - 12:00 p.m.
Location: Via Zoom (Please contact sshaw@wayne.edu for Zoom info)
Category: Seminar

Min-Hao Kuo, PhD, Associate Professor, Department of Biochemistry and Molecular Biology, Michigan State University

“Alzheimer's disease therapeutics and risk factors identification through the control of hyperphosphorylated tau”

Abstract

Alzheimer's disease (AD) is affecting 5.8 million Americans and more than 30 million people worldwide. There is currently no treatment or prevention for this devastating disease. AD is one of several neurodegenerative tauopathies that share a common pathology in the brain, that is, the deposition of hyperphosphorylated tau protein in selective neurons and other brain cells. AD patients suffer from progressive decline of cognitive and additional neurological functions. These clinical manifestations correlate with the spatiotemporal distribution of tau deposits. The pathological roles of abnormally phosphorylated tau have been recapitulated by intracranial injection experiments on mice. Accordingly, molecules that inhibit or enhance the pathological activities of hyperphosphorylated tau are potential therapeutics and risk factors, respectively, for AD. Identification of such molecules will likely lead to efficacious treatment or prevention. One of the formidable hurdles of tau-centric AD drug discovery has been the lack of a means to produce pathophysiologically relevant hyperphosphorylated tau for in vitro uses. We have developed the PIMAX system to synthesize hyperphosphorylated tau (p-tau) in E. coli that enables disease mechanism and drug discovery studies. We showed that p-tau produced by PIMAX possesses a core phosphorylation pattern highly relevant to the disease, and that the aggregates of p-tau causes cell death in vitro. Using a suite of different assays, we conducted a chemical library pilot screen from which we identified both p-tau aggregation inhibitors (apomorphine and raloxifene) and enhancers (certain benzodiazepines) that had been linked to cognitive impairments. These are active prescription drugs treating different clinical conditions, and have previously been linked to cognitive integrity. Our discoveries suggest a molecular mechanism underlying these prior findings, and that these drugs are excellent candidates for further development. Medicinal chemistry refinement of these compounds, as well as a larger-scale screen of novel compounds are ongoing in our lab.

References:

1. For the development and uses of the PIMAX system: Sui et al., Protein Interaction Module-assisted Function X (PIMAX) Approach to Producing Challenging Proteins Including Hyperphosphorylated Tau and Active CDK5/p25 Kinase Complex. Mol Cell Proteomics 14, 251-262 (2015).

2. Molecular characterization of recombinant hyperphosphorylated tau produced by PIMAX: Liu et al., Hyperphosphorylation Renders Tau Prone to Aggregate and to Cause Cell Death. Molecular neurobiology 57, 4704 - 4719 (2020).

3. Results of compound library screening: Liu et al., Hyperphosphorylated tau aggregation and cytotoxicity modulators screen identified prescription drugs linked to Alzheimer's disease and cognitive functions. Scientific reports 10, 16551 (2020).

 

Contact

Suzanne Shaw
577-5325
sshaw@wayne.edu

Cost

Free
November 2020
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