Inhibiting Formation of Alzheimer's Disease Pathology

Kurt R Brunden, PhD
University of Pennsylvania (Philadelphia, PA, United States)
Year Awarded:
2011
Grant Duration:
July 1, 2011 to June 30, 2013
Disease:
Alzheimer's
Award Amount:
$150,000
Grant Reference ID:
A2011303
Award Type:
Pilot
Award Region:
US Northeastern

In Vivo Testing of Novel Tau Fibrillization Inhibitors

Summary

The accumulation of insoluble fibrils of tau protein within neurons is a hallmark pathological feature of the Alzheimer's disease brain. A body of evidence suggests that these tau fibrils are pathogenic and contribute to the neuron loss observed in Alzheimer's disease. The research proposed here is to further characterize novel drug-like inhibitors of tau fibril formation, and the results of these studies will provide important information about the therapeutic potential of such compounds for the treatment of Alzheimer's disease.

Details

One of the hallmarks of Alzheimer's disease is the unnatural clumping of misfolded tau proteins into tangles in the brain. These tangles, along with beta‐amyloid plaques, cause brain cell death and problems with memory and other important activities. Dr. Kurt Brunden and colleagues will be testing a number of drugs on Alzheimer's disease mice to see whether one of them can prevent tau from clumping. The drug that works in mice may be a candidate for future Alzheimer's disease human clinical trials.

Research Updates

The dementia of Alzheimer's disease (AD) is believed to be caused, at least in part, by clumps of aggregated material within nerve cells. These aggregates are made from misfolded tau protein and are referred to as neurofibrillary tangles (NFTs). The objective of this research program is to test a set of novel molecules that act to prevent the formation of NFTs. These molecules are to be tested first for their distribution and safety in healthy mice, and those molecules that enter and persist in the brain while being free of side-effects will then be tested in mice that have been engineered to form NFT-like tau aggregates like those seen in AD. If one of the tested molecules is found to prevent the formation of NFTs in these mice, this would provide important evidence that this or a related molecule (called an analogue) might serve as a future drug candidate for the treatment of AD.

In the first 10 months of this program, Dr. Brunden’s team identified molecules that have desirable properties, including good brain levels in healthy mice, which suggested that these molecules were appropriate candidates for testing in mice with AD. However, additional research into these compounds and related analogues indicated that they act by an undesirable mechanism that would likely cause side-effects upon long-term administration. Therefore, the team has halted further optimization of these compounds, and will refocus their efforts on the identification of alternative compounds that prevent tau aggregate formation in a novel cell-based model. Use of this unique cell-based assay, in which NFT-like tau aggregates develop, will allow for the discovery of molecules that can reduce NFTs through multiple mechanisms. This approach could increase the likelihood of finding compounds that might ultimately lead to AD therapeutics.

About the Researcher

Dr. Kurt R. Brunden is Director of Drug Discovery and Research Associate Professor in the Center for Neurodegenerative Disease Research (CNDR) at the University of Pennsylvania.  There he oversees drug discovery programs in the areas of Alzheimer's disease, Frontotemporal lobar degeneration, and Parkinson's disease. Brunden received his B.S. degree from Western Michigan University, with dual majors of biology and health chemistry. He obtained his Ph.D. in biochemistry from Purdue University and did a post-doctoral fellowship at the Mayo Clinic in Rochester, MN. Brunden joined the biochemistry faculty at the University of Mississippi Medical Center in 1988, with a research focus on the regulation of myelination.

He was recruited to the biotechnology sector in 1991, serving as vice president of Research at Gliatech, Inc. and later as senior vice president of Drug Discovery at Athersys, Inc. In these positions, he oversaw projects in Alzheimer's disease, cognition, schizophrenia, inflammation, and metabolic disease. Brunden was recruited to the University of Pennsylvania in 2007.  He also serves as the chair of the NSD-C translational research study section for the National Institutes of Neurological Diseases and Stroke, is a reviewer and consultant for the Alzheimer's Drug Discovery Foundation, and is an ad hoc reviewer for several scientific journals. He has more than 65 publications, a number of issued U.S. patents, and several active patent applications.

Publications

Crowe, A., James, M.J., Lee, V.M-Y., Smith, A.B. III, Trojanowski, J.Q., Ballatore, C. and Brunden, K.R. (2013) Aminothienopyridazines and methylene blue affect tau fibrillization via cysteine oxidation. J. Biol. Chem. 288:11024-11037. PubMed Icon Google Scholar Icon