By Mary L. Martialay
With support from the Warren Alpert Foundation, researchers at Rensselaer Polytechnic Institute have launched a search for drug candidates to block a biological process associated with Alzheimer’s disease. Lead researcher Chunyu Wang said the project hopes to identify compounds that will act as selective gamma-secretase inhibitors – molecules that can block production of the toxic peptide Amyloid Beta-42 –from an initial field of tens of millions of compounds.
“A key pathology in Alzheimer’s is accumulation of senile plaque in the brain, which is mainly composed of the Amyloid Beta-42 peptide,” said Wang, an associate professor of biological sciences and member of the Rensselaer Center for Biotechnology and Interdisciplinary Studies. “The gamma secretase inhibitors that made it to clinical trials blocked many other important functions and were unsuccessful. We hope our approach, which will search for a gamma secretase inhibitor with a highly selective target will be more successful.”
Amyloid Beta-42 (Ab-42) is produced from the amyloid precursor protein (APP) which starts its life embedded in the membrane of brain cells. In a multi-step process, enzymes make several cuts to APP, and the location of the cuts dictates whether a resulting snippet of APP becomes the toxic Ab-42, or a more benign peptide called Ab-40.
Critically, if the enzyme g-secretase makes an initial cut at the amino acid residue of Threonine 48 on APP, the remaining cuts result in Ab-42, whereas if the first cut is made at the Leucine 49 residue, the process results in Ab-40.
“Rensselaer offers a potent approach to medical discovery and innovation,” said Rensselaer President Shirley Ann Jackson. “In collaboration with our partners at the Icahn School of Medicine at Mount Sinai, we are translating foundational research from the nexus of scientific and technological disciplines into fresh inspiration and perspectives on human health and drug discovery.”
The research draws on the extensive resources at Rensselaer in partnership with the Icahn School of Medicine at Mount Sinai. At Rensselaer, Wang is joined in his work by Jonathan Dordick, Rensselaer Professor of Chemical and Biological Engineering, as well as Icahn School of Medicine professors Dr. Nikolaos Robabkis and Dr. Iban Ubarretxena.
In 2014, Wang discovered that one of the genetic mutations found in patients with Familial Alzheimer’s Disease – which affects a small fraction of the Alzheimer’s population – causes a change that makes it more likely for g-secretase to cut at Threonine 48, enhancing the production of Ab-42, and increased concentrations of Ab-42 as found in the brains of patients with Familial Alzheimer’s Disease.
In the current research, Wang will begin the search for a selective g-secretase inhibitor with “in silico screening” – using computer models to test the ability to tens of millions of compounds to selectively bind to target molecules. Initial screening may yield thousands of compounds, which will then be examined using Nuclear Magnetic Resonance to confirm initial results. The most promising compounds will advance to in vitro tests to verify that they bind with the target. And successful compounds will move forward to enzyme assays, experiments in cell culture and mouse models, which test whether the compounds selectively inhibit g-secretase.
“This is a lengthy and thorough process. And if all goes well, the end product of this grant is a lead compound for selective inhibition of g-secretase in the production of Ab-42,” said Wang.
Research into neurodegenerative diseases including Alzheimer’s fulfills The New Polytechnic, an emerging paradigm for higher education which recognizes that global challenges and opportunities are so great they cannot be adequately addressed by even the most talented person working alone. Rensselaer serves as a crossroads for collaboration — working with partners across disciplines, sectors, and geographic regions — to address complex global challenges, using the most advanced tools and technologies, many of which are developed at Rensselaer. Research at Rensselaer addresses some of the world’s most pressing technological challenges — from energy security and sustainable development to biotechnology and human health. The New Polytechnic is transformative in the global impact of research, in its innovative pedagogy, and in the lives of students at Rensselaer.