During Alzheimer’s Awareness Month, Chemical Engineers Reach for a Cure

During Alzheimer’s and Brain Awareness Month, researchers at the University of Maryland (UMD) work towards a cure for neurodegenerative diseases impacting millions around the world.

Looking at a cascade of events leading to the progression of Alzheimer’s disease, Professor Jeffery Klauda and doctoral student Tejaswi Tammareddy, both in the Department of Chemical and Biomolecular Engineering, aim to develop a drug that mitigates the central mechanism triggering the different pathologies of the disease.

Alzheimer’s disease, which mainly affects the elderly population, is caused by multiple pathologies, but mainly the accumulation of amyloid-beta plaques and neurofibrillary (Tau) tangles in the brain, leading to cell death and brain shrinkage, which have been the primary focus of therapeutic research efforts.

Initially, Alzheimer’s presents as mild memory lapses and confusion, progressing into severe cognitive impairments and resulting in the inability to perform simple everyday functions. In order to improve quality of life for patients, on-going research efforts aim to manage the disrupted molecular processes that drive these symptoms by targeting senile plaques and tau tangles.

Using computational modeling techniques, Klauda and Tammareddy observe drug interactions with a target protein that is linked to these pathological mechanisms. They say that the “cyclin-dependent kinase 5” protein (CDK5), key to developmental functions in the nervous system, becomes dysregulated in those showing symptoms of the disease.

“The protein that we’re looking at, CDK5, in its normal healthy state is activated by another protein. But in Alzheimer’s disease, the activator protein gets cleaved, and therefore hyperactivates CDK5 in an unusual way that results in these detrimental effects,” said Klauda.

The candidate drug is designed to shield CDK5 from its attacker while maintaining its full functionality in the nervous system, a solution that current therapies are unable to provide.

Their work, which focuses on analyzing drug interactions at a molecular level through computational models, is part of a larger collaboration that aims to develop a cure by targeting the central mechanism leading to different Alzheimer’s disease pathologies.

“Incorporating molecular simulations in the early stages of drug design allows us to save time and resources, by reducing drug attrition rates during clinical trials. Our discovery techniques allow us to predict and explain the performance of the drug and conduct rational design to improve the efficacy and safety of the drug,” said Tammareddy.

The collaboration began in 2019 with Tammareddy’s co-advisor, Antonio Cardone, a research associate at the National Institute of Standards and Technology with a dual appointment at UMD’s Institute for Advanced Computer Studies.

So far, the developing drug has been tested on animal models at the National Institute of Neurological Disorders and Stroke, has undergone wet-lab testing followed by rounds of simulation model analysis. Additional layers of feedback loops could set the treatment for clinical trials, researchers say.

Currently, there are eight treatment options approved by the U.S. Food and Drug Administration, as reported by the latest Alzheimer’s Association’s Annual Report: two of which are effective in slowing disease progression by targeting amyloid-beta plaques, while the rest treat cognitive and behavioral symptoms. As of January 1 of 2023, 156 clinical trials were conducted for novel disease-modifying therapies, while 31 clinical trials were focused on therapies for symptoms, latest data from the same report suggests.

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