Brown researcher to lead $16M grant to explore potential cause, treatment for Alzheimer’s disease

Led by principal investigator John Sedivy, a multi-university effort will build on recent discoveries about mechanisms of aging to understand causes and potential treatments for neurodegenerative diseases.

PROVIDENCE, R.I. [Brown University] — A National Institutes of Health grant expected to total more than $16 million over five years will fund research into potential causes of Alzheimer’s disease and neurodegeneration, and assist a team of scientists in the search for targets to inform therapeutic strategies to treat those conditions.

With support from a prior NIH grant, the team of biologists from Brown University, New York University and the University of Rochester has been researching the mechanisms of aging with special attention to potentially harmful DNA snippets called retrotransposable elements (or retrotransposons). Evidence from this team and from other scientists has implicated retrotransposons in promoting aging.

With the new NIH funding, the research team will join colleagues from the Salk Institute for Biological Studies to focus specifically on how retrotransposons contribute to neurodegeneration and Alzheimer’s disease.

“For the past five years, we worked on discovering how retrotransposons promote aging,” said principal investigator John Sedivy, a professor of biology and medical science at Brown, and director of the University’s Center on the Biology of Aging. “While these mechanisms are universal and occur in many different types of cells, it’s important to understand variation in cell response. In the renewal phase of this grant, we will investigate how the cells of the central nervous system ­— neurons, astrocytes, microglia — respond to the detrimental challenges posed by retrotransposons.”

In addition to his role in Brown’s Division of Biology and Medicine, Sedivy is affiliated with the University’s Carney Institute for Brain Science, which is home to a range of clinical and research efforts focused on the causes and treatments for Alzheimer’s and other neurodegenerative diseases.

Retrotransposons are parasitic strands of genetic material that use a copy-and-paste mechanism to replicate and move within the human genome — with mostly harmful consequences. When the first NIH grant was awarded to the team in 2016, the retrotransposon theory of aging was still new. Sedivy was among the researchers who had shown in 2013 that aging cells lose their ability to defend against transposons, resulting in a decline in cell function. In 2019, the team published studies in the journals Nature and Cell Metabolism showing that an HIV drug could halt harmful retrotransposon activity in old cells, significantly reducing age-related inflammation and other signs of aging in mice (which led to an ongoing clinical trial funded by the Alzheimer’s Association). In 2021, the team published a review article in Nature discussing the latest research on retrotransposons. 

The long-term hope is that if we can understand the role of retrotransposons in Alzheimer’s, this can inform treatments so that one day a patient may be able to take medication to decrease neuroinflammation and prevent the loss of neurons, ultimately staving off memory loss.

John Sedivy Director of the Center on the Biology of Aging at Brown University
 
John Sedivy, Ph.D.

The new work funded by the renewal grant will serve as a continuation of the same story of retrotransposable elements, Sedivy said, with an exciting new chapter: “The translational potential of our discoveries has become clear, and we are shifting our attention in the direction of chronic, age-associated diseases,” the researchers noted in their grant proposal.

The central nervous system appears to be a “privileged site” for retrotransposon activity, Sedivy said, with relatively high levels of expression.

Over the next five years, the intention is to thoroughly investigate the emerging biology of retrotransposons in the central nervous system in the context of Alzheimer’s disease. Specifically, the team will investigate the mechanisms that lead to the failure of host defense systems against retrotransposons and study the consequences of their activation on cellular and tissue function.

In an effort to inform the development of Alzheimer’s treatments, the team will use mice and human cell research models to examine and define therapeutic targets specific to the central nervous system and explore possible strategies for therapeutic interventions.

“This will lay the groundwork for future pharmaceutical research,” Sedivy said. “The long-term hope is that if we can understand the role of retrotransposons in Alzheimer’s, this can inform treatments so that one day a patient may be able to take medication to decrease neuroinflammation and prevent the loss of neurons, ultimately staving off memory loss.”

The research will be supported by the National Institute on Aging of the National Institutes of Health under award number P01AG051449.