Searching for cure for devastating disease
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.
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.