Here’s how renegade protein interrupts brain cell function in Alzheimer’s disease
According to a recent study, dozens of molecules may tangle up with rogue bundles of tau, a protein that normally gives nerve fibres structure to cause brain cell damage that contributes to neurodegenerative diseases.
Neuroscientists have previously found that tau can become toxic when extra
chemical molecules accumulate with its structure in the brain, causing it to
form tangles of protein that destroy surrounding tissue.
Led by researchers from NYU Grossman School of Medicine, the new study analysed the make-up of such tangles and found 12 proteins that they say have not before been tied to both tau and Alzheimer’s disease.
They also uncovered several dozen other proteins that appear in the latest
stages of the disease as well as in the earliest phases of dementia.
“Our findings expand our understanding of the molecular interactions that drive
Alzheimer’s and other brain-damaging diseases related to misbehaving tau
proteins,” says study co-lead author Eleanor Drummond, PhD, a research
assistant professor in the Department of Neurology at NYU Langone Health.
“Now that we have better insight into possible ‘key players’ in
neurodegeneration, we may have clearer targets for potential therapies,” says
co-lead author Geoffrey Pires, a doctoral student in neurology at NYU Langone.
An estimated 5 million Americans are living with Alzheimer’s, a progressive
disease that affects mostly those over 65 and interferes with memory, language,
and decision making. Currently, there are no effective treatments or prevention
strategies for Alzheimer’s. Experts have long linked it to a buildup of extra
phosphate molecules on tau proteins. However, how these tangles damage neurons
and what other proteins are involved in the development of Alzheimer’s
signature bundles have been poorly understood, says Drummond.
The new study, publishing online in the journal Brain, provides what Drummond
and her colleagues say is the largest overview to date of proteins present in
these tau tangles.
For the investigation, the research team analysed donated brain tissue samples
from 12 men and women with Alzheimer’s disease. After separating the tau knots
from the surrounding tissue, the researchers examined the bundles to identify
the many proteins tangled within.
According to the findings, the tangles were composed of 542 different proteins
in total, some of which are involved in essential processes within cells, such
as energy production (vacuolar-ATPase subunit ATP6V0D1), the reading of genetic
material (RNA binding protein HNRNPA1), and cell breakdown and digestion (PSMC
1 through 5). These results provide clues to how the tangles lead to neuron
death, says Drummond.
“Alzheimer’s has been studied for over a century, so it is eye-opening that we
are still uncovering dozens of proteins that we had no idea are associated with
the disease,” says study senior author Thomas Wisniewski, MD, the Gerald J. and
Dorothy R. Friedman Professor in the Department of Neurology at NYU Langone.
Wisniewski, also a professor in the departments of Pathology and Psychiatry at
NYU Langone, plans next to investigate the newly identified proteins in tissue
samples of people with other tau-linked neurodegenerative diseases, such as
Pick’s disease and chronic traumatic encephalopathy, as well as other forms of
dementia.