Scientists may have found a target for new treatments for Alzheimer’s disease.
- With an aging population
worldwide, neurodegenerative diseases, such as dementia, are an increasing
problem.
- Although there are treatments
for neurodegenerative diseases, these generally alleviate symptoms, rather
than changing the course of the disease.
- Now, research has found that
a protein that regulates cell repair could be a promising new target for
treating several of these conditions, including the most common,
Alzheimer’s disease.
Neurodegenerative diseases occur when nerve cells in the
brain and peripheral nervous system lose function and eventually die. They
include Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS — also known as motor
neuron disease), among others.
In the United States, an
estimated 6.9 million people aged 65 and over are living with
Alzheimer’s disease, and around a million have Parkinson’s. ALS is less common; the CDC
estimates that around 31,000 people in the U.S. have the condition.
Current treatments can alleviate
symptoms and some slow the progression of the diseases, but no cures are yet
available. New monoclonal antibody treatments for Alzheimer’s have shown some
potential for modifying the course of the disease, but many experts are
concerned about side effects.
In the search for new therapies,
research from Penn State University has identified a group of proteins that
could be a target for new treatments for Alzheimer’s and other
neurodegenerative disorders.
The researchers, who have a patent related to this work, found that reducing the function
of heparan-sulfate-modified proteoglycans (HSPGs) helped reverse cell damage
from neurodegenerative diseases.
Their study is published iniScience.
“This is interesting research which
shows how cells might be protected from the effects of genetic mutations that
cause Alzheimer’s disease. However, as it has only been shown in fruit flies
and human cells from outside of the brain, it’s hard to say just how relevant
the findings are at the moment. We’re excited to see the next stage of this
research, to see if similar effects can be seen in human brain cells.”—
Katherine Gray, Alzheimer’s
Society’s head of research
Proteins influence cell repair
HSPGs, which are found on the
surface of cells and in the extracellular matrix, regulate cell repair and
enhance cell growth-signaling systems. The heparan
sulfate (sugar) chains attach to proteins so they can influence
processes including cell growth, interaction between the cell and its
environment, and autophagy — a process that clears out protein aggregates (a
feature of Alzheimer’s disease) and damaged parts of cells.
Research leader Scott Selleck,
professor of biochemistry and molecular biology at the Penn State Eberly
College of Science, said in a press release:
“In the early stages of several
neurodegenerative diseases, autophagy is compromised, which means cells have a
reduced repair capacity.”
Reducing proteins’ effects reversed neurodegenerative
changes
“In this study, we determined that
heparan sulfate-modified proteins suppress autophagy-dependent cell repair.
What’s more, we show that by compromising the structure and function of the
sugar modifications of these proteins, the levels of autophagy increase so
cells can take care of damage.— Scott Selleck, research leader
Studies have noted heparan sulfate abnormalities in
Alzheimer’s disease, but their specific role in the development of the disorder
has not yet been uncovered.
By carrying out analyses on human
cell lines and mouse brain cells that express aspects of Alzheimer’s,
researchers in this study first showed that HSPGs regulate cell processes that
are affected in several neurodegenerative diseases.
They then
reduced the function of the HSPGs in these cells and found that two changes
that happen early in the course of neurodegenerative diseases were reversed.
The function of the mitochondria — which provide energy for the cell — was
improved, and that lipid (fat) buildup in the cells was reduced.
To verify their findings, the
researchers used an animal model of Alzheimer’s. They used fruit flies that had
been modified to have deficits in presenilin protein, which mimics the effect
of a mutation in the presenilin
gene, PSEN1, the most common cause of familial (early-onset)
Alzheimer’s.
Selleck explained that a rare
genetic change in another protein, APOE, can delay the effect
of the PSEN1 mutation, sometimes for decades. He suggested that targeting these
two substances and the enzymes that make heparan sulfate could help prevent
neurodegeneration in people.
In the fruit flies, the researchers
reduced the functioning of HSPGs, which suppressed the death of nerve cells and
corrected other cell defects.
They
suggest that disrupting the structure of heparan sulfate modifications blocks
or reverses early cellular problems in these models of Alzheimer’s.
Potential treatment for early stage neurodegeneration
Selleck highlighted the potential of
the team’s findings:
“There is a critical need to focus
on cellular changes that occur at the earliest times in disease progression and
develop treatments that block or reverse them,” he said in a press release.
“We
demonstrate that reduced autophagy, mitochondrial defects and lipid build-up —
all common changes in neurodegenerative disease — can be blocked by altering
one class of proteins, those with heparan sulfate modifications. We think these
molecules are promising targets for drug development,” he added.
Courtney Kloske, Ph.D., Alzheimer’s Association director of scientific
engagement, welcomed the findings but emphasized that further research was
needed:
“This interesting but very
preliminary study is based on research in a fruit fly model of Alzheimer’s.
While animal models of the disease are somewhat similar to how Alzheimer’s
progresses in humans, they do not replicate the disease in humans exactly.”
“Models are important in helping us
understand the basic biology of the disease, but we need human studies in
representative populations for ideas to be fully validated. Therefore, more
research is needed to understand the possible role of heparan sulfate-modified
proteins in Alzheimer’s as studied in this manuscript” she told Medical
News Today.
https://www.medicalnewstoday.com/articles/possible-new-target-early-treatment-alzheimers-disease
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