Western Reserve University School of Medicine researchers say newly found
protein is bio-marker for disease; suggest suppression of ‘aggregatin’ could
lead to future treatments to slow Alzheimer’s progression
Researchers at Case Western Reserve University School of Medicine say they have identified a previously unknown gene and associated protein that could potentially be suppressed to slow the advance of Alzheimer’s disease.
“Based on the data we have, this protein can be an unrecognized new risk factor for Alzheimer’s disease (AD),” said Xinglong Wang, an associate professor of pathology at the School of Medicine. “We also see this as a potential novel therapeutic target for this devastating disease.”
Wang said proving the latter
assertion, which has not yet been tested in humans, would require additional
research to corroborate the function of the protein they have dubbed “aggregatin.”
Eventually, that would someday mean clinical trials with
Alzheimer’s patients, he said.
“This protein characteristically accumulates, or aggregates, within the center of plaque in AD patients, like the yolk of an egg—which is part of the reason we named it ‘aggregatin,’” Wang said.
A research team led by Wang and Xiaofeng Zhu, a professor of population and quantitative health sciences at the School of Medicine, has filed for a patent through the university’s Office of Research and Technology Management for “novel Alzheimer’s disease treatments and diagnosis based on this and related study,” Wang said.
“We’re very excited about this because our study
is likely the first systematic work combining the identification from a genome-wide
association study of high dimensional brain-imaging data and experimental
validation so perfectly in Alzheimer’s disease,” Zhu said.
More than 5.7 million Americans have Alzheimer’s disease,
which is the primary cause of dementia and sixth-leading cause of death in the
United States. That population is predicted to reach 14 million by the year
2050, according to the Alzheimer’s Association.
The relationship between Alzheimer’s (and subsequent
brain atrophy) and amyloid plaques—the hard
accumulations of beta amyloid proteins
that clump together between the nerve cells (neurons) in the brains of
Alzheimer’s patients—has been well-established among researchers.
Less understood is precisely how that amyloid-beta actually
leads to plaque formation—and where this new work appears to have broken new
ground, Wang said.
Further, while there has been much research
into what genes might influence whether or not someone gets Alzheimer’s, there
is less understanding of genes that might be linked to the progression of the disease, meaning the formation of plaque and
subsequent atrophy in the brain.
role of ‘aggregatin’ protein
In the new work, the researchers began by correlating
roughly a million genetic markers (called single-nucleotide polymorphisms, or SNPs)
with brain images. They were able to identify a specific SNP in the FAM222, a
gene linked to different patterns of regional brain atrophy.
Further experiments then suggested that the
protein encoded by gene FAM222A is not only associated with AD patient-related
beta-amyloid plaques and regional brain atrophy, but that “aggregatin” attaches
to amyloid beta peptide—the major component of plaque and facilitates the plaque
So when researchers injected mouse models with
the “aggregatin” protein (made from the FAM222A gene), plaque
(amyloid deposits) formation accelerated in the brain, resulting in more neuroinflammation
and cognitive dysfunction. This happened, they report, because the protein was
found to bind directly the amyloid beta peptide, thus facilitating the
aggregation and placque formation, Wang said.
Conversely, when they suppressed the protein, the plaques
were reduced and neuroinflammation and cognitive impairment alleviated.
Their findings indicate that reducing levels of this
protein and inhibition of its interaction with amyloid beta peptide could
potentially be therapeutic—not necessarily to prevent Alzheimer’s but to slow its
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