PRESS-NEWS.org - Press Release Distribution
PRESS RELEASES DISTRIBUTION

Researchers at Rensselaer Polytechnic Institute uncover mechanism of genetic mutations known to cause familial Alzheimer's disease

New study pinpoints structural effects of V44M and V44A mutations

2014-01-10
(Press-News.org) Contact information: Mary Martialay
martim12@rpi.edu
518-276-2146
Rensselaer Polytechnic Institute
Researchers at Rensselaer Polytechnic Institute uncover mechanism of genetic mutations known to cause familial Alzheimer's disease New study pinpoints structural effects of V44M and V44A mutations Troy, N.Y. - New research, led by Rensselaer Polytechnic Institute researcher Chunyu Wang, has solved one mystery in the development of Familial Alzheimer's Disease (FAD), a genetic variant of the disease that affects a small fraction of the Alzheimer's population. In a paper published online January 6 in the journal Nature Communications, Wang and his team follow the trail of two genetic mutations – V44M and V44A – known to cause FAD, and show how the mutations lead to biochemical changes long linked to the disease.

The hallmark of FAD is the accumulation of the Amyloid Beta 42 peptide (a short chain of amino acids) in unusually high concentrations within the brain. In a healthy brain, Amyloid Beta-42 (Aß42) and a similar peptide, Amyloid Beta-40 (Aß40), are found in a ratio of about 1 to 9. In a brain affected by FAD, this ratio is much higher. The two peptides are nearly identical: Aß40 is a chain of 40 amino acids in length; Aß42 is 42 amino acids in length. However, Aß42 is much more toxic to neurons and plays a critical role in memory failure.

"The mutations that cause FAD lead to an increased ratio of Aß42 over Aß40," said Wang, an associate professor of biological sciences within the School of Science, director of the biochemistry and biophysics graduate program, and member of the Rensselaer Center for Biotechnology and Interdisciplinary Studies, who co-wrote the paper with Wen Chen, who recently earned his doctorate at Rensselaer. "That's the biochemistry, and that has been observed by many people. But the question we asked is: how? How do the mutations lead to this increased ratio?"

There are hundreds of known genetic mutations linked to FAD, but they are all related to the processing of a large protein, the amyloid precursor protein (APP), which starts its life partially embedded in the cell membrane of brain cells, and is later cut into several pieces, one of which becomes either Aß42 or Aß40.

In a multi-step process, enzymes make several cuts to APP, and the location of the cuts dictates whether a resulting snippet of APP becomes Aß42 or Aß40. If an enzyme, γ-secretase, makes an initial cut at an amino acid within APP called Threonine 48 (T48), the remaining cuts result in Aß42, whereas if the first cut is made at amino acid Leucine 49, the process will result in Aß40.

Wang's team used solution nuclear magnetic resonance spectroscopy to study the three-dimensional structure and dynamics of the transmembrane portion of APP affected by the two genetic mutations, and they discovered that the mutations cause a critical change to the T48 amino acid. That change makes it more likely that γ-secretase will prefer a cut at T48, leading to production of Aß42, and increased concentrations of Aß42 found in the brains of patients with FAD.

"The basic idea is that - in the mutated versions - this site, T48, becomes more open, more accessible to γ-secretase," said Wang. "What we found is that the FAD mutation basically opens up the T-48 site, which makes it more likely for γ-secretase to produce Aß42 peptide."

### The paper, titled "Familial Alzheimer's mutations within APPTM increase Aß42 production by enhancing accessibility of ɛ-cleavage site," is available online at: http://go.nature.com/EIkz6C


ELSE PRESS RELEASES FROM THIS DATE:

Bacteria-invading virus yields new discoveries

2014-01-10
Bacteria-invading virus yields new discoveries TALLAHASSEE, Fla. — Innovative work by two Florida State University scientists that shows the structural and DNA breakdown of a bacteria-invading virus is being featured on the cover of the February issue of ...

'Hip-hop' students unfairly targeted, study finds

2014-01-10
'Hip-hop' students unfairly targeted, study finds EAST LANSING, Mich. - Black and Latino "hip-hop" students are disproportionately punished in urban schools, finds a two-year study that sheds light on some of the unfair disciplinary practices newly targeted by the Obama ...

Comprehensive, nonsurgical treatment improves pelvic floor dysfunction in women

2014-01-10
Comprehensive, nonsurgical treatment improves pelvic floor dysfunction in women Women who completed therapy experienced significant improvement in urinary incontinence, defecatory dysfunction and pelvic pain COLUMBIA, Mo. – One in three women suffer from pelvic ...

Mood stabilizing drug may help treat acute kidney injury

2014-01-10
Mood stabilizing drug may help treat acute kidney injury A single dose of lithium helped restore kidney function in mice with acute kidney injury Washington, DC (January 9, 2014) — A mood stabilizer used to treat bipolar affective disorders may also help treat acute kidney ...

Targeting certain kidney cells may help treat kidney failure

2014-01-10
Targeting certain kidney cells may help treat kidney failure Cells cause destructive scarring that contributes to kidney function decline Washington, DC (January 9, 2014) — New research reveals that certain cells contribute to kidney function decline, making them attractive ...

The human Y chromosome is not likely to disappear

2014-01-10
The human Y chromosome is not likely to disappear Is the male Y chromosome at risk of being lost? Recent work by Dr Wilson Sayres and colleagues at UC Berkeley, published in PLOS Genetics, demonstrates that the genes on the Y chromosome are important: ...

Loss of large carnivores poses global conservation problem

2014-01-10
Loss of large carnivores poses global conservation problem CORVALLIS, Ore. – In ecosystems around the world, the decline of large predators such as lions, dingoes, wolves, otters, and bears is changing the face of landscapes from the tropics to the Arctic ...

Capturing a hard-wired variability

2014-01-10
Capturing a hard-wired variability Single cell analysis captures a genomic phenomenon that fuels the complexity and diversity of living things January 09, 2013, New York, NY– A Ludwig Cancer Research study has uncovered a phenomenon that alters ...

Study dispels theories of Y chromosome's demise

2014-01-10
Study dispels theories of Y chromosome's demise Stripped-down chromosome retains key genes for fertility A comparison of Y chromosomes in eight African and eight European men dispels the common notion that the Y's genes are mostly unimportant and ...

Penn research helps lay out theory for metamaterials that act as an analog computer

2014-01-10
Penn research helps lay out theory for metamaterials that act as an analog computer The field of metamaterials has produced structures with unprecedented abilities, including flat lenses, invisibility cloaks and even optical "metatronic" devices that can manipulate ...

LAST 30 PRESS RELEASES:

Exercise as an anti-ageing intervention to avoid detrimental impact of mental fatigue

UMass Amherst Nursing Professor Emerita honored as ‘Living Legend’

New guidelines aim to improve cystic fibrosis screening

Picky eaters by day, buffet by night: Butterfly, moth diets sync to plant aromas

Pennington Biomedical’s Dr. Leanne Redman honored with the E. V. McCollum Award from the American Society for Nutrition

CCNY physicists uncover electronic interactions mediated via spin waves

Researchers’ 3D-printing formula may transform future of foam

Nurture more important than nature for robotic hand

Drug-delivering aptamers target leukemia stem cells for one-two knockout punch

New study finds that over 95% of sponsored influencer posts on Twitter were not disclosed

New sea grant report helps great lakes fish farmers navigate aquaculture regulations

Strain “trick” improves perovskite solar cells’ efficiency

How GPS helps older drivers stay on the roads

Estrogen and progesterone stimulate the body to make opioids

Dancing with the cells – how acoustically levitating a diamond led to a breakthrough in biotech automation

Machine learning helps construct an evolutionary timeline of bacteria

Cellular regulator of mRNA vaccine revealed... offering new therapeutic options

Animal behavioral diversity at risk in the face of declining biodiversity

Finding their way: GPS ignites independence in older adult drivers

Antibiotic resistance among key bacterial species plateaus over time

‘Some insects are declining but what’s happening to the other 99%?’

Powerful new software platform could reshape biomedical research by making data analysis more accessible

Revealing capillaries and cells in living organs with ultrasound

American College of Physicians awards $260,000 in grants to address equity challenges in obesity care

Researchers from MARE ULisboa discover that the European catfish, an invasive species in Portugal, has a prolonged breeding season, enhancing its invasive potential

Rakesh K. Jain, PhD, FAACR, honored with the 2025 AACR Award for Lifetime Achievement in Cancer Research

Solar cells made of moon dust could power future space exploration

Deporting immigrants may further shrink the health care workforce

Border region emergency medical services in migrant emergency care

Resident physician intentions regarding unionization

[Press-News.org] Researchers at Rensselaer Polytechnic Institute uncover mechanism of genetic mutations known to cause familial Alzheimer's disease
New study pinpoints structural effects of V44M and V44A mutations