December 03, 2020
04/12/2020
December 03, 2020
LA JOLLA, CA A new study on Alzheimer's disease by Scripps Research scientists has revealed a previously unknown biochemical cascade in the brain that leads to the destruction of synapses, the connections between nerve cells that are responsible for memory and cognition.
The findings present a fresh angle for discovering drugs that treat Alzheimer's disease, which affects roughly 50 million people worldwide. The study, led by Scripps Research Professor and Step Family Foundation Endowed Chair Stuart Lipton, MD, PhD, appears in the journal Science.
This newly-discovered series of abnormal chemical events, termed protein transnitrosylation reactions, contribute to synapse loss, the main driver of memory loss and cognitive decline in Alzheimer's.
Lipton, who is also a clinical neurologist, explains that most recent attempts to develop Alzheimer's treatments have targeted the sticky protein known as beta amyloid that accumulates in the brain of patients, disrupting cell communication and causing inflammation. However, for a variety of reasons, these attempts have failed in clinical trials.
This work gives us new hope for better therapeutic targets, as the reactions we discovered are downstream of amyloid action, Lipton says. We've opened up a whole new avenue for drug development.
Lipton is no stranger to drug development for Alzheimer's and Parkinson's diseases. Drugs developed in and patented by his laboratory have led to four FDA-approved medicines for these diseases, including the widely prescribed drug, memantine (Namenda ). Much better drugs are needed, however, Lipton says.
A chemistry success story
In the new study, Lipton and his team used physical chemistry techniques to quantify how electrons participate in chemical reactions, as they suspected unknown processes may be taking place in the brain. Through this, they uncovered the entirely new series of biochemical events in nerve cells affected by Alzheimer's.
They found that small clumps of beta amyloid protein trigger excessive neuron activity and inflammation, leading to the destructive series of transnitrosylation reactions.
The process begins with excessive levels of nitrogen (N) and oxygen (O) atoms joining together as an NO group, which is then transferred to a protein building block called cysteine to regulate the activity of the protein. A series of these aberrant protein reactions cuts off energy to the brain's nerve cells by disrupting their mitochondria organelles that generate power for the cell's biochemical reactions. This eventually leads to loss of synapses connecting the nerve cells.
We were able to show that these reactions occur in brains of Alzheimer's patients, and when we prevented these reactions in the brains of animal models of the disease, we protected the synapses, Lipton says. Our findings suggest that it may be possible to intercede to reverse synapse damage in spite of plaques and tangles, he added, referring to plaques of beta amyloid and tangles of misfolded tau protein, both of which are characteristic of Alzheimer's disease.
He notes that while normal levels of NO foster memory and learning, excessive levels can build up as we age and become harmful to synapses.
With this new knowledge, we may be able to restore synaptic connections in Alzheimer's patients after extensive plaques and tangles have formed in their brains, adds Tomohiro Nakamura, PhD, senior staff scientist in the Lipton laboratory group and first author of the study.
Revealing secret connections
Lipton says that one of the team's most incredible findings was that the three enzymes discovered to pass NO to each other along a concerted chain of events, resulting in energy failure, were previously not thought to be even remotely related to one another. Each of the enzymes is important in its own right in a completely disparate normal biochemical pathway, and yet they interact under disease conditions in a novel manner to trigger intense neuronal stress and synapse damage.
This type of hidden or ghost' pathway may only become evident under disease conditions and may represent an important fundamental tenet of why we did not understand the disease process previously, Lipton says. If we do not know about a pathway, scientists cannot study its contribution to disease or develop drugs to treat it.
While many molecular biochemical pathways have been discovered, an over-reliance on this existing body of evidence can actually impede discovery of disease processes, he adds.
Hence, the most important aspect of the work is that we have to be on our guard to look for new pathways and new relationships of existing enzymes in order to understand and treat neurodegenerative disorders such as Alzheimer's, Lipton says.
In addition to Nakamura and Lipton, other authors of Non-canonical transnitrosylation network contributes to synapse loss in Alzheimer's disease, include Chang-ki Oh, Xu Zhang, Kevin Lopez, Amanda Deal, Henry Scott, Lujian Liao and John R. Yates III from Scripps Research; and Daniel Gibbs, Brian Spencer, Robert Rissman and Eliezer Masliah from the University of California, San Diego.
The work was funded by the National Institutes of Health and philanthropic support.
Neurological Disorders Lipton, Stuart
LINK: | https://www.scripps.edu/news-and-events/press-room/2020/20201204-lipto... |
See more stories from scripps |
More from Scripps
20/04/2024
April 19, 2024
New copper-catalyzed C-H activation strategy from Scripps Research Two-mode reactions inspired by human detox enzymes offer powerful new tools for drug discover...
12/04/2024
April 11, 2024
Scripps Research chemists devise easier new method for making a common type of building block for drugs Scientists transform simple linear amines into saturated...
06/04/2024
April 05, 2024
A simple, inexpensive way to make carbon atoms bind together A Scripps Research team uncovers a cost-effective method for producing quaternary carbon molecules,...
04/04/2024
April 03, 2024
Developing a vaccine for the zombie drug xylazine Scripps Research chemical biologists design an early proof-of-concept vaccine that could lead to the first...
30/03/2024
March 29, 2024
How blocking a neural receptor responsible for addiction could reduce alcohol use A Scripps Research team found that a new therapeutic that targets the kappa op...
13/03/2024
March 13, 2024
New computational strategy boosts the ability of drug designers to target proteins inside the membrane Customized-design approach could streamline the design of...
29/02/2024
February 29, 2024
Scripps Research scientists reveal how first cells could have formed on Earth New phospholipid discovery brings researchers closer to understanding how primordi...
29/02/2024
February 28, 2024
How molecular handedness emerged in early biology Scripps Research chemists fill a major gap in origin-of-life theories. February 28, 2024 LA JOLLA, CA Mole...
22/02/2024
February 21, 2024
Snaking toward a universal antivenom Scripps Research scientists discovered antibodies that protect against a host of lethal snake venoms. February 21, 2024 ...
06/02/2024
February 06, 2024
Calibr-Skaggs announces expansion of option and license agreement with AbbVie to develop novel cell therapies for solid tumors and autoimmune diseases AbbVie...
26/01/2024
January 25, 2024
Re-energizing mitochondria to treat Alzheimer's disease Scripps Research team restored neuron-to-neuron connections in human cells. January 25, 2024 LA JO...
24/01/2024
January 04, 2024
100 years of Science Changing Life: Scripps Research celebrates a century of transforming human health For the last century, institute leaders and renowned scie...
23/01/2024
January 23, 2024
New technology lets researchers track brain cells' off switches The method could shed light on what goes awry in numerous brain conditions when neurons ar...
09/01/2024
January 08, 2024
Three decades of giving: Announcing the Calibr-Skaggs Institute for Innovative Medicines The ALSAM Foundation, founded by the Skaggs family, provides lasting g...
04/01/2024
January 03, 2024
Life science entrepreneur Gene Lay joins Scripps Research Board of Directors Lay, founder of the global biotech company BioLegend, brings invaluable experience ...
21/12/2023
December 20, 2023
Taming a plant-derived toxin Scripps Research team modifies the traditional poison picrotoxinin for potential neurological drugs and anti-parasite treatments. ...
19/12/2023
December 18, 2023
Scripps Research Executive Vice President Eric Topol gives TED talk on transformative power of AI in medicine Topol provides an overview of how AI models can i...
13/12/2023
December 12, 2023
New AI-powered algorithm could better assess people's risk of common heart condition Early detection of atrial fibrillation can reduce the risk of stroke an...
07/12/2023
December 06, 2023
Nanoparticle flu vaccine design shows promise in early tests Scripps Research-designed vaccine could provide broad, enduring protection against influenza A str...
16/11/2023
November 15, 2023
Numerous Scripps Research scientists named Highly Cited Researchers Clarivate's annual, global list represents researchers who have demonstrated significant...
07/11/2023
November 06, 2023
Multiple sclerosis drug invented at Scripps Research slows long-term devastating disease progression Late-breaking data reinforces the effectiveness and safety ...
05/10/2023
October 04, 2023
Keren Lasker named a 2023 Moore Inventor Fellow The prestigious award will support Lasker's inventive research in membraneless organelles and their applica...
22/09/2023
September 21, 2023
Michael Bollong named a 2023 Amgen Young Investigator The prestigious award will support Bollong's research identifying new molecular targets and therapeuti...
09/09/2023
September 08, 2023
Philip Dawson receives 2024 American Chemical Society National Award Dawson is honored with the Arthur C. Cope Late Careers Scholar Award for his foundational c...
07/09/2023
September 06, 2023
Scripps Research chemists devise a method for C-H activation of alcohols The method represents a new toolkit for making drugs and other compounds. September 06...
31/08/2023
August 30, 2023
Scripps Research receives $1.5M to surveil infectious disease threats in wastewater Bill & Melinda Gates Foundation award to support the development of multi-pa...
16/08/2023
August 16, 2023
How cold temperatures trigger the brain to boost appetite Scripps Research scientists' discovery could lead to new weight loss and metabolic health treatmen...
08/08/2023
August 07, 2023
Human antibody that targets carfentanil, fentanyl and related opioids reverses overdose effects in preclinical study Scripps Research-developed antibody therapy...
04/08/2023
August 03, 2023
How sensory neurons impact the gut Scripps Research scientists show that the receptor PIEZO2 in sensory neurons controls gut motility and transit time, which a...
26/07/2023
July 26, 2023
AbbVie and Calibr Expand Strategic Collaboration to Advance Several Preclinical and Early-stage Clinical Assets The expanded strategic collaboration will advan...
23/07/2023
July 21, 2023
Scripps Research scientists develop AI-based tracking and early-warning system for viral pandemics Machine-learning system effectively predicts emergence of pro...
19/07/2023
July 19, 2023
Monitoring T cells may allow prevention of type 1 diabetes Scripps Research study shows that analyzing T cells in blood samples could be used to select at-risk ...
19/07/2023
July 18, 2023
Scripps Research mourns passing of leading organic chemist Albert Eschenmoser Eschenmoser pioneered key reactions in synthetic chemistry and shaped the understa...
15/06/2023
June 14, 2023
Scripps Research awarded $46.8 million by NIH to promote human health through innovative translational science and training The Translational Institute is harne...
13/06/2023
June 13, 2023
Scripps Research's Danielle Grotjahn named 2023 Pew Scholar in the Biomedical Sciences The award will support Grotjahn's study of how cells assemble the...
31/05/2023
May 31, 2023
Crossing the ring: new method enables C-H activation across saturated carbocycles Scripps Research chemists add another powerful tool to their molecular editin...
24/05/2023
May 23, 2023
Scripps Research develops behind-the-scenes tool for better biomedical data discovery The new resource makes datasets more discoverable for life science communi...
19/05/2023
May 15, 2023
Scripps Research neuroscientist Hollis Cline elected to American Academy of Arts and Sciences Cline is recognized for her discoveries about the role of sensory ...
19/05/2023
May 18, 2023
Scripps Research's Skaggs Graduate School awards doctoral degrees to 31st graduating class Commencement ceremony will be livestreamed via Zoom and on instit...
13/05/2023
May 12, 2023
A better route to benzocyclobutenes, sought-after building blocks for drugs Scripps Research chemists devise a new, C-H activation-based method for the synthesi...
09/05/2023
May 08, 2023
Renowned Scripps Research professor Jeffery Kelly elected to National Academy of Sciences Kelly's groundbreaking work on protein misfolding has led to thera...
28/04/2023
April 27, 2023
Mirror-image molecules pave new path for cancer drug discovery By comparing how mirror image versions of small molecules impact clusters of proteins, Scripps R...
22/04/2023
April 21, 2023
How alcohol consumption contributes to chronic pain A Scripps Research team showed how both alcohol intake and alcohol withdrawal can lead to increased pain and...
21/04/2023
April 20, 2023
Xin Jin receives dual awards to study autism risk genes in neurodevelopment Major grants from the National Institutes of Health and California Institute for Reg...
20/04/2023
April 19, 2023
Trim the sugar: New HIV vaccine design improves immune response Scripps Research vaccine candidate headed for clinical trials. April 19, 2023 LA JOLLA, CA A...
18/04/2023
April 17, 2023
Therapeutic can seek and destroy potent opioid to treat overdoses Scripps Research chemists developed a new biologic to work against the synthetic opioid carfen...
07/03/2023
March 06, 2023
How heavy alcohol consumption increases brain inflammation The findings by a Scripps Research team point toward a potential new drug target for treating alcohol...
02/03/2023
March 01, 2023
Scientists find human antibodies that can block multiple coronaviruses including SARS-CoV-2 Results from a Scripps Research and UNC team pave the way for a vacc...
28/02/2023
February 28, 2023
$10 million grant funds Scripps Research Alcohol Research Center through its 50th year The five-year grant supports research into the neurobiology of alcohol us...
28/02/2023
February 27, 2023
Immune system drug shows promise in treating alcohol use disorder, a Scripps Research clinical trial reports Scientists at Scripps Research found that apremilas...