Hidden network of enzymes accounts for loss of brain synapses in Alzheimer's The discovery of abnormal chemical reactions may lead to novel targets for drugs that treat neurodegenerative diseases.
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 Molecular and Cellular Biology Lipton, Stuart
Most recent headlines
22/12/2025
SVG New Sponsor Spotlight: Presidio's Neerav Shah on the Role of Its Captiva...
22/12/2025
Hitting the bullseye: Sky Sports readies itself for the biggest PDC World Darts ...
22/12/2025
Unique skillset: Bringing new directors to the world of darts at The Worlds with...
22/12/2025
Gravity Media prepares for a flight of fancy with the PDC World Darts Championsh...
22/12/2025
One hundred and eighty: Gravity Media on hitting the production bullseye at the ...
22/12/2025
The Famous Group's Jon Slusser on Fascinating Fans Through Immersive Content...
22/12/2025
ESPN's Meg Aronowitz on Continuing High-Quality Broadcasts of Collegiate Spo...
22/12/2025
ESPN Takes Data-Driven Storytelling to New Heights with MNF Playbook with Next ...
22/12/2025
For a decade, popular German podcast Fest & Flauschig has hosted an annual Chris...
22/12/2025
Paramount Scores Largest Share Increase Among Distributors as Paramount and CBS...
22/12/2025
New multi-year deal integrates Roku's data to fuel Nielsen's measurement suite
Roku gains access to Nielsen's streaming ratings, showing The Roku C...
22/12/2025
Share Share by:
Copy link
Facebook
X
Whatsapp
Pinterest
Flipboard...
22/12/2025
Berklee Wrapped 2025: Our Top News and Stories A look back at a year highlighted by faculty milestones, major film and television projects, Bob Dylan's ho...
22/12/2025
Partnership integrates complementary satellite data and AI analytics to enhance security, infrastructure, and environmental monitoring solutions for global cust...
22/12/2025
Workflows allow you to create a sequence of planned events which may be added to your template(s) or inserted directly into your sequential or background playli...
22/12/2025
Monday 22 December 2025
Sky extends PGA TOUR partnership until 2029, as Sky Spo...
22/12/2025
Back to All News
Global Anime Hits and New Releases Take Center Stage at Jump Festa 2026
Entertainment
22 December 2025
GlobalJapan
Link copied to clipboar...
22/12/2025
Siobh n McSweeney, Rory McIlroy, Elon Musk, Catherine Connolly, Jim Gavin, Ivan Yates and Traitor Paudie Moloney lead new characters for Callan Kicks the Year 2...
22/12/2025
Winner announced in the picturesque surroundings of Wicklow's Avondale Tower and Treetop Walk
Andrew Trimble wins the show in his first series as coach
Th...
22/12/2025
The 2025 winners have been announced today, Sunday 21 December, for Ireland's largest choral competition Choirs for Christmas hosted by RT lyric fm.
Ove...
21/12/2025
Back to All News
Legoshi and Haru's Story Reaches Its Finale: BEASTARS Fin...
21/12/2025
John Shortt named Young Sportsperson of the Year Kerry are the Team of the Year
...
20/12/2025
Atomos announced the immediate availability of a new firmware update for its Ninja TX GO and Ninja TX monitor-recorders, unlocking ProRes RAW recording from the...
20/12/2025
CJP Broadcast has completed the digitisation of the European Gymnastics tape archive, converting 328 tapes containing more than forty years of recorded material...
20/12/2025
Bitmovin, the leading provider of video streaming solutions, today announced the launch of the Stream Lab MCP Server, to give AI agents and large language model...
20/12/2025
Share Share by:
Copy link
Facebook
X
Whatsapp
Pinterest
Flipboard...
20/12/2025
Share Share by:
Copy link
Facebook
X
Whatsapp
Pinterest
Flipboard...
20/12/2025
Share Share by:
Copy link
Facebook
X
Whatsapp
Pinterest
Flipboard...
20/12/2025
Share Share by:
Copy link
Facebook
X
Whatsapp
Pinterest
Flipboard...
20/12/2025
Share Share by:
Copy link
Facebook
X
Whatsapp
Pinterest
Flipboard...
20/12/2025
Share Share by:
Copy link
Facebook
X
Whatsapp
Pinterest
Flipboard...
20/12/2025
Barack Obama Includes Laufey on His 2025 Favorite Music List The former presidents roundup of books, music, and movies includes a song from the Berklee alums ...
20/12/2025
Study reveals a key hormonal circuit in the kidneys Scripps Research scientists identify the protein that helps kidney cells regulate renin, providing foundatio...
19/12/2025
With Playout Release 2025.4, ToolsOnAir continues to push professional playout w...
19/12/2025
SVG Sit-Down: Diversified's Jared Timmins on AI for Broadcast Sports and Cre...
19/12/2025
2025 SVG Summit Audio Recap: Say What?The Audio Production and Distribution Workshop at the SVG Summit 20 took on issues including speech intelligibility, Next-...
19/12/2025
Gamified fun: Channel 5 on its NFL Big Game Night ambitions with Hungry Bear Med...
19/12/2025
College Football Playoff Preview: For ESPN, Round 1 is a Fantastic Yet Familia...
19/12/2025
AWS's Jason Dvorkin on Developing Partnerships With the NBA and PGA Tour, Em...
19/12/2025
Netflix Kicks Off Packed Sports Week with Paul-Joshua Fight Before Shifting to N...
19/12/2025
SVG New Sponsor Spotlight: Presidio's Nareev Shah on the Role of Its Captiva...
19/12/2025
Mounted to the pylon of an AH-1Z Viper helicopter, a Red Wolf vehicle successful...
19/12/2025
L3Harris technology for the SDA Tranche 3 Tracking Layer program will provide in...
19/12/2025
Partnership brings Nielsen ONE measurement activation directly into XR's adv...
19/12/2025
Share Share by:
Copy link
Facebook
X
Whatsapp
Pinterest
Flipboard...
19/12/2025
Share Share by:
Copy link
Facebook
X
Whatsapp
Pinterest
Flipboard...
19/12/2025
Berklee Announces Spring 2026 Signature Series This season's highlights include the Gospel Extravaganza, the 40th International Folk Festival, special gue...
19/12/2025
Performing arts centres across the globe have doubled down on live production infrastructure in recent years. For venues like the Queensland Performing Arts Cen...
19/12/2025
Share Share by:
Copy link
Facebook
X
Whatsapp
Pinterest
Flipboard...
Hidden network of enzymes accounts for loss of brain synapses in Alzheimer's The discovery of abnormal chemical reactions may lead to novel targets for drugs that treat neurodegenerative diseases. 
