Nav: Home

New research adds evidence on potential treatments targeting amyloid beta in Alzheimer's

July 28, 2016

New research findings from the Center for Cognitive Neurology at NYU Langone Medical Center could provide additional clues for future treatment targets to delay Alzheimer's disease and related dementias. This is according to the group's latest findings that will be presented at the Alzheimer's Association International Conference (AAIC), July 24 to July 28 in Toronto.

Alzheimer's disease, the most common form of dementia, is an incurable, degenerative disease that causes problems with memory, thinking and behavior. Alzheimer's and other dementias affect 47 million people worldwide and 5.3 million Americans, numbers that are expected to triple by 2050, according to the Alzheimer's Association. At this time, there is no cure -- but research such as that presented at the AAIC meeting is aimed at finding ways to delay symptom onset and improve quality of life for patients, and may ultimately pave the way for more treatments.

New Target for Prevention

New research in mice by NYU Langone researchers may pave the way for clinical trials to test medications known as Carbonic Anhydrase Inhibitors (CAIs) as potential treatments for Alzheimer's, targeting the mechanism thought to be behind the neural and vascular death often associated with the disease.

It is now widely accepted that mitochondrial dysfunction -- a destruction of the organelles that regulate energy metabolism and death in a cell - triggers the progression of the neuronal and vascular death seen in many Alzheimer's patients. Mitochondrial dysfunction is caused by a buildup of amyloid beta proteins, which, in turn leads to plaque accumulation in the brain.

In their study, NYU Langone researchers found that CAI medications -- previously approved by the U.S. Food and Drug Administration (FDA) for other conditions like glaucoma -- target the mechanism behind this dysfunction.

"Therapies aimed at preventing mitochondrial failure may represent promising new strategies as we search for a cure for this devastating disease," says lead study author Silvia Fossati, PhD, an assistant professor of neurology and psychiatry at NYU Langone.

For the study, Fossati and colleagues looked at two FDA-approved CAIs: methazolamide and acetazolamide. For the first time, these medications were tested in cell cultures and mouse models that showed a buildup of amyloid-beta protein in the brain, known as amyloidosis. In the mice with amyloidosis, the researchers showed for the first time a positive effect of these drugs on memory, amyloid deposition, and activation of enzymes called caspases that drive cell death mechanisms in the brain.

The researchers believe that the protective effects of these compounds may be due to their prevention of mitochondrial dysfunction, as well as their known effects as activators of cerebral blood flow, which induce more efficient elimination of amyloid beta proteins from the brain. Further studies aim to test similar compounds in animal models, and since these drugs are already FDA-approved, Fossati adds that future research may involve the planning of a fast-track clinical trial in early stage Alzheimer's or mild cognitive impaired (MCI) patients.

Embargoed for Monday, Monday July 25, 2016, 9:30-10:30 AM. Fossati et al. Carbonic Anhydrase is a Crucial Target for Prevention of Mitochondrial Pathology in Alzheimer's Models. Poster Presentation #P2-099; Monday July 25, 2016, 9:30-10:30 AM, Metro Toronto Convention Centre Room: Hall D/E

Immunotherapy Used to Reduce Levels of Amyloid Beta Proteins

Reducing amyloid-beta proteins through immunotherapy has shown benefits in previous mice studies. However, new research led by Martin Sadowski, MD, an associate professor of neurology, psychiatry, and biochemistry and molecular pharmacology, at NYU Langone, suggests that more studies are needed to reduce potential risks associated with this possible approach to treatment.

Genetic variants of apolipoprotein E (APOE), a specific gene mapped to chromosome 19, is among the most significant factors predicting susceptibility to Alzheimer's disease caused by buildup of amyloid beta plaques. There are three variants of APOE: APOE ε2, APOE ε3 and APOE ε 4. Previous research has shown that variant APOE ε4 significantly increases Alzheimer's disease risk, while APOE ε 2 reduces risk for the disease; the impact of APOEε3 is less known. An estimated 20 percent of people carry the risk-increasing APOE ε4 genetic variant.

Immunotherapy has been studied to target amyloid beta plaque build-up, but previous studies have shown that APOE ε4 subjects are prone to develop specific adverse effects called Amyloid Related Imaging Abnormalities (ARIA), which include micro-hemorrhages, or bleeding of the brain, when given this treatment.

In the new study, Sadowski and colleagues examined the effect of amyloid beta immunotherapy in Alzheimer's transgenic mice, engineered to have each of the three genetic variants of human APOE. They found a greater effect of immunotherapy on reducing the load of amyloid-beta deposits in mice expressing the APOE ε 4 variant than in mice expressing other APOE variants. Clearance of amyloid-beta deposits was associated with increased activation of brain cells called microglia, which uptake and digest amyloid beta. Microglia activation was much greater in mice expressing the APOE ε 4 variant than in mice expressing other APOE variants, which may cause harmful effect of stimulated microglia on the brain.

The researchers also discovered that in Alzheimer transgenic mice, APOE variants have different effects on amyloid beta deposition in the walls of brain vessels, with the APOE ε 4 promoting deposition of amyloid beta in large vessels, while APO ε2 lead to more amyloid beta deposition in the brain's micro-vessels.

Immunotherapy cleared brain vessels of amyloid beta, but it was associated with increased incidence of brain bleeding. The greatest incidence of brain bleeds was noticed in APOE ε 2 mice while the lowest was found in APOE ε 3 mice.

These new findings provide previously unknown information that may aid in development of immunologic treatments for Alzheimer's.

"Our study identifies the previously underappreciated risk-promoting effect of APOE ε 2 and the protective effect of APOE ε 3 on the incidence of brain bleeding associated with amyloid-beta immunization," says Sadowski. "This is an important observation in a mouse model that may influence how immunotherapy treatments, such as vaccines, for Alzheimer's are developed and one day tested in humans."
Embargoed for Thursday, July 28, 11:45 AM - 12:00 PM
Sadowski et al. Apolipoprotein E Genotype Differentially Modulates Effects of Anti-AB Immunotherapy.
Oral Presentation # O5-03-01: Thursday, July 28, 2016: 11:45 AM - 12:00 PM, Metro Toronto Convention Centre Room: 718

NYU Langone Medical Center / New York University School of Medicine

Related Brain Articles:

Unique insight into development of the human brain: Model of the early embryonic brain
Stem cell researchers from the University of Copenhagen have designed a model of an early embryonic brain.
An optical brain-to-brain interface supports information exchange for locomotion control
Chinese researchers established an optical BtBI that supports rapid information transmission for precise locomotion control, thus providing a proof-of-principle demonstration of fast BtBI for real-time behavioral control.
Transplanting human nerve cells into a mouse brain reveals how they wire into brain circuits
A team of researchers led by Pierre Vanderhaeghen and Vincent Bonin (VIB-KU Leuven, Université libre de Bruxelles and NERF) showed how human nerve cells can develop at their own pace, and form highly precise connections with the surrounding mouse brain cells.
Brain scans reveal how the human brain compensates when one hemisphere is removed
Researchers studying six adults who had one of their brain hemispheres removed during childhood to reduce epileptic seizures found that the remaining half of the brain formed unusually strong connections between different functional brain networks, which potentially help the body to function as if the brain were intact.
Alcohol byproduct contributes to brain chemistry changes in specific brain regions
Study of mouse models provides clear implications for new targets to treat alcohol use disorder and fetal alcohol syndrome.
Scientists predict the areas of the brain to stimulate transitions between different brain states
Using a computer model of the brain, Gustavo Deco, director of the Center for Brain and Cognition, and Josephine Cruzat, a member of his team, together with a group of international collaborators, have developed an innovative method published in Proceedings of the National Academy of Sciences on Sept.
BRAIN Initiative tool may transform how scientists study brain structure and function
Researchers have developed a high-tech support system that can keep a large mammalian brain from rapidly decomposing in the hours after death, enabling study of certain molecular and cellular functions.
Wiring diagram of the brain provides a clearer picture of brain scan data
In a study published today in the journal BRAIN, neuroscientists led by Michael D.
Blue Brain Project releases first-ever digital 3D brain cell atlas
The Blue Brain Cell Atlas is like ''going from hand-drawn maps to Google Earth'' -- providing previously unavailable information on major cell types, numbers and positions in all 737 brain regions.
Landmark study reveals no benefit to costly and risky brain cooling after brain injury
A landmark study, led by Monash University researchers, has definitively found that the practice of cooling the body and brain in patients who have recently received a severe traumatic brain injury, has no impact on the patient's long-term outcome.
More Brain News and Brain Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Meditations on Loneliness
Original broadcast date: April 24, 2020. We're a social species now living in isolation. But loneliness was a problem well before this era of social distancing. This hour, TED speakers explore how we can live and make peace with loneliness. Guests on the show include author and illustrator Jonny Sun, psychologist Susan Pinker, architect Grace Kim, and writer Suleika Jaouad.
Now Playing: Science for the People

#565 The Great Wide Indoors
We're all spending a bit more time indoors this summer than we probably figured. But did you ever stop to think about why the places we live and work as designed the way they are? And how they could be designed better? We're talking with Emily Anthes about her new book "The Great Indoors: The Surprising Science of how Buildings Shape our Behavior, Health and Happiness".
Now Playing: Radiolab

The Third. A TED Talk.
Jad gives a TED talk about his life as a journalist and how Radiolab has evolved over the years. Here's how TED described it:How do you end a story? Host of Radiolab Jad Abumrad tells how his search for an answer led him home to the mountains of Tennessee, where he met an unexpected teacher: Dolly Parton.Jad Nicholas Abumrad is a Lebanese-American radio host, composer and producer. He is the founder of the syndicated public radio program Radiolab, which is broadcast on over 600 radio stations nationwide and is downloaded more than 120 million times a year as a podcast. He also created More Perfect, a podcast that tells the stories behind the Supreme Court's most famous decisions. And most recently, Dolly Parton's America, a nine-episode podcast exploring the life and times of the iconic country music star. Abumrad has received three Peabody Awards and was named a MacArthur Fellow in 2011.