Navigation Links
New Tel Aviv University research links Alzheimer's to brain hyperactivity
Date:6/30/2014

Patients with Alzheimer's disease run a high risk of seizures. While the amyloid-beta protein involved in the development and progression of Alzheimer's seems the most likely cause for this neuronal hyperactivity, how and why this elevated activity takes place hasn't yet been explained until now.

A new study by Tel Aviv University researchers, published in Cell Reports, pinpoints the precise molecular mechanism that may trigger an enhancement of neuronal activity in Alzheimer's patients, which subsequently damages memory and learning functions. The research team, led by Dr. Inna Slutsky of TAU's Sackler Faculty of Medicine and Sagol School of Neuroscience, discovered that the amyloid precursor protein (APP), in addition to its well-known role in producing amyloid-beta, also constitutes the receptor for amyloid-beta. According to the study, the binding of amyloid-beta to pairs of APP molecules triggers a signalling cascade, which causes elevated neuronal activity.

Elevated activity in the hippocampus the area of the brain that controls learning and memory has been observed in patients with mild cognitive impairment and early stages of Alzheimer's disease. Hyperactive hippocampal neurons, which precede amyloid plaque formation, have also been observed in mouse models with early onset Alzheimer's disease."These are truly exciting results," said Dr. Slutsky. "Our work suggests that APP molecules, like many other known cell surface receptors, may modulate the transfer of information between neurons."

With the understanding of this mechanism, the potential for restoring memory and protecting the brain is greatly increased.

Building on earlier research

The research project was launched five years ago, following the researchers' discovery of the physiological role played by amyloid-beta, previously known as an exclusively toxic molecule. The team found that amyloid-beta is essential for the normal day-to-day transfer of information through the nerve cell networks. If the level of amyloid-beta is even slightly increased, it causes neuronal hyperactivity and greatly impairs the effective transfer of information between neurons.

In the search for the underlying cause of neuronal hyperactivity, TAU doctoral student Hilla Fogel and postdoctoral fellow Samuel Frere found that while unaffected "normal" neurons became hyperactive following a rise in amyloid-beta concentration, neurons lacking APP did not respond to amyloid-beta. "This finding was the starting point of a long journey toward decoding the mechanism of APP-mediated hyperactivity," said Dr. Slutsky.

The researchers, collaborating with Prof. Joel Hirsch of TAU's Faculty of Life Sciences, Prof. Dominic Walsh of Harvard University, and Prof. Ehud Isacoff of University of California Berkeley, harnessed a combination of cutting-edge high-resolution optical imaging, biophysical methods and molecular biology to examine APP-dependent signalling in neural cultures, brain slices, and mouse models. Using highly sensitive biophysical techniques based on fluorescence resonance energy transfer (FRET) between fluorescent proteins in close proximity, they discovered that APP exists as a dimer at presynaptic contacts, and that the binding of amyloid-beta triggers a change in the APP-APP interactions, leading to an increase in calcium flux and higher glutamate release in other words, brain hyperactivity.

A new approach to protecting the brain

"We have now identified the molecular players in hyperactivity," said Dr. Slutsky. "TAU postdoctoral fellow Oshik Segev is now working to identify the exact spot where the amyloid-beta binds to APP and how it modifies the structure of the APP molecule. If we can change the APP structure and engineer molecules that interfere with the binding of amyloid-beta to APP, then we can break up the process leading to hippocampal hyperactivity. This may help to restore memory and protect the brain."

Previous studies by Prof. Lennart Mucke's laboratory strongly suggest that a reduction in the expression level of "tau" (microtubule-associated protein), another key player in Alzheimer's pathogenesis, rescues synaptic deficits and decreases abnormal brain activity in animal models. "It will be crucial to understand the missing link between APP and 'tau'-mediated signalling pathways leading to hyperactivity of hippocampal circuits. If we can find a way to disrupt the positive signalling loop between amyloid-beta and neuronal activity, it may rescue cognitive decline and the conversion to Alzheimer's disease," said Dr. Slutsky.


'/>"/>

Contact: George Hunka
ghunka@aftau.org
212-742-9070
American Friends of Tel Aviv University
Source:Eurekalert

Related medicine news :

1. University of Cincinnati researchers win $3.7M grant from US Department of Defense
2. Leading experts on congenital muscular dystrophy convene at University of Nevada, Reno
3. Rice University student engineers automate limb lengthening for kids
4. Louisiana Tech University professor earns NSF Early Career Development grant
5. Neuropsychologist receives University of Houstons highest faculty honor
6. University of Houston Graduate College of Social Work announces partnership with MD Anderson
7. Columbia University Medical Center and NY-Presbyterian experts at APA meeting
8. University of Minnesota startup to treat challenging bacterial infection
9. University studies and career expectations of medical students
10. McMaster University researchers discover drug destroys human cancer stem cells but not healthy ones
11. Feola, at University of Kentucky, receives NIH grant to study cystic fibrosis
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:10/12/2017)... ... October 12, 2017 , ... IsoComforter, Inc. ( ... today the introduction of an innovative new design of the shoulder pad. The ... get maximum comfort while controlling your pain while using cold therapy. By utilizing ice ...
(Date:10/12/2017)... , ... October 12, 2017 , ... ... a leader in post-acute health care, have expanded their existing home health joint ... Health. , AccentCare has been operating a joint venture home health company with ...
(Date:10/12/2017)... ... 2017 , ... Dr. Parsa Mohebi, the Los Angeles based ... the newly revamped Cosmetic Town journal section, featuring articles written by ... as Follicular Unit Extraction (FUE). , Dr. Mohebi says “I enjoy ...
(Date:10/12/2017)... ... October 12, 2017 , ... Leading pediatric oncology experts at Children’s National ... 49th Congress of the International Society of Paediatric Oncology (SIOP) Oct. 12-15. ... for Cancer and Blood Disorders at Children’s National, and Stephen P. Hunger, M.D., ...
(Date:10/12/2017)... Mich. (PRWEB) , ... October 12, 2017 , ... ... has been named one of Michigan’s 2017 Best and Brightest in Wellness® by ... Brightest in Wellness® awards program on Friday, Oct. 20 from 7:30 a.m. to ...
Breaking Medicine News(10 mins):
(Date:10/12/2017)... 2017 AVACEN Medical , Inc. (AVACEN) announced ... 2017 New Product Innovation Award for Its fibromyalgia pain ... secondary medical device market research by Frost & Sullivan,s industry ... drug-free pain relief product, the AVACEN 100, offers a safe ... widespread pain. ...
(Date:10/11/2017)... Calif. , Oct. 11, 2017  BioPharmX Corporation ... scientific team that developed an innovative way to use ... of the delivery of new drugs. ... Fall Clinical Dermatology Conference will show how researchers from ... Hospital, Harvard Medical School used a suite of imaging ...
(Date:10/11/2017)... Holdings, Inc. ("Hill-Rom") (NYSE: HRC), today provided an update ... Puerto Rico , where the company manufactures ... Following a comprehensive onsite assessment, the ... temporary loss of power and minimal water damage due ... have resumed, and the company expects to return to ...
Breaking Medicine Technology: