Researchers find major clue toward Alzheimer’s cure

Brain hyperactivity caused by protein binding may be important factor in disease’s development: Israeli team

Medical researchers (Photo credit: Courtesy)
Medical researchers (Photo credit: Courtesy)

Researchers at Tel Aviv University believe they have tracked down one of the main reasons for the seizures, memory loss and cognitive impairment that Alzheimer’s patients suffer. Following up on the finding may show the way toward a cure for the debilitating disease that hobbles millions of seniors.

The research shows how a molecular mechanism involving proteins interferes with brain neuron function and shifts them into dangerous overdrive. The discovery gives researchers a clue towards solving the Alzheimer’s puzzle, according to Dr. Inna Slutsky of TAU’s Sackler Faculty of Medicine and Sagol School of Neuroscience.

“We have now identified the molecular players in hyperactivity,” said Slutsky, adding that the discovery “may help to restore memory and protect the brain.”

The effects of Alzheimer’s have been widely observed — clumps of proteins build up in the brains of patients, interfering with cognitive functions. The challenge has been to find the mechanism behind the progression.

Slutsky published the results of a study on how brain hyperactivity affects Alzheimer’s patients in the latest edition of Cell Reports. The study was supported by European Research Council, Israel Science Foundation, and Alzheimer’s Association grants.

The culprit, according to research by Slutsky’s team, appears to be enhanced neuronal activity in Alzheimer’s patients, caused by a molecular mechanism involving amyloid precursor protein (APP). APP is well-known by researchers for producing a substance called amyloid-beta. APP also acts as a receptor for the substance. According to the study, the binding of amyloid-beta to pairs of APP molecules triggers a “signaling cascade,” in which messages shared by brain cells are amplified, elevating neuronal activity and essentially “short-circuiting” the brain’s communications network.

Doctors have observed this hyperactivity in the hippocampus — the area of the brain that controls learning and memory — among early stage Alzheimer’s patients, as well as in individuals suffering from mild cognitive disorders, like poor memory. Studies of mice have shown how the hyperactive hippocampal neurons precede the formation of amyloid plaque — the protein clumps that may block cell-to-cell signaling at synapses — leading to the eventual death of brain cells and advanced Alzheimer’s.

In a five-year search for the underlying cause of neuronal hyperactivity, TAU doctoral student Hilla Fogel and postdoctoral fellow Samuel Frere found that amyloid-beta is essential for the everyday transfer of information through the nerve cell networks. However, if the level of amyloid-beta is even slightly increased, it causes neuronal hyperactivity and greatly impairs the effective transfer of information between neurons.

Using cutting-edge technology and in collaboration 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, the researchers found that the binding of amyloid-beta triggers a change in the APP molecule interactions, leading to an increase in calcium flux and higher glutamate release — in other words, brain hyperactivity.

The problem emerges when too much of this binding takes place — so the key, according to the research, is to figure out a way to interfere with the binding of amyloid-beta to APP. “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,” said Slutsky. “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.” Years of research are likely still needed before this finding could be turned into practice.

Slutsky added, “One way of doing that may be a reduction of an element called “tau” (microtubule-associated protein), another key player in Alzheimer’s, which reverses synaptic deficits and decreases abnormal brain activity in animal models. It will be crucial to understand the missing link between APP and ‘tau’-mediated signaling pathways leading to hyperactivity of hippocampal circuits. If we can find a way to disrupt the positive signaling loop between amyloid-beta and neuronal activity, it may rescue cognitive decline and the conversion to Alzheimer’s disease.”

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