Scientists have identified the molecular mechanism that may trigger elevated neuronal activity in Alzheimer's patients, which ultimately damages memory and learning functions.
The study, by Tel Aviv University researchers, found 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.
"Our work suggests that APP molecules, like many other known cell surface receptors, may modulate the transfer of information between neurons," said Dr Inna Slutsky of TAU's Sackler Faculty of Medicine and Sagol School of Neuroscience.
With the understanding of this mechanism, the potential for restoring memory and protecting the brain is greatly increased, researchers said.
Researchers 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.
Researchers 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 Slutsky.
The researchers examined APP-dependent signalling in neural cultures, brain slices, and mouse models.
Researchers used 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.
"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," said Slutsky.
The study was published in the journal Cell Reports.
