Study links Alzheimer’s to brain hyperactivity
Patients with Alzheimer’s 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 has only now been explained.
A new study by researchers at Tel Aviv University, part-funded by the European Research Council, 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 Tel Aviv University, 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. Hyperactive hippocampal neurons, which precede amyloid plaque formation, have also been observed in mouse models with early onset Alzheimer’s. With the understanding of this mechanism, the potential for restoring memory and protecting the brain is greatly increased.
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.
Researchers have now 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 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.
The results are published in Cell Reports.
