Cancer drug could reverse hyperconnectivity in early Alzheimer’s
Original story from King’s College London (UK).
Neuroscientists at King’s College London (UK) have pinpointed a mechanism behind the increased neural connectivity seen in very early stages of Alzheimer’s disease.
Published in Translational Psychiatry, the study then demonstrated that a cancer medication has the potential to reverse this early-stage hyperconnectivity.
The research, conducted in brain cells of rats, showed that low levels of the protein amyloid-beta could induce hyperconnectivity and this pattern closely resembled changes seen in the brains of people of people with mild cognitive impairment (MCI). Amyloid-beta is thought to be instrumental in Alzheimer’s disease, where it creates plaques – or sticky clumps of amyloid-beta proteins – around the neurons.
These new findings suggest that low levels of amyloid-beta alone are enough to trigger early, disease-relevant changes in how brain cells connect.
Changes in neural connectivity in early stages of Alzheimer’s disease
Previous research has found that the number of connections (synapses) between neurons in the brain increases during the earliest stages of Alzheimer’s disease and it has been shown that these initial changes correlate with MCI in patients. MCI is characteristic of the early stages of Alzheimer’s disease, prior to widespread cell death and memory loss.
It was previously unknown what causes the initial increase in connectivity, and it remains unclear how it then relates to the progression and ultimate loss of connections later in the disease.
Amyloid-beta is a protein that has been associated with Alzheimer’s disease. Research has shown that in early stages of the disease, neurons start to produce more amyloid-beta than normal. As the disease progresses, the amyloid-beta proteins start to form clumps, known as plaques.
This new study from King’s College London shows that low doses of amyloid-beta over a short period of 5 days can cause hyperconnectivity between brain cells. The study also identifies a series of changes in levels of other proteins that work together to increase the connectivity in the early stages of the disease.
Creating Alzheimer’s disease in the lab
To create the conditions of early stages of Alzheimer’s disease, similar to those seen whilst patients experience MCI, researchers exposed neurons from rats to amyloid-beta for just 5 days. The neurons soon started to produce more amyloid-beta proteins than normal.
Researchers then used a state-of-the-art microscopy technique called expansion microscopy to look at individual connections – or synapses – between neurons. Expansion microscopy causes biological samples to expand five to six times, allowing researchers to examine structures as small as 30 nm in size, with fluorescence microscopy. Expansion microscopy revealed that exposing the neurons to amyloid-beta for 5 days caused the number of synapses between neurons to increase significantly.
Widespread cellular changes caused by early stages of the disease
The researchers then used a method called liquid-chromatography mass-spectrometry to investigate what was happening inside the neurons exposed to amyloid-beta. Many changes inside neurons involve changes in gene-expression: the process by which genes are ‘read’ and proteins are made, a bit like a production line in a factory. Liquid-chromatography mass-spectrometry allows scientists to see which proteins are being made more than others, a bit like checking the stock in the factory example.
They found that amyloid-beta didn’t cause the neurons to change how many proteins they produced. Rather, it changed which proteins were being made. The researchers identified 49 proteins that were affected by exposure to amyloid-beta. In healthy neurons, these proteins play important roles, such as maintaining the shape and structure of the cell, signaling between neurons and energy production.
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“Amyloid-beta doesn’t simply increase or decrease protein production – it rewires it. This shift may push neurons into an unstable state that promotes abnormal synapse formation,” explained Kaiyu Wu, first author on the study.
One of the proteins that was produced more by neurons exposed to amyloid-beta was amyloid precursor protein, the protein that eventually becomes amyloid-beta.
“This suggests the system may act as a self-reinforcing loop in which amyloid-beta promotes conditions that lead to even more amyloid-beta,” added Wu.
A drug that helps restore normality
Previous work from the same research group at King’s has identified a drug target that might be able to alter protein production associated with synapse increases. This target, MAP kinase interacting kinase, is also the target of the clinically licensed drug eFT508, currently used in cancer clinical trials. The drug is also known to decrease neuroinflammation and inhibit the synthesis of proteins involved in tumor growth. It has never been used to investigate or treat Alzheimer’s disease before.
Karl Peter Giese and his team found eFT508 prevented the increase in connectivity caused by amyloid-beta exposure. Using liquid-chromatography mass-spectrometry, they also found that the drug was able to restore 70% of the altered protein production after amyloid-beta exposure.
Rethinking how AD begins
“The results of this new study contribute to a new way of thinking about Alzheimer’s disease,” explained Wu. “Instead of starting with synapse loss, the disease may begin with too many poorly organized connections, combined with subtle but targeted changes in protein production. Over time, this unstable state could make brain circuits more vulnerable, eventually leading to the synaptic failure and cognitive decline seen in later stages of the disease.”
Michelle Dyson, Chief Executive Officer at Alzheimer’s Society (London, UK) said: “This study builds our knowledge of brain cell changes in early-stage Alzheimer’s disease and suggests that with intervention we may be able to counteract some of these changes as Alzheimer’s disease develops.
“It’s important to note this was very early-stage work in animal cells rather than human participants so more research is needed. But it shows how drug repurposing is a promising avenue for us to explore if we are to end the devastation of dementia – a condition that affects around 1 million people in the UK.
“For decades, cancer research has set the benchmark for what can, and should, be done for dementia. Research will beat dementia and we look forward to seeing how this research progresses.”
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