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Scientists neutralise significant Alzheimer's gene

Scientists have claimed an important breakthrough in the battle against Alzheimer’s after neutralising the most significant gene responsible for the disease for the first time. The Daily Telegraph reports that a team in California successfully identified the protein associated with the high-risk apoE4 gene and then managed to prevent it damaging human neuron cells.

The study could open the door to a potential new drug capable of halting the disease, however the researchers have urged caution because so far, their compound has only been tried on collections of cells in a laboratory.

Having one copy of the apoE4 gene more than doubles a person’s likelihood of developing Alzheimer’s disease, whereas having two copies increases the risk 12-fold. Previous studies have indicated that roughly one in four people carry the gene.

In human neurons, misshapen apoE4 protein cannot function properly and is broken down into disease-causing fragments in the cells.

This results in several of the problems commonly found in Alzheimer’s disease, which affects 7.1% of Britons above the age of 65, including the accumulation of protein tau and amyloid peptides.

The report says the team at Gladstones Institutes set out to establish whether the presence of the protein was causing the damage, or whether a lack of it was to blame. Using stem cell technology, they created neurons from skin cells donated by Alzheimer’s patients with two copies of the apoE4 gene.

By comparing the cells with those which did not produce an apoE protein they concluded that it was the mere presence of the apoE4 protein was causing brain damage. They then applied a genetic “structure corrector”, which eliminated the signs of Alzheimer’s.

The report says the researchers are now working with the pharmaceutical industry to improve the compounds so they can be tested on human patients.

The experiment is particularly significant because it took place in human cells. Yadong Huang, at the Gladstone Institute and the University of California – San Francisco, who led the study, said: “Drug development for Alzheimer’s disease has been largely a disappointment over the last 10 years. “Many drugs work, beautifully in a mouse model, but so far they’ve all failed in clinical trials. One concern within the field has been how poorly these mouse models really mimic human disease.”

The report says Huang and his colleagues went straight for human brain cells rather than the traditional mouse trial because they realised the presence of the apoE4 gene does not change the production of amyloid beta in a mouse brain.

Last month senior British scientists predicted that within the next few decades Alzheimer’s sufferers will be able to live with the disease without the devastating symptoms.

Abstract
Efforts to develop drugs for Alzheimer's disease (AD) have shown promise in animal studies, only to fail in human trials, suggesting a pressing need to study AD in human model systems. Using human neurons derived from induced pluripotent stem cells that expressed apolipoprotein E4 (ApoE4), a variant of the APOE gene product and the major genetic risk factor for AD, we demonstrated that ApoE4-expressing neurons had higher levels of tau phosphorylation, unrelated to their increased production of amyloid-β (Aβ) peptides, and that they displayed GABAergic neuron degeneration. ApoE4 increased Aβ production in human, but not in mouse, neurons. Converting ApoE4 to ApoE3 by gene editing rescued these phenotypes, indicating the specific effects of ApoE4. Neurons that lacked APOE behaved similarly to those expressing ApoE3, and the introduction of ApoE4 expression recapitulated the pathological phenotypes, suggesting a gain of toxic effects from ApoE4. Treatment of ApoE4-expressing neurons with a small-molecule structure corrector ameliorated the detrimental effects, thus showing that correcting the pathogenic conformation of ApoE4 is a viable therapeutic approach for ApoE4-related AD.

Authors
Chengzhong Wang, Ramsey Najm, Qin Xu, Dah-eun Jeong, David Walker, Maureen E Balestra, Seo Yeon Yoon, Heidi Yuan, Gang Li, Zachary A Miller, Bruce L Miller, Mary J Malloy, Yadong Huang

[link url="https://www.telegraph.co.uk/science/2018/04/09/alzheimers-gene-neutralised-human-brain-cells-first-time/"]The Daily Telegraph report[/link]
[link url="https://www.nature.com/articles/s41591-018-0004-z"]Nature Medicine abstract[/link]

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