Gene APOE4 causes Alzheimers disease in humans and a fix has been created

Researchers have found differences in how Alzheimers disease originates and develops in mice and humans. They determined which gene causes Alzheimers in humans and have developed a fix for it.

Dementia and Alzheimer’s disease aren’t the same. Dementia is an overall term used to describe symptoms that impact memory, performance of daily activities, and communication abilities. Alzheimer’s disease is the most common type of dementia. Alzheimer’s disease gets worse with time and affects memory, language, and thought.

Dementia is a syndrome, not a disease. A syndrome is a group of symptoms that doesn’t have a definitive diagnosis. Dementia is a group of symptoms that affects mental cognitive tasks such as memory and reasoning. Dementia is an umbrella term that Alzheimer’s disease can fall under. It can occur due to a variety of conditions, the most common of which is Alzheimer’s disease.

The World Health Organization says that 47.5 million people around the world are living with dementia.

Alzheimer’s disease is responsible for about 50 to 70 percent of all cases of dementia.

Other causes of dementia include:

infections, such as HIV
vascular diseases
stroke
depression
chronic drug use

Mice and humans have differences in genetics of Alzheimers so mouse models were flawed

Applying stem cell technology to skin cells from people with Alzheimer’s who had two copies of the APOE4 gene, Dr. Huang and his team created neurons.

Nature Medicine – Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector

The researchers also created brain cells using skin cells from people who didn’t have Alzheimer’s and had two copies of the APOE3 gene.

APOE4 gene causes Alzheimers in humans

The scientists found that in human brain cells, the APOE4 protein has a “pathogenic conformation” — meaning that it has an abnormal form that prevents it from functioning properly, leading to a series of disease-causing problems.

Namely, “APOE4-expressing neurons had higher levels of tau phosphorylation,” the authors write, which was “unrelated to their increased production of amyloid-[beta] peptides, and […] they displayed GABAergic neuron degeneration.”

Importantly, they also found that “APOE4 increased [amyloid-beta] production in human, but not in mouse, neurons.”

“There’s an important species difference in the effect of APOE4 on amyloid beta,” explains first study author Chengzhong Wang.

They determined gene APOE4 causes Alzheimers disease.

Small molecule fix for APOE4 in humans could cure Alzheimers

As a final step, Dr. Huang and his team looked for ways in which to fix the faulty gene. To this end, they applied a previously developed APOE4 “structure corrector.”

The so-called structure corrector has been shown in previous research, led by the same Dr. Huang, to change the structure of APOE4 so that it looks and behaves more like the inoffensive APOE3.

Applying this compound to human APOE4 neurons corrected the defects, thereby eliminating signs of the disease, restoring normal cell function, and helping the cells to live longer.

The researchers conclude:

“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 [Alzheimer’s disease].”

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.

logo

Don’t miss the latest future news

Subscribe and get a FREE Ebook