Alzheimer's Effects Reversed in Mice by Targeting 'Bad' Gene, Not Plaque

Paradigm changer? After treatment, mice with 'bad' Alzheimer gene identify Coke bottles and perform other stunts, say Tel Aviv University scientists.

Ruth Schuster
Ruth Schuster
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Super-smart mice also turn out to be low on anxiety, based on the cat-urine response test.
Super-smart mice also turn out to be low on anxiety, based on the cat-urine response test.Credit: Dreamstime
Ruth Schuster
Ruth Schuster

Efforts to find a cure for Alzheimer's have consistently disappointed. Despite some successes in slowing its progression, the neurodegenerative disease remains classified as incurable. Now Israeli scientists at Tel Aviv University hope to have changed the paradigm, by changing the therapeutic target from the plaque that gunks up affected brains to the underlying genes.

The study, published last month in the Journal of Alzheimer's Disease, targets a gene called APOE, which codes for a protein called apolipoprotein E (ApoE).

Not all genes are created equal. The human race has three different variants (alleles) of APOE , called e2, e3 and e4. Since everybody has double chromosomes, one from mother and one from father, everybody has two of the APOE genes. A given person's APOE type will be the combination inherited from the parents - e2/e2, e2/e3, e2/e4, e3/e3, e3/e4, or e4/e4.

The most common form is APOE3, or e3, which is the "healthy" form as far as Alzheimer's is concerned. E2 is considered to slightly lower the probability of developing Alzheimer's.

E4 is considered pathological and is expressed in approximately 60% of Alzheimer's sufferers. Note however that possessing e4/e4 doesn't mean you're doomed to develop the disease, just that your probability is higher.

"Good" apolipoprotein effectively moves fat molecules, fat-soluble vitamins and other crucial components in and out of cells, Michaelson explains. "Bad" e4 apolipoprotein does the same, but inefficiently.

The Tel Aviv researchers, led by Prof. Daniel M. Michaelson, say their novel mechanism can convert “bad” APOE4 to “good” APOE3. How?

Bad apolipoprotein! Bad!

Working with Anat Boehm-Cagan and the support of a Californian company named Artery, Michaelson had already learned that "bad" APOE4 is lousy at carrying its lipid cargo while APOE is good at it.

Using mice genetically engineered to express good or bad APOE, the researchers discovered that e4/e4 mice (double whammy of bad) exhibited impaired learning and memory. The synapses (spaces between nerve cells) in their brains were damaged and the rodents suffered various physical hallmarks of Alzheimer’s.

Having successfully reproduced the effects of bad APOE in mice, the researchers felt ready to start testing therapeutic approaches that tackle APOE4 itself, Michaelson explains.

Message in a Coke bottle

They already knew that APOE4 is bad at carrying the lipids. So they set about counteracting the lipidation deficiency, he explains – and discovered that the impaired lipidation of APOE4 could be successfully reversed by activating the enzymatic machinery that loads lipid molecules onto APOE4, called ABCA1.

Excitingly, repairing the impaired lipidation of APOE4 reversed the behavioral impairments and brain damage seen in non-treated APOE4 mice, say the scientists. After treatment, mice that had seemed lost, managed to reorient themselves. Mice who had forgotten familiar objects – like Coca Cola bottles —suddenly exhibited sharp object recognition, they say.

So have they cured Alzheimer's? Hold on. First of all, there is no consensus that Alzheimer's is even one single disease, let alone that it could have one single cure. Second of all, what worked in a diddled mouse may not work in grandma.

Meanwhile, in April, a collaboration between scientists at Bar-Ilan and Tel Aviv universities reported that a new drug under development caused the complete disappearance of symptoms in mice used as a model for the sickness. It is much too early for the new drug to help Alzheimer’s sufferers, but the team said their preliminary findings present a worthy candidate for a future treatment. In September, a human monoclonal antibody named aducanumab, designed to recognize plaque, showed indications of actually working in both mice and men, and reversing the effects of the disease.

"Is there really a magic bullet? One treatment that covers all aspects of Alzheimer's? Not likely," said Prof. Michaelson. “Therefore there is a need to define specific subpopulations and to develop treatments targeted at genetic risk factors of the disease, like APOE4, which affects more than half of the Alzheimer’s population.”



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