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Enzyme Treatment of Gene May Reverse Effects of Alzheimer’s

Summary: Researchers suggest the ApoE gene could be a promising new target for therapeutic approaches for Alzheimer’s disease.

Source: AFTAU.

APOE gene is a promising target for therapeutic approaches to Alzheimer’s, says Tel Aviv University researcher.

For the last 20 years, researchers have focused on amyloid beta peptides and the “plaque” they sprout in diseased brains as the main target of Alzheimer’s research. But the pace of progress in treating — not to mention curing — the debilitating, neurodegenerative disease has been painfully slow.

A Tel Aviv University study published last month in the Journal of Alzheimer’s Disease suggests a new target for Alzheimer’s research: the APOE gene. This gene, like Dr. Jekyll and Mr. Hyde, has two faces: a healthy form called APOE3 and a disease-related pathological form called APOE4. Researchers have developed a novel mechanism and approach with which to convert the “bad” APOE4 to the “good” APOE3.

The research was led by Prof. Daniel M. Michaelson, Director of the Eichenbaum Laboratory of Alzheimer’s Disease Research and incumbent of the Myriam Lebach Chair in Molecular Neurodegeneration at TAU’s Faculty of Life Sciences, together with Anat Boehm-Cagan, the Eleanore and Harold Foonberg Doctoral Fellow in Alzheimers Disease Research, and in collaboration with the commercial company Artery Ltd., based in California.

Focus on a new approach

“APOE4 is a very important and understudied target,” Prof. Michaelson said. “It is expressed in more than 60 percent of Alzheimer’s patients. Anti-APOE4 treatments are thus expected to have a major impact on the patient population.

“The normal APOE gene provides the interface that moves lipids — naturally occurring molecules that include fats, cholesterol, fat-soluble vitamins and other components essential to the health of cells — in and out of cells,” Prof. Michaelson continued. “Whereas the healthy APOE3 does so effectively, the bad form — APOE4 — is impaired.”

Prof. Michaelson and other groups found in past research that the bad APOE4 and the good APOE3 differed in their interactions with lipid cargo. The good APOE3, for example, is associated with substantially more lipids than APOE4.

The researchers devised an experimental approach to measure the “bad” features of APOE4, utilizing genetically manipulated mice expressing either good or bad forms of APOE. Mice with APOE4 exhibited impaired learning and memory, as well as damaged brain synapses and an accumulation of phosphorylated tau and a-beta molecules — two pathological hallmarks of Alzheimer’s.

Turning a bad gene to good

“Once this model was established and the pathological effects of APOE4 could be reproduced in mice, we could test therapeutic approaches and tackle APOE4 itself,” Prof. Michaelson said. “Because we know that APOE4 carries fewer lipids, we looked at the means of counteracting the lipidation deficiency.

Image shows DNA.

The researchers devised an experimental approach to measure the “bad” features of APOE4, utilizing genetically manipulated mice expressing either good or bad forms of APOE. NeuroscienceNews.com image is for illustrative purposes only.

“We focused on an enzymatic machinery called ABCA1 that loads lipid cargo onto APOE4. We found that the impaired lipidation of APOE4 could be successfully reversed by activating ABCA1. Most importantly, we discovered that this increased lipidation of APOE4 reversed the behavioral impairments and brain damage seen in non-treated APOE4 mice.”

The researchers found in the course of administering treatment that mice, which prior to the treatment exhibited disoriented behavior and seemed “lost,” were able following treatment to locate a submerged island in the middle of an artificial pond. Mice had forgotten familiar objects — like Coca Cola bottles — suddenly exhibited sharp object recognition.

“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.”

About this Alzheimer’s disease research article

Source: George Hunka – AFTAU
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “ABCA1 Agonist Reverses the ApoE4-Driven Cognitive and Brain Pathologies” by Boehm-Cagan, Anat; Bar, Roni; Liraz, Ori; Bielicki, John K.; Johansson, Jan O.; and Michaelson, Daniel M. in Journal of Alzheimer’s Disease. Published online October 2016 doi:10.3233/JAD-160467

Cite This NeuroscienceNews.com Article
AFTAU “Enzyme Treatment of Gene May Reverse Effects of Alzheimer’s.” NeuroscienceNews. NeuroscienceNews, 5 October 2016.
<http://neurosciencenews.com/alzheimers-genetics-apoe4-5213/>.
AFTAU (2016, October 5). Enzyme Treatment of Gene May Reverse Effects of Alzheimer’s. NeuroscienceNew. Retrieved October 5, 2016 from http://neurosciencenews.com/alzheimers-genetics-apoe4-5213/
AFTAU “Enzyme Treatment of Gene May Reverse Effects of Alzheimer’s.” http://neurosciencenews.com/alzheimers-genetics-apoe4-5213/ (accessed October 5, 2016).

Abstract

ABCA1 Agonist Reverses the ApoE4-Driven Cognitive and Brain Pathologies

The allele ɛ4 of apolipoprotein E (apoE4) is the most prevalent genetic risk factor for Alzheimer’s disease (AD) and is therefore a promising therapeutic target. Human and animal model studies suggest that apoE4 is hypolipidated; accordingly, we have previously shown that the retinoid X receptor (RXR) agonist bexarotene upregulates ABCA1, the main apoE-lipidating protein, resulting in increased lipidation of apoE4, and the subsequent reversal of the pathological effects of apoE4, namely: accumulation of Aβ42 and hyperphosphorylated tau, as well as reduction in the levels of synaptic markers and cognitive deficits. Since the RXR system has numerous other targets, it is important to devise the means of activating ABCA1 selectively. We presently utilized CS-6253, a peptide shown to directly activate ABCA1 in vitro, and examined the extent to which it can affect the degree of lipidation of apoE4 in vivo and counteract the associated brain and behavioral pathologies. This revealed that treatment of young apoE4-targeted replacement mice with CS-6253 increases the lipidation of apoE4. This was associated with a reversal of the apoE4-driven Aβ42 accumulation and tau hyperphosphorylation in hippocampal neurons, as well as of the synaptic impairments and cognitive deficits. These findings suggest that the pathological effects of apoE4 in vivo are associated with decreased activation of ABCA1 and impaired lipidation of apoE4 and that the downstream brain-related pathology and cognitive deficits can be counteracted by treatment with the ABCA1 agonist CS-6253. These findings have important clinical ramifications and put forward ABCA1 as a promising target for apoE4-related treatment of AD.

“ABCA1 Agonist Reverses the ApoE4-Driven Cognitive and Brain Pathologies” by Boehm-Cagan, Anat; Bar, Roni; Liraz, Ori; Bielicki, John K.; Johansson, Jan O.; and Michaelson, Daniel M. in Journal of Alzheimer’s Disease. Published online October 2016 doi:10.3233/JAD-160467

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