Enzyme treatment of gene may reverse Alzheimer’s effects
Amyloid beta peptides and the plaque they sprout in diseased brains have been blamed for the last two decades on Alzheimer’s disease. However, progress in treating – not to mention curing – the debilitating, neurodegenerative disease has been extremely slow.
A Tel Aviv University study published recently 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 at TAU’s life sciences faculty together with doctoral fellow Anat Boehm-Cagan and in collaboration with the California-based company Artery Ltd.
“APOE4 is a very important and understudied target,” Michaelson said. “It is expressed in more than 60% 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,” he continued.
“Whereas the healthy APOE3 does so effectively, the bad form – APOE4 – is impaired.”
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.
“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,” Michaelson said. “Because we know that APOE4 carries fewer lipids, we looked at the means of counteracting the lipidation deficiency.
“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 team 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 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 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.”
A TOOTHPASTE AGAINST BODILY INFLAMMATION
For decades, research has suggested a link between oral health and inflammatory diseases affecting the entire body – in particular, heart attacks and strokes. Now a randomized trial of a novel plaque identifying toothpaste, (Plaque HD), shows statistically significant reductions not only in dental plaque but also inflammation throughout the body.
Inflammation throughout the body is accurately measured by high sensitivity C-reactive protein (hs-CRP), a sensitive marker for future heart attacks and strokes. These results, published recently in the American Journal of Medicine with an accompanying editorial by the editor-in-chief show that Plaque HD produced statistically significant reductions in dental plaque and inflammation throughout the body as measured by hs-CRP.
In this trial, all randomized subjects were given the same brushing protocol and received a 60-day supply of toothpaste containing either Plaque HD or an identical non-plaque identifying placebo toothpaste. To assess dental plaque, all subjects utilized a fluorescent mouth rinse, and intraoral photographs were taken under black light imaging. For hs-CRP, levels were measured by an independent laboratory using an enzyme linked immunosorbent assay.
“While the findings on reducing dental plaque extend a previous observation, the findings on decreasing inflammation are new and novel,” said lead author Dr. Charles Hennekens of Florida Atlantic University. Last month, the prestigious New England Journal of Medicine ranked the original manuscript by Hennekens and colleagues on aspirin, inflammation and cardiovascular disease, published in 1997, as their most influential original report of the last 20 years.
In the accompanying editorial titled “Can a Toothpaste Reduce Heart Attacks and Strokes?,” internationally renowned cardiologist Dr. Joseph S. Alpert noted the importance and timeliness of these findings and commented on how his father, a dentist, had told him even before he went to medical school that dental health may affect heart attacks and strokes.