Lead authors Ramon Velazquez and Salvatore Oddo, alongside with their colleagues in the ASU-Banner Neurodegenerative Disease Research Center (NDRC), inspect the outcomes of choline, a necessary nutrient that may also hold promise in the fighting against the memory-stealing disorder.
The study focuses on mice bred to display AD-like symptoms. Results demonstrate that when these mice are given high choline in their diet, their offspring exhibit improvements in spatial memory, compared with those receiving a normal choline regimen in the womb.
Remarkably, the really useful results of choline supplementation appear to be transgenerational, not only protecting mice receiving choline supplementation during gestation and lactation, but also the subsequent offspring of these mice.
While this second generation received no direct choline supplementation, they nevertheless reaped the advantages of treatment, likely due to inherited modifications in their genes.
The exploration of such epigenetic alterations may further interesting new avenues of research and recommend approaches to treat a wide range of transgenerational afflictions, inclusive of fetal alcohol syndrome and obesity.
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Supplementing the brain
Choline acts to shield the brain from Alzheimer’s disease in at least two ways, both of which are explored in the new study. First, choline reduces levels of homocysteine‚ an amino acid that can act as a mighty neurotoxin, contributing to the hallmarks of AD: neurodegeneration and the formation of amyloid plaques.
Homocysteine is known to double the risk of developing Alzheimer’s disease and is found in elevated levels in patients with AD. Choline performs a chemical transformation, converting the harmful homocysteine into the beneficial chemical methionine.
Secondly, choline supplementation reduces the activation of microglia—cells responsible for clearing away debris in the brain. While their housekeeping functions are vital to brain health, activated microglia can get out of control, as they usually do during AD.
Over-activation of microglia causes brain irritation and can eventually lead to neuronal death. Choline supplementation reduces the activation of microglia, providing further protection from the ravages of AD.
The findings appear in the research of the Nature journal Molecular Psychiatry. The NDRC researchers had been joined by co-authors from the Translational Genomics Research Institute in Phoenix. (Oddo is also a researcher with ASU’s School of Life Sciences.)
Alzheimer’s disease is now believed to start its course of destruction in the brain a long time earlier than the onset of scientific symptoms. Once diagnosed, the disease is invariably fatal, shutting down one vital system after another. Mental decline is relentless, with patients experiencing a range of symptoms that may additionally include confusion, disorientation, delusions, forgetfulness, aggression, agitation, and progressive loss of motor control.
The disease is poised to afflict 13.5 million people in the U.S. alone by mid-century if nothing is accomplished to tackle the disease. The staggering costs of Alzheimer’s are projected to exceed $20 trillion in the next 40 years.
Developing effective treatments rooted in a greater thorough understanding of this complex disease is one of the most daunting challenges facing modern medication and the global healthcare infrastructure.
Research into the origins of Alzheimer’s disease strongly suggests that a great variety of factors are at play. While advancing age remains the greatest risk factor, other hazards that have been implicated in the disease include genetic predisposition and lifestyle.
To this end, research suggests that diet can have a sizeable impact in increasing or lowering the risk of cognitive decline, and the dangers can also be transmitted across generations. A basic case is recognized as the Dutch Hunger Winter—a severe famine in 1944-45 that affected pregnant women and their offspring.
When a recent study examined the adult health records of those born in the Netherlands in the course of this period, outcomes suggested that the extreme dietary deprivation persisted by the mothers of these kids heightened the prevalence of obesity, above-average LDL cholesterol and, intriguingly, schizophrenia in their offspring.
Mortality after 68 years of age increased by 10 percent in this population. It is believed that these unfavourable health consequences occur as a result of the silencing of genes in unborn children. These health-related genes remain silenced at some stage in life, leading to negative health outcomes.
On a greater hopeful note, a healthy weight-reduction plan has been proven to provide protection from diseases, together with most cancers and Alzheimer’s disease.
Patients following a Mediterranean weight loss plan for 4.5 years decreased their danger of AD by 54 percent. Another study pointed to the results of a Mediterranean diet rich in fruits and vegetables, whole grains, legumes, and nuts, as nicely as fish and poultry in reducing the accumulation of Aβ-amyloid, the protein responsible for plaque formation.
Effects of choline
Choline is a vitamin-like essential nutrient that is naturally present in some foods and also accessible as a dietary supplement. It is a source of methyl groups needed for many steps in metabolism. All plant and animal cells require choline to hold their structural integrity.
Choline is used by the body to produce acetylcholine, an important neurotransmitter essential for brain and nervous system functions which include memory, muscle control, and mood. Choline also plays a crucial role in regulating gene expression.
It has long been identified that choline is particularly essential in early brain development. Pregnant girls are advised to maintain choline levels of 550 mg per day for the health of their developing fetus. “There’s a twofold hassle with this,” lead creator Velazquez says.
Studies have proven that about 90 percent of women don’t even meet that requirement. Choline deficits are related with failure in developing fetuses to fully meet expected milestones like on foot and babbling. But we show that even if you have the endorsed amount, supplementing with more in a mouse model offers even greater benefit.
Indeed, when the AD study mice received supplemental choline in their diet, their offspring showed significant improvements in spatial memory, which used to be examined in a water maze.
Subsequent examination of mouse tissue extracted from the hippocampus, a brain region known to play a central role in memory formation, validated the epigenetic modifications induced by choline supplementation.
Modified genes associated with microglial activation and brain inflammation and decreased levels of homocysteine resulted in the observed performance improvements in spatial memory tasks.
Due to the epigenetic modifications triggered with the aid of choline, the enhancements carried over to the offspring of mice receiving supplemental choline in the womb. “
We found that early choline supplementation diminished homocysteine while increasing methionine, suggesting that high choline levels convert homocysteine to methionine. This conversion occurs thanks to an enzyme known as betaine-homocysteine methyltransferase (BMHT). We located that choline supplementation increased the production of BMHT in 2 generations of mice- Velazquez.
The study’s significance is two-fold, establishing beneficial effects from nutrient supplementation in successive generations and proposing epigenetic mechanisms to account for the reduction of AD memory deficit in mice. “No one has ever shown transgenerational advantages of choline supplementation,” Velazquez said. “That’s what is novel about our work.”
Choline is an attractive candidate for the cure of AD as it is considered a very safe alternative, compared with many pharmaceuticals. The authors note that it takes about 9 times the recommended daily dose of choline to produce hazardous side effects.
Future work will explore the effects on AD of choline administered in adult rather than fetal mice. The authors stress however that while results in mice are promising, a controlled clinical trial in humans will finally determine the effectiveness of choline as a new weapon in the combat against Alzheimer’s disease.
Originally appeared in https://biodesign.asu.edu/news/essential-nutrient-may-help-fight-alzheimer’s-across-generations