Common nutrient may help combat Alzheimer’s disease

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A lifelong dietary regimen of choline holds the potential to prevent Alzheimer’s disease (AD) according to a new study.

Lead author Ramon Velazquez and his colleagues at the ASU-Banner Neurodegenerative Disease Research Center (NDRC) looked into whether this nutrient could alleviate the effects of Alzheimer’s disease.

The nutrient that holds this promise, choline, is found in many common foods including eggs, spinach, steak and shellfish. Choline is a safe and easy-to-administer nutrient that is naturally present in common foods and can be used as a dietary supplement.

Earlier this year, Velazquez and colleagues found transgenerational benefits of AD-like symptoms in mice whose mothers were supplemented with choline. The latest work expands this line of research by exploring the effects of choline administered in adulthood rather than in foetal mice.

The study focuses on female mice bred to develop AD-like symptoms. Given the higher prevalence of AD in human females, the study sought to establish the findings in female mice. Results showed that when these mice are given high choline in their diet throughout life, they exhibit improvements in spatial memory, compared with those receiving a normal choline regimen.

Notably, findings published in July 2019 from a group in China found benefits of lifelong choline supplementation in male mice with AD-like symptoms.

Intriguingly, the beneficial effects of lifelong choline supplementation reduce the activation of microglia, which are specialised cells that rid the brain of deleterious debris. Although they naturally occur to keep the brain healthy, if they are overactivated, brain inflammation and neuronal death, common symptoms of AD, will occur.

The observed reductions in disease-associated microglia, which are present in various neurodegenerative diseases, offer exciting new avenues of research and suggest ways of treating a broad range of disorders, including traumatic brain injuries, multiple sclerosis and Parkinson’s disease.

The findings appear in the current issue of the journal Aging Cell.

Supplementing the brain with additional choline

The research found that choline acts to protect the brain from Alzheimer’s disease in at least two ways, both of which are explored in the new study. First, choline blocks the production of amyloid-beta plaques. Amyloid-beta plaques are the hallmark pathology observed in Alzheimer’s disease.

Secondly, choline supplementation reduces the activation of microglia. Over-activation of microglia causes brain inflammation and can eventually lead to neuronal death, thereby compromising cognitive function. Choline supplementation reduces the activation of microglia, offering further protection from the ravages of AD.

Mechanistically, the reductions in microglia activation are driven by alteration of two key receptors, the alpha7 nicotinic acetylcholine and Sigma-1 receptor. A new report this year found that choline can act as an agonist for Sigma-1 receptors.

These results confirm that lifelong choline supplementation can alter the expression of the Sigma-1 receptor, which thereby attenuates microglia activation. (An agonist is a substance that activates a given receptor.)

Alzheimer’s disease

In the scientific community, it is well understood that Alzheimer’s disease causes harm to the brain long before clinical symptoms are made evident. Once these symptoms are identified, it is too late – the disease has become irreversible. In addition to causing disorientation and memory loss, the disease causes loss of motor control in those who are afflicted.

Approximately six million individuals are living with AD in the US currently, and the disease is projected to afflict 14 million Americans in the next four decades. Economically, the costs associated with managing Alzheimer’s are expected to exceed $20 trillion (~€18.29tr) in the same time span.

To develop more effective treatments, we first need to understand the disease itself, which is one of the tallest orders facing modern medicine today.

Women are at a particular increased risk of developing Alzheimer’s disease. This study shows that the simple addition of choline in the diet throughout life may reduce AD pathology in those most affected by the disease. Additionally, these results have implications for other neurodegenerative afflictions where activated microglia are rampant says Velazquez.

Guidelines for dietary choline

Prior research concerning Alzheimer’s has indicated that there is no one factor at play. Rather, a multitude of factors that are believed to contribute to the development of the disease, including genetics, age and lifestyle. Additionally, studies suggest that diet can have a significant effect in increasing or lowering the risk of cognitive decline.

A recent report suggested that plant-based diets may be determinantal due to the lack of important nutrients, including choline, and another found that the increase in cases of dementia in the United Kingdom may be associated with a lack of recommendations for choline in the diet throughout life. In fact, as of August 2019, AD and other forms of dementia are now the leading cause of death in England and Wales.

A converging line of evidence indicates that even the current recommended daily intake (RDI) may not be optimal for a proper aging process, especially in women. This is relevant, given the higher incidence of AD seen in women. This suggests that additional choline in diet may be beneficial in preventing neuropathological changes associated with the ageing brain.

The tolerable upper limit of choline unlikely to cause side effects for adult females and males.

Velazquez said: “Our choline supplemented diet regimen was only 4.5 times the RDI, which is well below the TUL and makes this a safe strategy.”

Vitamin supplements containing choline, for example choline bitartrate and choline chloride, are widely available at affordable costs. The vitamin supplements containing choline are particularly relevant for those who are on plant-based diets.

Effects of choline

All plant and animal cells require choline to maintain their structural integrity and it has long been recognised that choline is particularly important for brain function.

The human body uses choline to produce acetylcholine, a neurotransmitter responsible for functioning memory, muscle control and mood. Choline also is used to build cell membranes and plays a vital role in regulating gene expression. Additionally, a new report in Jan 2019 found that choline acts as an agonist for Sigma-1 receptors, which are implicated in AD pathogenesis.

In this study, researchers used a water maze to determine whether the mice with AD-like symptoms that received lifelong supplemental choline exhibited improvements in spatial memory. It was found that this was indeed the case, and subsequent examination of mouse tissue extracted from the hippocampus, a brain region known to play a central role in memory formation, confirmed changes in toxic amyloid-beta and reductions in microglia activation, which reduces brain inflammation.

Due to alterations of key microglia receptors induced by choline, the improvements in behaviour may be attributed to reduced microglia activation.

Velazquez said: “We found that lifelong choline supplementation altered the alpha7 nicotinic acetylcholine and Sigma-1 receptor, which may have resulted in the reduction of diseased associated activated microglia.

“These receptors regulate CNS immune response and their dysregulation contributes to AD pathogenesis.

The study’s significance establishes beneficial effects of nutrient supplementation in females throughout life.

Velazquez continued: “Our work nicely complements recent work showing benefits in male AD-mice on a lifelong choline supplementation regimen. No one has shown lifelong benefits of choline supplementation in female AD-mice. That’s what is novel about our work.”

Choline is an attractive candidate for prevention of AD as it is considered a very safe alternative, compared with many pharmaceuticals.

Although the results improve the understanding of the disease, the authors suggest that clinical trials will be necessary to confirm whether choline can be used as a viable treatment in the future.

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