It is estimated that in 2020 nearly six million people were living with Alzheimer’s disease in the United States alone; and this number is expected to increase in the coming decades. Attempts to develop drugs to treat the neurodegenerative condition have had limited success and only five drugs are currently approved. The researchers also explored the potential of existing drugs to improve the conditions of people suffering from this form of dementia. Niacin, a form of vitamin B3 also known as nicotinic acid, has recently attracted the attention of some researchers in the field. Niacin is an essential nutrient obtained from foods, such as fish, beef, chicken, whole grains and from supplements. The vitamin, in its pharmacological form, is prescribed to raise HDL cholesterol, although its intake is not associated with a reduced risk of death, heart attack, or stroke. A niacin deficiency can cause pellagra, a condition that also causes (among other consequences) cognitive decline. Since the 1980s, researchers have been exploring whether dietary niacin could help ward off certain neurodegenerative diseases.
The vitamin has sparked interest in the past 20 years with some epidemiological studies reporting an association between niacin intake and a reduction in the risk of general cognitive decline. More recently, researchers have begun to explore whether the compound has a positive effect on individuals with neurodegenerative diseases. Data published in recent years have suggested that niacin may modulate the activity of brain microglia in mouse models of Parkinson’s and multiple sclerosis. Initial evidence for this protective effect has now been shown in a mouse model for Alzheimer’s disease. A study conducted between 1993 and 2002 in a cohort of older adults found that intake from both sources together was inversely associated with the development of Alzheimer’s, and intake from food sources was also negatively associated with cognitive decline. A study published in 2017 confirmed a beneficial relationship between dietary niacin intake in young adulthood and improved cognitive function later in life.
Aside from the epidemiological link between niacin, cognitive function and Alzheimer’s, there was another evidence regarding how the so-called ketogenic diet has been associated with the treatment or prevention of Alzheimer’s and other neurodegenerative diseases. One of the things this diet does, he adds, is to increase the synthesis of ketone bodies that bind to the G-protein-coupled HCAR2 receptor (also called GPR109A), for which niacin has a high affinity. Based on these two lines of evidence, scientists wondered where this niacin receptor was expressed in the brain. They first found that HCAR2 was significantly higher expressed in the hippocampus and cortex of affected mice than in mice of a control strain. Examining post-mortem brain tissue of humans, the authors also found that receptor expression is much higher in samples from Alzheimer’s patients than in those who were not diagnosed with dementia. And guess what: receptor expression was specifically associated with microglia.
When these immune cells were depleted, Hcar2 mRNA levels decreased significantly, while expression was restored when the microglia were repopulated. Furthermore, Hcar2 expression is increased in the microglia surrounding the amyloid-β plaques compared to those not involved with them. Its activity appeared to play a beneficial role in how microglia interact with amyloid plaques. Mice lacking Hcar2 showed greater plaque load in brain tissue and greater neuronal loss. Microglia constantly monitors the environment from microbial or parasitic infections. However, they don’t appear to have a specific program for targeting amyloid plaques in the context of Alzheimer’s. Microglia, therefore, likely has “a very mixed response to signals” from amyloid aggregation and other characteristics of the disease. Research shows that the phagocytic activity of microglia towards β-amyloid aggregates may be protective, but if these cells are overactive, they secrete inflammatory factors that worsen the pathogenesis of Alzheimer’s disease.
Therefore, the researchers tested whether a daily dose of the FDA-approved oral formulation of niacin, Niaspan, for 30 days could alter disease development in their mouse model. The team reports that the mice undergoing this treatment showed better working memory, reduced plaque formation, and decreased neuronal loss, compared to those not treated with Niaspan. As expected, Niaspan did not achieve this improvement in mice lacking the HCAR2 receptor. In the brain, HCAR2 is found almost exclusively in the microglia of animals with Alzheimer’s, making it “almost like a natural target” as only those cells will be sensitive to therapy. This is the first time that a link between niacin and Alzheimer’s has been shown in laboratory experiments. And recent studies by other teams have reported similar effects of niacin in other neurological disorders. In 2020, scientists found that niacin could enhance the phagocytic activity of microglia against myelin debris in cultured cells and in a mouse model of multiple sclerosis.
Research into Parkinson’s disease has also revealed a potential role for niacin. Treatment with this vitamin has been shown to reduce neuro-inflammation in these patients and analyzes of their blood samples suggest that HCAR2 is also a mediator in this mechanism. Researchers at the University of Augusta in Georgia reported that niacin can even stimulate macrophages, immune cells that often work in concert with microglia, to go from a pro-inflammatory to an anti-inflammatory form. Scientists are currently conducting clinical trials to test niacin treatment on this condition. Niacin has not yet been tested on humans in the context of Alzheimer’s disease. Perhaps the problem is that very large doses are needed in order to obtain a lasting therapeutic effect over time. And then there is another problem: niacin does not pass the blood-brain barrier very quickly, it is a fairly soluble vitamin in water while this structure prefers to pass lipid molecules or which dissolve in fats.
The problem could be overcome by constructing a vitamin pro-drug comprising a fat molecule or complexed to simple fatty acids. In doing so, it would not only serve for Alzheimer’s dementia, but also for the other clinical conditions mentioned. Other authors, however, have reiterated that in the medical situations described there is already a greater permeability of the EE barrier caused by the natural inflammatory component of the diseases. But even in this case, the free form of the vitamin would probably have a limited effect over time: once it had an anti-inflammatory effect on the barrier itself, its renewed impermeability would interfere with the free entry of nicotinamide into the brain. Ultimately, it is encouraging to know that niacin is yet another natural molecule that has shown effect in models of neurological diseases with a high health impact. After all, in most of the known neuro-degenerative pathologies there are known defects in energy metabolism (including proteins that work with vitamin coenzymes).
Adopting corrective medicine based on natural molecules, especially when they work, can be a further step towards managing the seemingly unbridled advance of highly disabling neurological diseases such as those mentioned.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Wakade C et al. Biomedicines. 2021; 9(12):1881.
Chong R et al. Front Aging Neurosci. 2021; 13:667032.
Titcomb TJ, Bisht B et al. Nutrient. 2020; 12(6):1844.
Rawji KS et al. Acta Neuropathol. 2020; 139(5):893.
Giri B et al. Internat J Mol Sci. 2019; 20(18):4559.
Gasperi V et al. Int J Mol Sci. 2019 Feb; 20(4):974.
Schöndorf DC et al. Cell Rep. 2018; 23(10):2976-88.
Kim EJ, Yang SJ. Clin Nutr Res 2017; 6(2):130-135.
Wakade C et al. Clinical Case Rep. 2015; 3(7):635.
Dott. Gianfrancesco Cormaci
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