Nutrition coming from traditional Chinese herbal medicine, say scientists, might be used as medicine in the field of restorative neurology and neuroscience in the form of an herbal compound. The new study's results, which may shed light on the neuropathology of Alzheimer's Disease and open up new avenues of treatment, are available this month in the current issue of the journal Restorative Neurology and Neuroscience | IOS Press.
The latest research was done with mice. The question is will it also help humans in the early stages of Alzheimer's disease? The answer at this time is that it does open a new area of research. But there are studies with other nutrients as well, including a UCLA study of vitamin D3's effects on the amyloid plaques found in the brains of Alzheimer's disease patients.
Also see the February 7, 2014 study, "Vitamin D, omega-3 may help clear amyloid plaques found in Alzheimer’s." In this study released last week, a team of academic researchers has pinpointed how vitamin D3 and omega-3 fatty acids may enhance the immune system's ability to clear the brain of amyloid plaques, one of the hallmarks of Alzheimer's disease.
In a small pilot study published in the Feb. 5 issue of the Journal of Alzheimer’s Disease, the scientists identified key genes and signaling networks regulated by vitamin D3 and the omega-3 fatty acid DHA (docosahexaenoic acid) that may help control inflammation and improve plaque clearance, according to the news release, "Vitamin D, omega-3 may help clear amyloid plaques found in Alzheimer’s."
Previous laboratory work by the team helped clarify key mechanisms involved in helping vitamin D3 clear amyloid-beta, the abnormal protein found in the plaque. The new study extends the previous findings with vitamin D3 and highlights the role of omega-3 DHA.
“Our new study sheds further light on a possible role for nutritional substances such as vitamin D3 and omega-3 in boosting immunity to help fight Alzheimer’s,” said study author Dr. Milan Fiala, a researcher at the David Geffen School of Medicine at UCLA in the news release. For the study, scientists drew blood samples from both Alzheimer’s patients and healthy controls, then isolated critical immune cells called macrophages from the blood. Macrophages are responsible for gobbling up amyloid-beta and other waste products in the brain and body.
The team incubated the immune cells overnight with amyloid-beta. They added either an active form of vitamin D3 called 1alpha,25–dihydroxyvitamin D3 or an active form of the omega-3 fatty acid DHA called resolvin D1 to some of the cells to gauge the effect they had on inflammation and amyloid-beta absorption.
Both 1alpha, 25-dihydroxyvitamin D3 and resolvin D1 improved the ability of the Alzheimer’s disease patients’ macrophages to gobble-up amyloid-beta, and they inhibited the cell death that is induced by amyloid-beta. Researchers observed that each nutrition molecule utilized different receptors and common signaling pathways to do this.
Previous work by the team, based on the function of Alzheimer’s patients’ macrophages, showed that there are two groups of patients and macrophages. In the current study, researchers found that the macrophages of the Alzheimer’s patients differentially expressed inflammatory genes, compared with the healthy controls, and that two distinct transcription patterns were found that further define the two groups: Group 1 had an increased transcription of inflammatory genes, while Group 2 had decreased transcription. Transcription is the first step leading to gene expression.
“Further study may help us identify if these two distinct transcription patterns of inflammatory genes could possibly distinguish either two stages or two types of Alzheimer’s disease,” said study author Mathew Mizwicki, an assistant researcher at the David Geffen School of Medicine at UCLA, according to the news release.
Vitamin D 3 greatly improved the clearance of amyloid-beta but subtleties in the effects are important to note when it comes to inflammation
While researchers found that 1alpha,25-dihydroxyvitamin D3 and resolvin D1 greatly improved the clearance of amyloid-beta by macrophages in patients in both groups, they discovered subtleties in the effects the two substances had on the expression of inflammatory genes in the two groups. In Group 1, the increased-inflammation group, macrophages showed a decrease of inflammatory activation; in Group 2, macrophages showed an increase of the inflammatory genes IL1 and TLRs when either 1alpha,25-Dihydroxyvitamin D3 or resolvin D1 were added.
More study is needed, Fiala said in the news release, but these differences could be associated with the severity of patients’ nutritional and/or metabolic deficiencies of vitamin D3 and DHA, as well as the omega-3 fatty acid EPA (eicosapentaenoic acid). “We may find that we need to carefully balance the supplementation with vitamin D3 and omega-3 fatty acids, depending on each patient in order to help promote efficient clearing of amyloid-beta,” Fiala said in the news release. “This is a first step in understanding what form and in which patients these nutrition substances might work best.”
Which nutrition works best when it's important to tailor the nutrient to the individual's genes and metabolism?
Watch out for oxidation. According to Fiala, an active (not oxidized) form of omega-3 DHA, which is the precursor of the resolvin D1 used in this study, may work better than more commercially available forms of DHA, which generally are not not protected against the oxidation that can render a molecule inactive. The next step is a larger study to help confirm the findings, as well as a clinical trial with omega-3 DHA, the researchers said in the news release. The Alzheimer’s Association contributed to the initial phase of the study. Fiala is a consultant for the Smartfish Company that is producing a drink with an active form of omega-3 DHA.
Additional study authors include Guanghao Liu, Larry Magpantay, James Sayre, Avi Siani, Michelle Mahanian, Rachel Weitzman, Eric Hayden, Mark J. Rosenthal, Ilka Nemere, John Ringman and David B. Teplow. For more news, visit the UCLA Newsroom and follow research on Twitter.
The Chinese herbal compound's effects on Alzheimer's disease
In another university's study, researchers found that the administration of the active compound tetrahydroxystilbene glucoside (TSG) derived from the Chinese herbal medicine Polygonum multiflorum Thunb, reversed both overexpression of α-synuclein, a small protein found in the brain, and its accumulation using a mouse model of Alzheimer's disease. Scientists found that aberrant accumulation of α-synuclein can form insoluble aggregates that have been implicated in several neurodegenerative diseases, including Parkinson's disease, dementia with Lewy bodies, and Alzheimer's disease (AD). Researchers have now found that overexpression of α-synuclein increases with age and have demonstrated that α-synuclein aggregates in the hippocampus of older mice compared to normal controls.
"Our results raise the possibility that TSG might be a novel compound for the treatment of AD and dementia with Lewy body," says co-lead investigator Lan Zhang, MD, PhD, Associate Professor, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Department of Pharmacology of Xuanwu Hospital of Capital Medical University in Beijing, according to the February 15, 2013 news release, "Novel herbal compound offers potential to prevent and treat Alzheimer's disease."
The study used an animal model of AD: APPV717I transgenic (Tg) mice with the London mutation. In previous work, the authors showed that these mice show cognitive impairments beginning at 4 months of age and develop amyloid plaques in the brain that are evident by 10 months.
In one series of experiments, 4 month old Tg mice were divided into 3 groups and received daily intragastric administration of distilled water (controls), low dose TSG (120 µmol/kg/d), or high dose TSG (240 µmol/kg/d). A fourth group consisted of age-matched non-Tg controls. The mice were treated until 10 months of age. In a second series of experiments, 10-month-old mice were divided into similar control and TSG-treated groups and were treated for 6 months.
The authors used a variety of techniques to hone in on what was happening in the brains of the Tg mice compared to age-matched controls: cDNA microarray analysis, reverse transcription PCR, western blotting, and immunochemistry. They found that α-synuclein messenger RNA (mRNA) and protein expression levels increase in a time-dependent manner in the hippocampus of Tg mice between ages 4 and 16 months and α-synuclein aggregation was noticeable at 16 months. Age-related increases in α-synuclein were also seen in the control mice but to a lesser degree, according to the February 15, 2013 the news release, Novel herbal compound offers potential to prevent and treat Alzheimer's disease.
"We suggest that, besides increased Aβ (beta-amyloid) and amyloid plaques, overexpression and aggregation of α-synuclein in the hippocampus might partially account for cognitive impairment in this Tg mouse model of Alzheimer's Disease (AD)," comments co-lead investigator Lin Li, MD, PhD, Professor and Director, Department of Pharmacology, Xuanwu Hospital of Capital Medical University in Beijing, according to the news release, Novel herbal compound offers potential to prevent and treat Alzheimer's disease. She adds that "α-synuclein overexpression occurs even in the early phase of AD and may accelerate Aβ production and deposition, which further facilitates α-synuclein overexpression and accumulation."
Chinese herbal compound has been found to be a "cognitive enhancer" in the study using mice
In the other study on how herbal compounds may help Alzheimer's patients which has been published this week in the journal Restorative Neurology and Neuroscience | IOS Press. In the new study, analysis of the TSG-treated groups showed that TSG-treatment from the age of 4 to 10 months significantly downregulated α-synuclein mRNA and protein overexpression in the hippocampus of the Tg mice, and the effect was stronger at the higher dose.
This suggests that TSG may have a role in preventing the neurotoxic effects of α-synuclein on synaptic function and cell activity. In addition, the finding that Tg reduced α-synuclein overexpression in older animals (>10 months) may indicate that it has therapeutic potential even after neuropathologic changes have occurred.
In previous work, the authors found that TSG acts as a "cognitive enhancer" to improve learning and memory in both APP transgenic mice and aged rats. The authors emphasize that while it is not completely clear how TSG works, their findings open up a new area of research. "The role of α-synuclein, especially in the early phase of Alzehimer's disease (AD), and its interaction with Aβ should be considered when developing new therapeutic strategies to target Alzheimer's disease (AD) pathogenesis," says Dr. Zhang.
Also check out the February 14, 2013 news release regarding another new study on using brain scans to detect dementia, "Most U.S. neurologists plan to use new brain scan for Alzheimer’s detection." A large majority of the nation's top neurologists say they would use a recently approved amyloid detection brain scan to evaluate their patients for Alzheimer's disease if the scan was paid for by health insurance, according to a survey recently published in the Journal of Alzheimer's Disease.
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