Studies Show How Vitamin D3 Helps Clear Amyloid in AD

Megan Brooks

March 15, 2012

March 15, 2012 — A team of researchers has uncovered the intracellular mechanisms regulated by vitamin D3 that may help clear amyloid-beta from the brain, the hallmark of Alzheimer's disease (AD).

"This new study helped clarify the key mechanisms involved, which will help us better understand the usefulness of vitamin D3 and curcumin as possible therapies for Alzheimer's disease," Milan Fiala, MD, of the David Geffen School of Medicine at University of California Los Angeles, notes in a written statement.

The study also supports mounting evidence that adequate levels of vitamin D "may be a key factor in AD prevention," the researchers say. Their work was published March 6 in the Journal of Alzheimer's Disease.

"The clinical implications,” Dr. Fiala told Medscape Medical News,"are that vitamin D3 protects the brain through the immune system and that recommended blood levels of the 25-hydroxy vitamin D3 should be maintained in all seasons including winter when the sun is not helping to produce vitamin D in the skin."

She said clinical trials assessing the therapeutic potential of vitamin D3 are "ongoing or planned."

Retuning AD Macrophages

Brain clearance of amyloid-beta 1-42 (Aβ-42) by innate immune macrophages is required for maintenance of normal brain function. This process of phagocytosis is defective in patients with AD.

In earlier laboratory studies, Dr. Fiala and colleagues identified 2 types of macrophages in patients with AD, type I and type II macrophages. They found that the function of type I macrophages can be improved by adding vitamin D3 and curcuminoids, a synthetic form of curcumin, a chemical found in turmeric spice. Type II macrophages, on the other hand, are improved only by adding vitamin D3. However, the exact mechanism of these effects remained unclear, until now.

Macrophages from AD patients without (Figure 1) and with (Figure 2) vitamin D3. Macrophages in Figure 2 show greatly increased uptake and absorption of amyloid-beta. (Source: UCLA)

In their latest laboratory studies, the team isolated macrophages from blood samples taken from patients with AD and healthy controls. They incubated the cells overnight with amyloid-beta, some in the presence of vitamin D3 and/or curcuminoids.

The researchers observed that vitamin D3 activates a specific chloride channel, CLC-3, that is important in the clearance of Aβ-42 in both type I and type II AD macrophages. Curcuminoids only weakly activated this chloride channel and only in type I macrophages.

Vitamin D3 also helps trigger the genetic transcription of the chloride channel and the receptor for vitamin D3 in type II macrophages. Vitamin D3 recovery of Aβ-42 phagocytosis in type II AD macrophages is dependent on calcium and signaling by the mitogen-activated protein kinase (MAPK) pathway, they report.

It appears from this work that vitamin D3 can "retune AD macrophages to efficiently phagocytose soluble Aβ-42 by regulating the function of both extranuclear proteins (ie, nongenomic signaling) and expression of genes (genomic signaling)," Dr. Fiala and colleagues report.

Together with the work of other researchers, it seems that active forms of vitamin D "attenuate the deleterious effects Aβ-42 has on cell signaling in cortical neurons and innate immune cells." These findings support the "recent speculation that vitamin D sufficiency may be a key factor in AD prevention," the researchers say.

'Illuminating' Study

Reached for comment on the study, David J. Llewellyn, PhD, from the University of Exeter Peninsula Medical School in the United Kingdom, said: "This illuminating study adds to the emerging evidence that vitamin D may play an important neuroprotective role in the human brain."

As reported by Medscape Medical News, Dr. Llewellyn and colleagues recently reported evidence from the Third National Health and Nutrition Survey (NHANES III) that vitamin D deficiency is associated with an increased risk for cognitive impairment in older Americans. Nutritional supplementation with vitamin D3 has also been shown to protect against cognitive decline in the elderly.

"Taken together," he said, "these converging lines of evidence provide a strong rationale for intervention trials aiming to prevent or treat dementia." He cautioned, however, that randomized controlled trials that are designed to examine other outcomes such as cardiovascular disease "may not give us reliable answers."

"Indeed, a more thoughtful approach is necessary to ensure an appropriate dose of vitamin D is given to elderly adults that are both vitamin D deficient and likely to experience cognitive decline during a follow-up period that is relevant to the natural history of dementia," Dr. Llewellyn said.

The study was funded in part by the Alzheimer's Association and the National Institutes of Health. Dr. Fiala and Dr. Llewellyn have disclosed no relevant financial relationships. A complete list of author disclosures can be found here.

J Alz Dis. 2012;29:51-62. Abstract

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