Activation of vitamin D receptor inhibits Tau phosphorylation is associated with reduction of iron accumulation in APP/PS1 transgenic mice

Alzheimer’s disease is a progressive neurologic disorder that causes the brain to shrink (atrophy) and brain cells to die. Alzheimer’s disease is the most common cause of dementia a condition characterized by continuous decline in thinking, behavioral and social skills that affects a person’s ability to function independently. The early signs of the disease include forgetting recent events or conversations. As the disease progresses, a person with Alzheimer’s disease develops severe memory impairment and may lose the ability to carry out everyday tasks.

People with very low levels of vitamin D in their blood, are referred to as vitamin D deficient and are more likely to develop Alzheimer’s disease and other forms of dementia. A large study published in Neurology showed that people with extremely low blood levels of vitamin D were more than twice as likely as those with normal vitamin D levels to develop Alzheimer’s disease or other types of dementia. Vitamin D is also vital to bone metabolism, calcium absorption and other metabolic processes in the body. However, vitamin D role in brain function, cognition and the aging process is still unclear. Some studies suggest that vitamin D may be involved in a variety of processes related to cognition, but more research is needed to better understand this relationship. Vitamin D deficiency is common among older adults, partly because the skin’s ability to synthesize vitamin D from the sun decreases with age. More studies are needed to determine if vitamin D deficiency is indeed a risk factor for Alzheimer’s disease and dementia.

Recent studies revealed that vitamin D deficiency promotes β-amyloid deposition in mouse brain, while treatment with paricalcitol which is a specific agonist of vitamin D receptor reduced Aβ generation. In a new study published in Neurochemistry International by Dr. Ling-Xiao Zhao, Dr. Yan-Hui Zhang and Dr. Yong-Gang Fan from China Medical University together with M.M. Ting-Yao Wu from Hospital of Jinzhou Medical University explain how activation of Vitamin D receptor reduces the iron content in mouse brain. The main objective of the investigation was to find out how vitamin D receptor activation reduces the accumulation of iron in brain and inhibits the phosphorylation of Tau protein. Researchers used paricalcitol to activate the vitamin D receptor. The research team treated the animals with vehicle and paricalcitol for 15 weeks. The authors observed that activation of vitamin D receptor can stop the accumulation of iron in brain of mouse. Iron deposition in neurons increases the amount of reactive oxygen species that can induce cell death. The activation of vitamin D receptor decreases the iron content by inhibiting the expression of transferrin receptor (TFR) via reducing expression of iron regulatory protein 2 (IRP2). Phosphorylation of Tau protein can be regulated by iron in the neurons. There are two forms of iron in cells, ferric and ferrous forms. Among these, ferric ion directly interacts with supposed iron-binding motif located within the microtubule-binding domains of Tau which promotes accumulation of hyperphosphorylation of Tau. Decreased phosphorylation of Tau was highly associated with reduced iron content and glycogen synthase kinase 3 β (GSK3β) activity in the paricalcitol treated animals that indicate vitamin D receptor activation blocked Tau phosphorylation. Now it is well established in the literature that hyperphosphorylation of Tau leads to Alzheimer’s disease and in the current study of Ting-Yao Wu and colleagues, they showed phosphorylation of Tau was inhibited in brain of mouse by activation of vitamin D receptor.

In summary, research team demonstrated in elegant cell and molecular biology experiments that vitamin D receptor activation successfully reduced the content of iron in mouse brain by blocking TFR-mediated iron import via down regulation of IRP2 that may lead to inhibition of Tau phosphorylation by depleting the activity of GSK3β. The new study confirms that boosting the activation of vitamin D receptor may be a potential new therapeutic approach for the treatment of Alzheimer’s disease.