Highly relevant new Vit-D / Alzheimer study

LeeLemonoil

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P53 substitutes the Retinoid-receptor in AD - certainly also many other pathologies. To me a major finding with huge implications.

@haidut






Abstract
Observational epidemiological studies have associated vitamin D deficiency with Alzheimer's disease (AD). However, whether vitamin D deficiency would result in some impacts on the vitamin D binding receptor (VDR) remains to be characterized in AD. Vitamin D helps maintain adult brain health genomically through binding with and activating a VDR/retinoid X receptor (RXR) transcriptional complex. Thus, we investigated the role of VDR in AD using postmortem human brains, APP/PS1 mice, and cell cultures. Intriguingly, although vitamin D was decreased in AD patients and mice, hippocampal VDR levels were inversely increased. The abnormally increased levels of VDR were found to be colocalized with Aβ plaques, gliosis and autophagosomes, implicating a non-genomic activation of VDR in AD pathogenesis. Mechanistic investigation revealed that Aβ upregulated VDR without its canonical ligand vitamin D and switched its heterodimer binding-partner from RXR to p53. The VDR/p53 complex localized mostly in the cytosol, increased neuronal autophagy and apoptosis. Chemically inhibiting p53 switched VDR back to RXR, reversing amyloidosis and cognitive impairment in AD mice. These results suggest a non-genomic rewiring of VDR to p53 is key for the progression of AD, and thus VDR/p53 pathway might be targeted to treat people with AD.
 

haidut

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Intriguingly, although vitamin D was decreased in AD patients and mice, hippocampal VDR levels were inversely increased.

Thanks, very good study. I don't know why they say it is surprising that VDR expression increased during vitamin D deficiency when this is what normally happens to compensate for the deficiency. Conversely, taking vitamin D may lower VDR expression and be therapeutic for AD.

Chemically inhibiting p53 switched VDR back to RXR, reversing amyloidosis and cognitive impairment in AD mice. These results suggest a non-genomic rewiring of VDR to p53 is key for the progression of AD, and thus VDR/p53 pathway might be targeted to treat people with AD.

A great finding. I have always been suspicious of the "glorious tumor suppressing gene p53" (as media/medicine present it). In-vitro studies and some animal in-vivo studies lately have shown that increasing p53 expression is actually a strong tumor-promoter and involved in many fibrotic processes. I am glad its fake reputation as "panacea" is being challenged/exposed.
"...Interestingly, some of these activities may protect the liver from cancer in the short term, yet in the long term, p53 may lead to malignant transformation. A better understanding of the complex clinical outcome of p53 function in the liver may shed light on future therapies."
 
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aliml

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Apr 17, 2017
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Substances That Decrease TP53 (Tumor protein p53):

-- Aspirin
-- Sodium Salicylate
-- Nicotine
-- Caffeine
-- Vitamin C
-- Niacinamide
-- Progesterone
-- Calcium
-- Sodium Chloride
-- Zinc
-- Glutathione
-- EGCG
-- Selenium
-- Melatonin
-- Thyroxine
-- Pergolide
-- Lycopene
-- Quinidine
-- Vanillin
-- Cinnamon
-- Ivermectin
-- Chloroquine
-- Gallic Acid
-- Butyric Acid
-- Choline
-- Phosphatidylcholine
-- Chlorophyllin
-- Astaxanthine
-- Sildenafil Citrate
-- Naringenin
-- Ginkgo Biloba
-- Beta-Carotene
-- Resveratrol

 
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LeeLemonoil

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Sep 24, 2016
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Thanks, very good study. I don't know why they say it is surprising that VDR expression increased during vitamin D deficiency when this is what normally happens to compensate for the deficiency. Conversely, taking vitamin D may lower VDR expression and be therapeutic for AD.

Wondered about that too. It seems the general competency and knowledge of lot of today’s scientists is meagre.
Co-authoring doctorants and post-docs often know ***t
 

ddjd

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Jul 13, 2014
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6,677
P53 substitutes the Retinoid-receptor in AD - certainly also many other pathologies. To me a major finding with huge implications.

@haidut






Abstract
Observational epidemiological studies have associated vitamin D deficiency with Alzheimer's disease (AD). However, whether vitamin D deficiency would result in some impacts on the vitamin D binding receptor (VDR) remains to be characterized in AD. Vitamin D helps maintain adult brain health genomically through binding with and activating a VDR/retinoid X receptor (RXR) transcriptional complex. Thus, we investigated the role of VDR in AD using postmortem human brains, APP/PS1 mice, and cell cultures. Intriguingly, although vitamin D was decreased in AD patients and mice, hippocampal VDR levels were inversely increased. The abnormally increased levels of VDR were found to be colocalized with Aβ plaques, gliosis and autophagosomes, implicating a non-genomic activation of VDR in AD pathogenesis. Mechanistic investigation revealed that Aβ upregulated VDR without its canonical ligand vitamin D and switched its heterodimer binding-partner from RXR to p53. The VDR/p53 complex localized mostly in the cytosol, increased neuronal autophagy and apoptosis. Chemically inhibiting p53 switched VDR back to RXR, reversing amyloidosis and cognitive impairment in AD mice. These results suggest a non-genomic rewiring of VDR to p53 is key for the progression of AD, and thus VDR/p53 pathway might be targeted to treat people with AD.

View: https://twitter.com/JikkyKjj/status/1485914575128399872?t=GPjmtFDwBRhwbjHfuCusFw&s=19
 

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