Vitamin D May Help Brain Cells Clear Toxi... - Cure Parkinson's

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Vitamin D May Help Brain Cells Clear Toxic Protein in Parkinson’s

Farooqji profile image
14 Replies

A study in Italy is the first to link vitamin D to astrocytes' ability to clear toxic protein clumps from the brains of Parkinson's patients.

onlinelibrary.wiley.com/doi...

14 Replies
Gioc profile image
Gioc

thanks Farooqji.

My tax money well spent.😄

Autophagy and α-Synuclein oligomer again,

Quote:

“The exact mechanism that drives astrocytes into detrimental alterations (eg, the secretion of neurotoxins) is unknown. Vitamin D prevents these astrocytes alterations in PD mouse model,29 while vitamin D signaling is unknown in PD patients. We found that activation of vitamin D pathway might be a novel mechanism to prevent the neurotoxic switch of astrocytes. Indeed, CYP27B1 positive astrocytes did not upregulate C3, thus protecting neurons from the complement component-driven synapse degeneration.

Recent evidence suggests that astrocytes participate in α-Synuclein oligomer clearance in vitro in primary cultures and patient-derived iPSC model.2, 5, 30 Starting from these previous papers on cellular model, showing that α-Synuclein fibrils co-localized with LAMP1, a marker for degradative autophagy-lysosomal organelles,28 we looked for the involvement of the autophagy pathway in α-Synuclein clearance occurring in our samples. The strategy of staining with LAMP1 allowed us to highlight the involvement of autophagy in α-Synuclein clearance that occurs in the complexity and uniqueness of the human brain. Hence, we show for the first time that an astrocyte subpopulation that is positive for CYP27B1 can internalize α-Synuclein oligomers through autophagy in PD patients. Interestingly, these cells morphologically resemble varicose projection astrocytes that are known to be fast conduit in neuron-vascular unit and are characterized by high speed calcium waves.25 In addition, the overexpression of wild-type or familial mutant α-Synuclein triggers calcium homeostasis alterations.31 Given the key role of vitamin D in calcium buffering,32 we speculate that the increase of CYP27B1 in PD astrocytes could be a positive strategy to counteract the calcium alterations. In line with that, CYP27B1 positive astrocytes are exclusively in contact with dopaminergic neurons without Lewy bodies suggesting their role in α-Synuclein oligomers clearance and osmoregulatory function.”

Bolt_Upright profile image
Bolt_Upright in reply to Gioc

I am still pulling for a one world government led by Rome!

Gioc profile image
Gioc in reply to Bolt_Upright

LoL Bolt, I propose instead to transfer all the capitals of the world to Rome, so ... just to make World War 3 difficult.

If Biden, Putin and Xi lived in the same city with everyone else would be difficult to bomb the enemy.

Rome, the capital of the capitals ... the food is good, the wine too. 😂

every time I take this route to the Colosseum I feel like I'm going home, I live in Como.
Biensur profile image
Biensur in reply to Gioc

I am so happy I live in Italy!

park_bear profile image
park_bear

They make a compelling case for the importance of vitamin D. Unfortunately the nature of the study is such that they are not able to designate a minimum level needed. Be that as it may, this is important work because it shows there is a mechanism by which toxic α-Synuclein aggregates can be cleared. If it is possible to up regulate this mechanism that may be a route to a disease modifying treatment.

"Interestingly, the majority of CYP27B1 [enzyme needed to activate vitamin D] positive astrocytes were in direct contact with neurons that did not contain Lewy bodies (Figure 5 B). Consistently with this data, we did not observe CYP27B1 positive astrocytes in locus coeruleus, where almost all the neurons we analyzed contained Lewy bodies. We therefore hypothesized that CYP27B1 positive astrocytes can be directly linked to α-Synuclein uptake and clearance. We performed proximity ligation assay to detect α-Synuclein oligomers in vivo and found that 74.4% of CYP27B1 positive astrocytes were able to uptake the toxic α-Synuclein aggregates (Figure 6 A-C and S4 A-B‴). Then, we used LAMP1, a marker for degradative autophagy-lysosomal organelles,28 in order to discover whether autophagy could be the mechanism involved in α-Synuclein clearance in CYP27B1 positive astrocytes. Notably, we found that α-Synuclein oligomers that are detected inside CYP27B1 positive astrocytes colocalize with LAMP1-positive vesicles (Figure 6 D and S4 C-D‴), thus suggesting the involvement of an autophagy pathway. Finally, we examined whether the increase in CYP27B1 positive astrocytes correlated with clinical aspects of PD patients (Table 1). We observed that CYP27B1 expression in the frontal cortex white matter was significantly increased in patients with Lewy body pathology, but without white matter alteration or dementia (Figure 7 A,B,D). Conversely, PD patients with white matter alterations and concomitant dementia had significantly fewer CYP27B1 positive astrocytes in the cortex (Figure 7 C,D), despite the total GFAP positive cells were unchanged (Figure 3 C)."

Bolt_Upright profile image
Bolt_Upright

This is quite a find Farooqj1!

"DISCUSSION

Our study unravels for the first time the alterations of vitamin D pathway in human brain of PD patients. While CYP24A1 and VDR did not display different expression between patients and controls, we showed that CYP27B1 increased in a subpopulation of astrocytes with neuroprotective features exclusively in brain areas involved in PD pathology (dorsal motor nucleus of vagus, substantia nigra and frontal cortex). Moreover, we found that CYP27B1 positive astrocytes are involved in an autophagy mediated-α-Synuclein uptake. These findings suggest an unprecedented role for CYP27B1 positive astrocytes in the pathology of PD.

Reactive astrocytes heavily contribute to neurodegeneration, and recent evidence suggests that neurotoxic astrocytes accumulate also in the substantia nigra of PD patients.6 The exact mechanism that drives astrocytes into detrimental alterations (eg, the secretion of neurotoxins) is unknown. Vitamin D prevents these astrocytes alterations in PD mouse model,29 while vitamin D signaling is unknown in PD patients. We found that activation of vitamin D pathway might be a novel mechanism to prevent the neurotoxic switch of astrocytes. Indeed, CYP27B1 positive astrocytes did not upregulate C3, thus protecting neurons from the complement component-driven synapse degeneration.

Recent evidence suggests that astrocytes participate in α-Synuclein oligomer clearance in vitro in primary cultures and patient-derived iPSC model.2, 5, 30 Starting from these previous papers on cellular model, showing that α-Synuclein fibrils co-localized with LAMP1, a marker for degradative autophagy-lysosomal organelles,28 we looked for the involvement of the autophagy pathway in α-Synuclein clearance occurring in our samples. The strategy of staining with LAMP1 allowed us to highlight the involvement of autophagy in α-Synuclein clearance that occurs in the complexity and uniqueness of the human brain. Hence, we show for the first time that an astrocyte subpopulation that is positive for CYP27B1 can internalize α-Synuclein oligomers through autophagy in PD patients. Interestingly, these cells morphologically resemble varicose projection astrocytes that are known to be fast conduit in neuron-vascular unit and are characterized by high speed calcium waves.25 In addition, the overexpression of wild-type or familial mutant α-Synuclein triggers calcium homeostasis alterations.31 Given the key role of vitamin D in calcium buffering,32 we speculate that the increase of CYP27B1 in PD astrocytes could be a positive strategy to counteract the calcium alterations. In line with that, CYP27B1 positive astrocytes are exclusively in contact with dopaminergic neurons without Lewy bodies suggesting their role in α-Synuclein oligomers clearance and osmoregulatory function.

Vitamin D deficiency may lead to cognitive impairments.14-17 Vitamin D supplementation can be beneficial in slowing down PD progression, but the underlying mechanisms are still unknown.13, 33 We found that the brains of PD patients without dementia have a threefold higher content of CYP27B1 positive astrocytes in the frontal cortex and do not have white matter degeneration, thus suggesting that vitamin D could exert its neuroprotective role through astrocytes.11 Although it would be appropriate to assess serum 25(OH)D and start supplementation to prevent PD or to slow its progression, the exact mechanisms underlying aberrant vitamin D pathways still need to be established. Considering that PD patients are usually characterized by low serum 25(OH)D,12 data in the different study groups presented low heterogeneity and VDR and CYP24A1 are similarly expressed in brains of PD patients and controls, a noteworthy question raised by our findings is how CYP27B1 can prevent neurotoxic alterations and promote α-Synuclein uptake by astrocytes? A limitation of our study is that we could not assess 25(OH)D levels and genetic status of the analyzed patients, and thus, we cannot exclude the potential contribution neither of concomitant vitamin D deficiency nor of polymorphisms in VDR.13 Further studies are warranted to clarify the complex relationship between vitamin D activation in astrocytes and PD.

Finally, our neuropathological investigation links for the first time vitamin D to the clearance of α-Synuclein aggregates and demonstrates that the presence of CYP27B1 positive astrocytes distinguishes PD patients."

JANVAN profile image
JANVAN in reply to Bolt_Upright

Yes, interesting ! A bit a big, easy thought perhaps from me…..but is it for this reason that Dr. Coimbra

used and use (in the beginning also a bit on P people) such high doses of

Vit D for his patients…….?

JANVAN profile image
JANVAN in reply to JANVAN

Ow Sorry…..I just discovered, that I had to scroll down a bit and then react a bit……..🤔🤓🤓

Bolt_Upright profile image
Bolt_Upright

Dr Berg is saying we can take 10,000 IUs of vitamin D a day. May want to drink a bunch of water and cut out the cheese.

youtu.be/gjJdzHIwDDU

Bolt_Upright profile image
Bolt_Upright in reply to Bolt_Upright

At about 4:18 he says if you have an autoimmune disease you might need up to 40,000 IUs with Magnesium, B6, and Zinc. I don't know how much of those.

Bolt_Upright profile image
Bolt_Upright

This seems to back up the Coimbra protocol. 38yroldmale

Bolt_Upright profile image
Bolt_Upright in reply to Bolt_Upright

Cicero Coimbra MD, PhD is a neurologist and professor at the Federal University of São Paulo, Brazil. Over the past two decades, he has created a clinical protocol to treat autoimmune diseases with the reestablishment of adequate systemic levels of vitamin D. This therapeutic approach relies on doses of vitamin D that range from 40,000 IU to 300,000 IU per day; therefore, this is a medical treatment that must always be carried out under the supervision of a qualified doctor.

Smittybear7 profile image
Smittybear7

Interesting thanks for sharing

If you take a high dose of D, make sure to also take K2.

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