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The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
zc_hl
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Re: The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation

Postby zc_hl » Sun Aug 18, 2019 2:32 am

Role of Osmolytes in Amyloidosis (https://www.intechopen.com/online-first/role-of-osmolytes-in-amyloidosis):
Osmolytes are naturally occurring small organic molecules present in all kingdoms of life. These organic molecules are accumulated by living systems to circumvent stress conditions. A number of human diseases have been grouped under the protein-misfolding diseases. These entire diseases share the same hallmarks of the presence of cellular inclusions and plaques that are deposited in the cells and tissues affected by the disease. These misfolded forms of protein are responsible for initiating toxic cascades in the cell, causing vesicle dystrafficking, synaptic and cell organelle dysfunction, and ultimately cell death. Published results suggest that cells regulate many biological processes such as protein folding, protein disaggregation, and protein-protein interactions via accumulation of specific osmolytes. Since, as of now, complete cure for these protein-misfolding disorders does not exist; therefore, it becomes increasingly important to review the recent works on this aspect to develop strategies for therapeutics. It has been shown that certain osmolytes can prevent the proteins from misfolding. Thus, osmolytes can be utilized as therapeutics for such diseases. In this review article, we discuss the role of naturally occurring osmolytes in various forms of amyloidosis associated with human diseases.


Intracellular Organic Osmolytes: Function and Regulation (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2276334/):
The basic concepts, as described then and still valid, are as follows. 1) All water-stressed organisms, except halobacteria, accumulate intracellular organic osmolytes in response to water stress. 2) The major systems of organic osmolytes include polyhydric alcohols, free amino acids and their derivatives, and combinations of urea and methylamines. 3) The evolutionary advantage of the organic osmolyte systems is compatibility with macromolecular structure and function at high and variable osmolyte concentrations without modifying cellular proteins to function in concentrated intracellular solutions. 4) Osmolyte compatibility results from non-perturbing or favorable effects of osmolytes on macromolecule-solvent interactions.


The osmolality of mammalian blood is normally kept remarkably constant at ∼290 mosmol/kg by a combination of thirst and varying urinary concentrations. Therefore, most mammalian cells are not normally exposed to the extreme osmolalities experienced by the cells discussed above. Nevertheless, certain mammalian cells contain considerable concentrations of organic osmolytes, and most of the rest are able to accumulate them if suitably stressed. Renal medullary cells contain the highest levels of organic osmolytes consequent to their being exposed to extremely high concentrations of NaCl and urea because of their roles in concentrating the urine. The principal organic osmolytes in renal medullary cells are sorbitol, betaine, inositol, taurine, and glycerophosphocholine (GPC). Cells in other tissues may also experience hyperosmolality, albeit to a lesser degree than in the renal medulla. Accordingly, they also accumulate organic osmolytes. The principal ones in brain are amino acids, choline, creatine, inositol, and taurine (20). Liver cells accumulate betaine, inositol, and taurine (21).


TonEBP/OREBP (also named NFAT5) is the transcription factor that mediates hypertonicity-induced transcription of AR, BGT1, SMIT, tauT, and NTE (2).

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Re: The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation

Postby Julie G » Sun Aug 18, 2019 11:58 am

Welcome zc_hi! Interesting concept. In terms of the ApoE4 allele, a reduction in cerebral vascularization is the first manifestation of our pathology. Newer (mouse) research shows that it's neutrophils that actually stick to the capillaries in the brain which cause the reduction in flow. With that understanding, I'd be pretty hesitant to reduce the viscosity of my blood for fear that it would contribute to this phenomenon. Have you looked into this angle?

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Re: The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation

Postby MarcR » Sun Aug 18, 2019 1:05 pm

Do you mean increase the viscosity?

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Re: The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation

Postby zc_hl » Sun Aug 18, 2019 1:13 pm

Julie G wrote:Welcome zc_hi! Interesting concept. In terms of the ApoE4 allele, a reduction in cerebral vascularization is the first manifestation of our pathology. Newer (mouse) research shows that it's neutrophils that actually stick to the capillaries in the brain which cause the reduction in flow. With that understanding, I'd be pretty hesitant to reduce the viscosity of my blood for fear that it would contribute to this phenomenon. Have you looked into this angle?


Hello Julie,

No I did not, I am not aware of this apoe4 "feature" :)

Is it some kind of autoimmune process? Do we also notice such a reduced cerebral vascularization issue in APOE4 of countries where Alzheimer rates are lower (developing countries)?

Thanks for your input !

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Re: The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation

Postby zc_hl » Sun Aug 18, 2019 1:28 pm

I don't know if it answers the issue of blood viscosity but dehydration should increase vasopressin and oxytocin which seem to produce vasodilatation in the brain.

Vasopressin and Oxytocin in Control of the Cardiovascular System (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637675/):
In some vascular beds, i.e. the lungs and the brain, VP and OT produce NO dependent vasodilatation.

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Re: The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation

Postby Julie G » Sun Aug 18, 2019 2:31 pm

Do you mean increase the viscosity?

YES! :? Thanks for the correction.
I don't know if it answers the issue of blood viscosity but dehydration should increase vasopressin and oxytocin which seem to produce vasodilatation in the brain.

Cerebral vasodilatation would be a good thing, but I worry that the more viscous blood simply wouldn't travel as well. See a study below that found dehydration appears to negatively impact cognition and the actual structural functioning of the brain when imaged.

Exercise‐heat stress with and without water replacement alters brain structures and impairs visuomotor performance
https://physoc.onlinelibrary.wiley.com/ ... phy2.13805
Abstract
Effects of exercise‐heat stress with and without water replacement on brain structure and visuomotor performance were examined. Thirteen healthy adults (23.6 ± 4.2 years) completed counterbalanced 150 min trials of exercise‐heat stress (45°C, 15% RH) with water replacement (EHS) or without (~3% body mass loss; EHS‐DEH) compared to seated rest (CON). Anatomical scans and fMRI Blood‐Oxygen‐Level‐Dependent responses during a visuomotor pacing task were evaluated. Accuracy decreased (P < 0.05) despite water replacement during EHS (−8.2 ± 6.8% vs. CON) but further degraded with EHS‐DEH (−8.3 ± 6.4% vs. EHS and −16.5 ± 10.2% vs. CON). Relative to CON, EHS elicited opposing volumetric changes (P < 0.05) in brain ventricles (−5.3 ± 1.7%) and periventricular structures (cerebellum: 1.5 ± 0.8%) compared to EHS‐DEH (ventricles: 6.8 ± 3.4, cerebellum: −0.7 ± 0.7; thalamus: −2.7 ± 1.3%). Changes in plasma osmolality (EHS: −3.0 ± 2.1; EHS‐DEH: 9.3 ± 2.1 mOsm/kg) were related (P < 0.05) to thalamus (r = −0.45) and cerebellum volume (r = −0.61) which, in turn, were related (P < 0.05) to lateral (r = −0.41) and fourth ventricle volume (r = −0.67) changes, respectively; but, there were no associations (P > 0.50) between structural changes and visuomotor accuracy. EHS‐DEH increased neural activation (P < 0.05) within motor and visual areas versus EHS and CON. Brain structural changes are related to bidirectional plasma osmolality perturbations resulting from exercise‐heat stress (with and without water replacement), but do not explain visuomotor impairments. Negative impacts of exercise‐heat stress on visuomotor tasks are further exacerbated by dehydration.

FWIW, I found a Chinese RCT examining the effect of dehydration on many parameters of cognition with imaging. See here. I don't think results have been published yet, but it should be very telling.

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Re: The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation

Postby zc_hl » Mon Aug 19, 2019 1:57 am

Julie G wrote:
Do you mean increase the viscosity?

YES! :? Thanks for the correction.
I don't know if it answers the issue of blood viscosity but dehydration should increase vasopressin and oxytocin which seem to produce vasodilatation in the brain.

Cerebral vasodilatation would be a good thing, but I worry that the more viscous blood simply wouldn't travel as well. See a study below that found dehydration appears to negatively impact cognition and the actual structural functioning of the brain when imaged.

Exercise‐heat stress with and without water replacement alters brain structures and impairs visuomotor performance
https://physoc.onlinelibrary.wiley.com/ ... phy2.13805
Abstract
Effects of exercise‐heat stress with and without water replacement on brain structure and visuomotor performance were examined. Thirteen healthy adults (23.6 ± 4.2 years) completed counterbalanced 150 min trials of exercise‐heat stress (45°C, 15% RH) with water replacement (EHS) or without (~3% body mass loss; EHS‐DEH) compared to seated rest (CON). Anatomical scans and fMRI Blood‐Oxygen‐Level‐Dependent responses during a visuomotor pacing task were evaluated. Accuracy decreased (P < 0.05) despite water replacement during EHS (−8.2 ± 6.8% vs. CON) but further degraded with EHS‐DEH (−8.3 ± 6.4% vs. EHS and −16.5 ± 10.2% vs. CON). Relative to CON, EHS elicited opposing volumetric changes (P < 0.05) in brain ventricles (−5.3 ± 1.7%) and periventricular structures (cerebellum: 1.5 ± 0.8%) compared to EHS‐DEH (ventricles: 6.8 ± 3.4, cerebellum: −0.7 ± 0.7; thalamus: −2.7 ± 1.3%). Changes in plasma osmolality (EHS: −3.0 ± 2.1; EHS‐DEH: 9.3 ± 2.1 mOsm/kg) were related (P < 0.05) to thalamus (r = −0.45) and cerebellum volume (r = −0.61) which, in turn, were related (P < 0.05) to lateral (r = −0.41) and fourth ventricle volume (r = −0.67) changes, respectively; but, there were no associations (P > 0.50) between structural changes and visuomotor accuracy. EHS‐DEH increased neural activation (P < 0.05) within motor and visual areas versus EHS and CON. Brain structural changes are related to bidirectional plasma osmolality perturbations resulting from exercise‐heat stress (with and without water replacement), but do not explain visuomotor impairments. Negative impacts of exercise‐heat stress on visuomotor tasks are further exacerbated by dehydration.

FWIW, I found a Chinese RCT examining the effect of dehydration on many parameters of cognition with imaging. See here. I don't think results have been published yet, but it should be very telling.


Hello Julie,

Once again, thanks for your input and the good debate environment that is available on this forum :)

Regarding the study you linked, I truly wonder whether these results are transposable to what would happen in the context of a reasonable dry fasting/intermittent drinking protocol for 2 reasons:
    - I'm pretty confident with the fact that there exists an adaptation period to intermittent drinking. It's a bit like judging the impact of a ketogenic diet on human performance before the end of the keto adaptation period. Or like testing mental performance of someone on his first day of intermittent fasting :D.
    - The people of this study were not only dehydrated, they had been exercising by 45°C (113°F) during 150 minutes, which could be an important confounding factor.

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Re: The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation

Postby Julie G » Mon Aug 19, 2019 10:32 am

Regarding the study you linked, I truly wonder whether these results are transposable to what would happen in the context of a reasonable dry fasting/intermittent drinking protocol for 2 reasons:
- I'm pretty confident with the fact that there exists an adaptation period to intermittent drinking. It's a bit like judging the impact of a ketogenic diet on human performance before the end of the keto adaptation period. Or like testing mental performance of someone on his first day of intermittent fasting :D
- The people of this study were not only dehydrated, they had been exercising by 45°C (113°F) during 150 minutes, which could be an important confounding factor.

True. I worried about the confounding effect of the exercise. I guess that was the researchers' way of inducing dehydration vs. simple water deprivation over time. I suspect that the Chinese study I linked will better put your hypothesis to the test. That said, understanding that the weight of the human brain is 75% water, I'm still pretty skeptical. Perhaps a bit of controlled dehydration, now and then, could have a positive hormetic effect over time. :?

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Re: The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation

Postby zc_hl » Mon Aug 19, 2019 12:41 pm

I think that the confounding effect seems to be confirmed.

Effect of water deprivation on cognitive-motor performance in healthy men and women (https://www.physiology.org/doi/full/10.1152/ajpregu.00501.2004)

Data on direct comparisons between heat- or exercise-induced dehydration and water deprivation are lacking. However, one reason for the discrepancy between our results and those of previous studies could be the fact that exercise and heat lead to vasodilatation and increased heart rate, affecting the cardiovascular system much more than water deprivation. Further, the velocity of fluid loss may play a role. While Cian et al. (2) and Gopinathan et al. (9) have tested cognitive performance after acute dehydration within 0.5–2 h, water deprivation over 28 h was necessary to reach identical levels of dehydration in the present protocol.

The results of the present study indicate therefore that young healthy subjects are able to adapt to a slowly progressive water deficit. This is in accordance with the results of Cian et al. (2), showing that the initial drop of short-term memory immediately after acute dehydration returned to baseline levels 3.5 h later independent of water intake. Interestingly, performance normalized after rehydration, as well as after ongoing dehydration. However, the mechanisms responsible for the adaptation remain unclear.

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Re: The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation

Postby Melanie R. » Tue Aug 20, 2019 9:24 pm

Dear Zac
Welcome to the site and thank you for sharing. You've posted some interesting things. I hope to learn more as time passes, as there is so much to be discovered here.
Kindly,
Melanie
Functional Medicine Certified Health Coach
Reversing Cognitive Decline for Coaches (ReCODE)


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