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

Postby zc_hl » Fri Aug 16, 2019 2:40 am

The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation (https://www.ncbi.nlm.nih.gov/m/pubmed/26986971/):

The brain maintains its mass and physiological functional capacity compared with other organs under harsh conditions such as starvation, a mechanism termed the 'selfish brain' theory. To further investigate this phenomenon, mice were examined following water and/or food deprivation. Although the body weights of the mice, the weight of the organs except the brain and blood glucose levels were significantly reduced in the absence of water and/or food, the brain weight maintained its original state. Furthermore, no significant differences in the water content of the brain or its energy balance were observed when the mice were subjected to water and/or food deprivation. To further investigate the mechanism underlying the brain maintenance of water and substance homeostasis, the expression levels of aquaporins (AQPs) and autophagy‑specific protein long‑chain protein 3 (LC3) were examined. During the process of water and food deprivation, no significant differences in the transcriptional levels of AQPs were observed. However, autophagy activity levels were initially stimulated, then suppressed in a time‑dependent manner. LC3 and AQPs have important roles for the survival of the brain under conditions of food and water deprivation, which provided further understanding of the mechanism underlying the 'selfish brain' phenomenon. Although not involved in the energy regulation of the 'selfish brain', AQPs were observed to have important roles in water and food deprivation, specifically with regards to the control of water content. Additionally, the brain exhibits an 'unselfish strategy' using autophagy during water and/or food deprivation. The present study furthered current understanding of the 'selfish brain' theory, and identified additional regulating target genes of AQPs and autophagy, with the aim of providing a basis for the prevention of nutrient shortage in humans and animals.

Autophagy levels comparison between no food/no water/both: Image
Last edited by zc_hl on Fri Aug 16, 2019 2:22 pm, edited 1 time in total.

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

Postby zc_hl » Fri Aug 16, 2019 12:10 pm

Intermittent drinking, oxytocin and human health (https://www.sciencedirect.com/science/article/abs/pii/S0306987716300792):

Looking at a waterhole, it is surprising that so many animals share the same space without visible signs of anxiety or aggression. Although waterholes are the preferred feeding locations of large carnivores, waterholes are shared by all type of herbivores of all sizes and shapes, including elephants. Recent research shows that the homeostatic disturbances leading to the "thirst feeling" not only activate specific substances regulating water and mineral household, but also the "trust and love" hormone oxytocin, while decreasing the production of the typical stress hormone cortisol. People using drugs, seem to be in search for oxytocin, as evidenced in studies with individuals on drugs such as ecstasy and gamma-hydroxybyturate. Hot environment, drought and increased sweating also activate specific oxytocin-producing parts of the hypothalamus, just as breastfeeding does in mother and infant. Water homeostasis is the only allostatic system activating trust neuro-anatomy and we suggest that this is due to the fact that all animals depend on water, whereas food type is species specific. Our hypothesis; regulating drinking behaviour through intermittent bulk drinking could increase oxytocin signalling, recover human trust and increase health by down-regulation of stress axis activity and inflammatory activity of the immune system. Intermittent bulk drinking should be defined as water (including tea and coffee) drinking up to a feeling of satiety and regulated by a mild feeling of thirst. This would mean that people would not drink less quantity but less frequently and that's how all animals, but also human newborns behave. It is the latter group, which is probably the only group of humans with a normal fluid homeostasis.

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

Postby zc_hl » Fri Aug 16, 2019 12:36 pm

Whole Body Stress and Immune Cell Responses to Exercise, Heat and Dehydration in the 2012 Ironman World Championship and Controlled Laboratory Study (https://opencommons.uconn.edu/dissertations/398/):

Our laboratory subsequently investigated the influence of a more severe and compound stress scenario, which included exercise, heat, and dehydration. This study served as a first time human examination of the novel, osmotic-specific HSP70 transcription factor, NFAT5. Trends suggested that NFAT5 could indicate whole body dehydration, but limitations caused requirement for further and broader study.


Intriguingly, PBMC NFAT5 expression indicated two diverse response patterns to 16h fluid deprivation, and subsequent stressors (Figure 4), such that one group increased ("positive responders"; n = 21) and one decreased ("negative responders"; n = 11) from Base to Pre, and maintained opposing patterns for subsequent time points.


PBMC expression of NFAT5:
https://imgur.com/AHrBF16
https://imgur.com/PS3z2TE

Note, they were not fasting:
Upon departing the lab, participants were instructed to 1) refrain from consuming all fluids and to avoid consuming foods
with high fluid content
(examples of these foods were provided) beginning 16 hours (h) prior to the experimental visit, and 2) complete an 8h, overnight fast.

which means that NFAT5 could be higher (amino acid restriction seems to increase NFAT5, https://www.ncbi.nlm.nih.gov/m/pubmed/11350742/ , TonEBP = NFAT5).

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TonEBP Suppresses the HO-1 Gene by Blocking Recruitment of Nrf2 to Its Promoter (https://www.frontiersin.org/articles/10.3389/fimmu.2019.00850/full):

"Here, we identified a novel function of TonEBP as a potent suppressor of HO-1 expression both in human and murine macrophages."

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Heme Oxygenase-1 Drives Metaflammation and Insulin Resistance in Mouse and Man (https://www.sciencedirect.com/science/article/pii/S0092867414006710):

Here, we show that HO-1 drives insulin resistance in mouse and man. In the absence of macrophage HO-1 animals fail to develop metaflammation and key hallmarks of metabolic disease. The findings redefine the current view of HO-1, have substantial implications for the stratification of healthy and unhealthy obesity, and open the door for HO-1 inhibitors as a new therapeutic strategy for obesity and diabetes.

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

Postby zc_hl » Fri Aug 16, 2019 12:40 pm

The dehydration treatment of epilepsy (https://pdfs.semanticscholar.org/6dda/a925825f4b402417f53a04cee4c6f4183266.pdf):

Bauer pointed out that of 25 infants, maintained on a ketogenic diet, he had obtained symptomatic relief on approximatively 35%. When these same infants were placed on fluid limitation and dehydration for one year, he was able to establish 100% symptomatic relief in his group.


In a later report, he mentions that he had observed 86-88 cases, with similar results. He says in conclusion, 'I am convinced that the use of the ketogenic diet is incomplete both in its hypothesis and in its execution as a relief for epilepsy'

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

Postby zc_hl » Fri Aug 16, 2019 2:05 pm

Astroglial water channel aquaporin 4-mediated glymphatic clearance function: A determined factor for time-sensitive treatment of aerobic exercise in patients with Alzheimer’s disease (https://www.sciencedirect.com/science/article/abs/pii/S0306987718305449):

Further studies also show that the clearance function of the glymphatic system depends on astroglial water channel aquaporin 4 (AQP4) that lines the paravascular CSF pathways [28–30]. AQP4, the most abundant water channel in the brain, is crucial for maintaining brain water homeostasis [31,32]. We demonstrated that AQP4 gene knockout (AQP4-/-) in mice results in slightly increased brain water content, reduced CSF production rate, and delayed postnatal brain water uptake [33–34]. AQP4-/-mice exhibit slowed CSF influx from the subarachnoid space into the brain parenchyma, as well as ISF outflow into the subarachnoid space again [28]. Apart from maintaining brain water balance, AQP4 facilitates ISF entering into astrocyte processes surrounding the synapses, which might drive astrocyte Ca2+ signaling transduction and reuptake of K+ and glutamate, thus regulating synaptic plasticity [35,36]. AQP4 is also involved in the regulation of neurotrophic factordependent synaptic plasticity [37]. Adult AQP4-/-mice exhibit defects in consolidation memory and location-specific object memory [38,39]. Furthermore, AQP4 is necessary for the glymphatic system to clear Aβ and Tau [28–30]. Adult AQP4-/-mice show a ∼45% reduction in clearance of intrastriatal injected radio-labeled Aβ1-40, compared with aged-match wild-type (WT) mice [28]. In order to define the function of AQP4 in AD pathology, we successfully established AQP4-/-/APP/PS1 mice. Twelve-month-old AQP4-/-/APP/PS1 mice exhibit heightened spatial learning and memory impairment along with increased Aβ plaques deposition, amyloid angiopathy, synaptic protein loss and atrophy of astrocytes in the hippocampus and cortex [30]. This revealed a mitigating role of AQP4 in Aβ pathogenesis, suggesting that regulating the glymphatic system via targeting at AQP4 may be an effective therapeutic strategy for clearing soluble Aβ in the brain of patients with AD.


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Water for thought: is there a role for aquaporin channels in delirium? (https://www.frontiersin.org/articles/10.3389/fpsyt.2014.00057/full):

The movement of water in and out of the neuropil occurs with the help of the glymphatic system via special molecular pumps, aquaporin water channels (AQP 4) located in astrocyte end-feet. Water circulation is enabled by the exchange between the cerebrospinal fluid (CSF) and interstitial fluid (ISF). The pressure gradient for this exchange is probably provided by pericytes’ contraction and arterial pulsations along with the suction, pump-like action of AQP 4 channels (4–6). This movement of water in and out of the neuropil enables both, clearance of molecular waste and volume transmission (VT) of chemical signals (7). Conversely, delayed water movement (glymphatic stasis) may predispose to the accumulation of misfolded proteins (4) and ultimately to neuroinflammation (8).

The relationship between water and delirium is complex. Both, brain edema and dehydration may predispose to delirium (9). Up-regulation of AQP 4 water channels seems to occur in both situations. In fact, a biphasic up-regulation was described in edema build-up and the resolution phase (10). Interestingly, AQP 4 receptors seem to be the common denominator between the neuropil water movement and neuroinflammation (10). Moreover, animal studies demonstrated that peripheral dehydration triggers central up-regulation of AQP 4 receptors (11–13). This in turn causes swelling and priming of astrocytes and microglia, predisposing to neuroinflammation (14).

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

Postby TheresaB » Fri Aug 16, 2019 2:18 pm

Hey zc_hl, welcome to our site. Your posts are pretty arbitrary, can you provide some discussion on who you are, your background, and the relevance of these posts to the ApoE4 allele.
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Re: The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation

Postby zc_hl » Fri Aug 16, 2019 2:49 pm

TheresaB wrote:Hey zc_hl, welcome to our site. Your posts are pretty arbitrary, can you provide some discussion on who you are, your background, and the relevance of these posts to the ApoE4 allele.


Hello TheresaB,

I am an APOE3/4 interested in fasting and keto, and have "lurked" APOE4.info for some time now.

The background of this is I think there is merit to dry fasting (for Alzheimer or health in general), or at least "Intermittent drinking" as described in one of the posts above.

They are not directly linked with APOE4 but can be related somewhat with Alzheimer I guess as they are related to autophagy, keto diet, metabolic health, etc.

I'm very aware that it's highly hypothetical (and controversial on top), could even be blatantly false, that's why I need feedback from people having knowledge on the topic.

Sorry if it seems arbitrary, not really sure what you meant by that. I packed these studies in a single thread as I didn't want to spam the forum (still a bit the case :)) I hope it fits in the Scientific and Research forum!

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

Postby floramaria » Sat Aug 17, 2019 12:30 pm

zc_hl wrote:I am an APOE3/4 interested in fasting and keto, and have "lurked" APOE4.info for some time now.
The background of this is I think there is merit to dry fasting (for Alzheimer or health in general), or at least "Intermittent drinking" as described in one of the posts above.


Hi zc_hl, this is the first I have heard of “intermittent drinking” . Have you experimented with either dry fasting of intermittent drinking yourself? Curious abou your personal experience with this if you have.
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Re: The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation

Postby zc_hl » Sat Aug 17, 2019 2:01 pm

floramaria wrote:
zc_hl wrote:I am an APOE3/4 interested in fasting and keto, and have "lurked" APOE4.info for some time now.
The background of this is I think there is merit to dry fasting (for Alzheimer or health in general), or at least "Intermittent drinking" as described in one of the posts above.


Hi zc_hl, this is the first I have heard of “intermittent drinking” . Have you experimented with either dry fasting of intermittent drinking yourself? Curious abou your personal experience with this if you have.


Hi Floramaria,

I'm not surprised you had not heard about intermittent drinking before as it's not really a common concept :), it's been introduced in the article that I linked in my second post. Dry fasting is of course a lot more widespread because of ramadan :)

I have experimented with both and I've yet to make it really work but I did see some testimonies about more profound results with dry than with water fasting in some cases. I am no surprised of those testimonies as I found that there are some theorerical results suggesting that dry fasting could improve/enhance the immune system response.

What I can tell you regarding my dry fasting experience is that it's not necessarily more difficult than water fasting. I expericienced "coldness" during water fasting that I've yet to experience with dry fasting. Otherwise, I have felt fatigue in both cases, but sometimes dry fasting gives more energy than with water! I've dry fasted 23h multiple times and 48h one Time. I'm currently trying to set up a 16/8 intermittent dry fasting.

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

Postby zc_hl » Sat Aug 17, 2019 2:41 pm

Osmolality controls the expression of cathelicidin antimicrobial peptide in human macrophages (https://www.biorxiv.org/content/10.1101/332635v1):
An imbalance between extracellular and intracellular fluid osmolality causes osmotic stress and affects cellular homeostasis. Recent research suggests that osmotic stress is also associated with various innate and adaptive immune responses. Here we present the surprising finding that osmolality tightly controls the expression of cathelicidin antimicrobial peptide (CAMP) in human macrophages. CAMP expression is strongly upregulated under hyperosmotic conditions and downregulated under hypoosmotic conditions. We also provide evidence that this osmolality-mediated antimicrobial response is dependent on nuclear factor of activated T-cells 5 (NFAT5) and mitogen-activated protein kinase (MAPK) p38. Finally, Toll-like receptor (TLR) activation inhibits osmolality-mediated expression of CAMP in human macrophages, suggesting that this osmolality-dependent regulation of CAMP is more relevant under homeostatic conditions, rather than during acute infections. This study expands our knowledge of the regulation of human antimicrobial peptides and highlights osmolality as an important and independent factor shaping host innate immune homeostasis.


This one is not about macrophages in the brain. Nonetheless, CAMP, which is also called LL-37, seems to interact with Aβ in the brain:

Evidence that the Human Innate Immune Peptide LL-37 may be a Binding Partner of Amyloid-β and Inhibitor of Fibril Assembly (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5611894/)

This work demonstrates that these two peptides, the cathelicidin peptide LL-37 and Aβ, both ubiquitous in human tissues, interact in vitro with each other in different aggregation states, with affinity constants typical of protein-protein interactions and close to values reported in the literature for the binding of Aβ with optimized synthetic peptides. The addition of LL-37 to Aβ42, in a buffer that mimics quasi-physiological conditions, strongly inhibits fibril formation. The protective effect of LL-37’s presence against microglia-mediated Aβ42 toxicity to SH-SY5Y neuroblastoma cells is an important new finding, revealing that in combination the two peptides are 90% less pro-inflammatory than either peptide alone.Literature reports suggest that numerous biophysical activities and signaling functions of Aβ peptides and LL-37 are related in vivo. The in vitro data presented here constitute a starting point from which to investigate whether factors that affect cathelicidin gene CAMP regulation, which will in turn control the production of LL-37 in vivo, modulate Aβ aggregation and/or microglia-induced neuroinflammation.


Moreover, LL-37 seems to induce autophagy in macrophages which could be necessary for phagocytosis of Aβ?


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