674 replies to this topic

[Turnbuckle]

Do you have any papers, official scientific research on HEPPS?

 

 

Really, ceridwen? You've been on this thread long enough that surely you've read the OP. The paper is there.

[ceridwen]

OP?

[Turnbuckle]

EPPS reduces Aβ-aggregate-induced memory deficits in mice

Previously, we reported a series of small ionic molecules that could accelerate the formation of Aβ aggregates in vitro. Unexpectedly, in addition to the compounds facilitating Aβ aggregation, we identified six small molecules that inhibited the formation of Aβ oligomers and fibrils13. In the current study, we tested whether these molecules could affect AD-like cognitive impairments of rodents. For this purpose, we induced memory deficits in 8.5-week-old Imprinting Control Region (ICR) mice (male, n=9–10 per group) by injecting Aβ42 aggregates (Fig. 1a,b) into the intracerebroventricular region14. This Aβ-infusion model allowed us to control the onset of abnormal Aβ deposition before or after the administration of our compounds. Among the six orally administered molecules, only 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS) ameliorated AD-like phenotypes in our mouse model.

https://www.nature.com/articles/ncomms9997

 

EPPS is another name for HEPPS

[resveratrol_guy]

Note that RPI's HEPPS at Amazon is 1/3 cheaper than ACTGene's. I've bough both and RPI's seems purer. At least, it's always pure white while the one bottle from ACTGene looked a bit yellowish. 

 

My ACTGene doesn't look at all yellowish. I bought it because, unlike the other brand, the Amazon page actually states the percentage of purity. Granted, it could be made up, but I don't know what else to go by, short of LC/MS.

 

It's good that you repeated the HEPES warning, as it's so dangerous and so easily mistaken.

 

This all really makes me wonder what other plaque disaggregators are buried in the literature, never to be pursued further because they're cheap and unpatentable. Lots of things thwart abeta and phosphotau, but it's a question of degree, and stuff like green tea just doesn't cut the mustard.

[Turnbuckle]

This all really makes me wonder what other plaque disaggregators are buried in the literature, never to be pursued further because they're cheap and unpatentable. Lots of things thwart abeta and phosphotau, but it's a question of degree, and stuff like green tea just doesn't cut the mustard.

 

 

It would be hard to beat the price tag and the safety of things like MB and HEPPS, which are really just cleaning agents for disolving crud that should never have gotten into the brain to begin with. If you go further upstream to where initial dysfunction lies--the disturbed cross-talk between the ER and mitochondria that results from the ApoE4 gene (the MAM hypothesis), then that might eventually provide a better fix. But for now this seems adequate.

 

In addition to the appearance of senile plaques and neurofibrillary tangles, Alzheimer's disease (AD) is characterized by aberrant lipid metabolism and early mitochondrial dysfunction. We recently showed that there was increased functionality of mitochondria‐associated endoplasmic reticulum (ER) membranes (MAM), a subdomain of the ER involved in lipid and cholesterol homeostasis, in presenilin‐deficient cells and in fibroblasts from familial and sporadic AD patients. Individuals carrying the ε4 allele of apolipoprotein E (ApoE4) are at increased risk for developing AD compared to those carrying ApoE3. While the reason for this increased risk is unknown, we hypothesized that it might be associated with elevated MAM function. Using an astrocyte‐conditioned media (ACM) model, we now show that ER–mitochondrial communication and MAM function—as measured by the synthesis of phospholipids and of cholesteryl esters, respectively—are increased significantly in cells treated with ApoE4‐containing ACM as compared to those treated with ApoE3‐containing ACM. Notably, this effect was seen with lipoprotein‐enriched preparations, but not with lipid‐free ApoE protein. These data are consistent with a role of upregulated MAM function in the pathogenesis of AD and may help explain, in part, the contribution of ApoE4 as a risk factor in the disease.

 

https://www.ncbi.nlm...les/PMC4718413/

 

[v_squared123]

Guys, what about marijuana? 

 

Cannabinoids remove plaque-forming Alzheimer's proteins from brain cells

https://www.scienced...60629095609.htm

 

Scientists have found preliminary evidence that tetrahydrocannabinol (THC) and other compounds found in marijuana can promote the cellular removal of amyloid beta, a toxic protein associated with Alzheimer's disease.

 

Medical Marijuana is very accessible in a lot of the US states. You just need a prescription from a marijuana clinic. I think over a dozen US states have allowed medical marijuana and over several have legal recreational use of it ie no prescription required. 

 

Its important to note that a low-dose thc strain would be best as indicated in the article. There are many high-cdb low thc strain available. In fact, low-dose thc strains would also mean the psycho-active component of marijuana would be very low so you wouldnt worry about getting high. Im talking about a 9-1 ratio of cdb to thc. 

 

I also understand that the purpose of this thread is a "quick-fix" approach.....smoking marijuana is by-far the fastest way to have the cannabinioids enter the body. Much faster than ingesting capsules or oils. 

[APBT]

 

Cannabinoids remove plaque-forming Alzheimer's proteins from brain cells

https://www.scienced...60629095609.htm

 

 

FULL TEXT:  https://www.nature.c...es/npjamd201612

[Turnbuckle]

 

I also understand that the purpose of this thread is a "quick-fix" approach.....smoking marijuana is by-far the fastest way to have the cannabinioids enter the body. Much faster than ingesting capsules or oils. 

 

 

The "quick fix" takes months, no matter the route of ingestion. A less problematical solution to intraneuronal Aβ (as opposed to Aβ plaques) is carnosine, as previously mentioned --

 

We found that carnosine supplementation in 3xTg-AD mice promotes a strong reduction in the hippocampal intraneuronal accumulation of Aβ and completely rescues AD and aging-related mitochondrial dysfunctions. No effects were found on tau pathology and we only observed a trend toward the amelioration of cognitive deficits.

https://www.ncbi.nlm...les/PMC3058055/

 

[resveratrol_guy]

The "quick fix" takes months, no matter the route of ingestion. A less problematical solution to intraneuronal Aβ (as opposed to Aβ plaques) is carnosine, as previously mentioned --

 

Thanks for that. I see that you mentioned L-carnosine (not to be confused with L-carnitine, which also has supposed cognitive benefits). Has anyone tried it, or is anyone aware of human experimentation for cognitive purposes?

[Turnbuckle]

You can find a dozen studies on Pubmed, mostly with rodent models of AD, and with positive results. Seems worthwhile trying it, perhaps alternating it with the other things.

[resveratrol_guy]

After a couple weeks on HEPPS, I'm going to stop here and see if the benefits endure, which they would have to if in fact they're due to disaggregation. I would say that they maxed out as of my previous report.

 

I like the idea of carnosine performing intraneuronal abeta cleanup, which in theory would be an elegant complement to the extraneuronal action of HEPPS.

 

You can find a dozen studies on Pubmed, mostly with rodent models of AD, and with positive results. Seems worthwhile trying it, perhaps alternating it with the other things.

 

You're not kidding. The carnosine listing goes on for 118 pages of citations! (Granted, you're talking about L-carnosine, but those citations don't seem to mention the particular enantiomer in question, which will require careful reading.) For the record, here are some of the more recent ones with neurological ramifications:

 

Carnosine-LVFFARK-NH2 Conjugate: A Moderate Chelator but Potent Inhibitor of Cu2+-Mediated Amyloid β-Protein Aggregation

 

Protective effect of carnosine on white matter damage in corpus striatum induced by chronic cerebral hypoperfusion

 

Anserine/Carnosine Supplementation Preserves Blood Flow in the Prefrontal Brain of Elderly People Carrying APOE e4
 

Potential of carnosine, a histamine precursor in rat model of bilateral common carotid artery occlusion-induced vascular dementia

 

Neuroprotective effect of the carnosine - α-lipoic acid nanomicellar complex in a model of early-stage Parkinson's disease

 

Glycotoxins: Dietary and Metabolic Origins; Possible Amelioration of Neurotoxicity by Carnosine, with Special Reference to Parkinson's Disease

 

A neuroprotective action of carnosine in conditions of experimental focal cerebral ischemia-reperfusion

 

Zinc, Carnosine, and Neurodegenerative Diseases

Edited by resveratrol_guy, 26 July 2018 - 07:00 AM.

[Turnbuckle]

After a couple weeks on HEPPS, I'm going to stop here and see if the benefits endure, which they would have to if in fact they're due to disaggregation. I would say that they maxed out as of my previous report.

 

I like the idea of carnosine performing intraneuronal abeta cleanup, which in theory would be an elegant complement to the extraneuronal action of HEPPS.

 

 

 

I think you'll find you've only cleared out the tip of the plaque iceberg. Buildup has gone on for decades while you've probably only noticed symptoms recently, so eliminating symptoms only requires a minor portion of the buildup to be removed. As for carnoisne cleaning up intraneuronal Aβ, there may be tau involvement as with extracellular plaque. In which case adding something like MB might be required to really get at it. And better yet, adding carnosine to the protocol (with MB) rather than using it separately as I suggested above.

 

 

hyperphosphorylated tau can be observed within some

of the dystrophic neurites around plaques in APP mutant

transgenic mice and in the brains of humans with AD.

Dual immunofluorescence and dual immuno-EM revealed

that dystrophic neurites around plaques showed the colocalization of hyperphosphorylated tau with Ab42.

 

https://www.ncbi.nlm...pubmed/28261941

 

 

 

 

Edited by Turnbuckle, 26 July 2018 - 11:16 AM.

[v_squared123]

Old FDA-approved drug, Zileuton, reduces tau in tau-driven mouse models. 

 

https://www.scienced...80608101905.htm

Edited by v_squared123, 26 July 2018 - 12:49 PM.

[Turnbuckle]

Old FDA-approved drug, Zileuton, reduces tau in tau-driven mouse models. 

 

https://www.scienced...80608101905.htm

 

The full paper -- https://www.ncbi.nlm...les/PMC5946065/

 

This sounds convenient as a pill is far preferable than a liquid dye that can make nearly permanent stains. The price, however, is around $2,000 for 60 tablets. Whereas a bottle of MB sufficient for years costs about $4.

[resveratrol_guy]

I think you'll find you've only cleared out the tip of the plaque iceberg.

 

The study has 3 different periods of administration: 5 days, 14 days, and 3.5 months. It's the longest period that resulted in the cognitive rescue, although it stands to reason that the abeta oligomer concentration decreased via exponential decay (or perhaps a bit slower if we assume that plaques are spheres that can only dissolve at the surface), so most of the benefit would have occurred early on. Anyway your comment still makes sense, so perhaps I'll resume after a short break.

 

I did definitely notice more brain fog in the 3 days since ceasing HEPPS, but this mitigated after taking another 300 mg of oleuropein. Granted, around the same time, I also had grapefruit juice and mushrooms, both of which give me a noticeable cognitive boost (even though the former reduces my tinnitus and the latter increases it!). At least it shouldn't be too hard to determine what did what, given a bit more experimentation.

 

Assuming your approach is valid, then the early brain fog would be due to the huge and sudden production of abeta monomers (because we have maximum oligomer supply on day one, with perhaps insufficient oleuropein for binding). Then the late brain fog would be due to continuing monomerization due to the long halflife of HEPPS in the brain, while oleuropein supplementation has been be stopped. So my advice would be that anyone trying this should take oleuropein starting a few days before, and ending a few days after, the HEPPS period.

 

I hypothesize that abeta oligomers basically disable memory retrieval in the plaque region itself, but nowhere else; whereas abeta monomers migrate more easily, so they cause generalized brain fog, but not such dramatic and specific memory inhibition. This would at least be consistent with my own experience of suddenly remembering old names, at the cost of a temporary increase in overall brain fog.

 

Zileuton is really interesting, although I have yet to see any anecdotes of experimentation for brain health purposes. MB has a checkered history; certainly compared to something like C60 or NR, the reports are all over the map. I wouldn't want to just write it off, but I feel I don't understand the reason for the mixed results.

Edited by resveratrol_guy, 28 July 2018 - 07:51 AM.

[Turnbuckle]

 So my advice would be that anyone trying this should take oleuropein starting a few days before, and ending a few days after, the HEPPS period.

 

 

 

Good point. Or else one could start off with a lower dose of HEPPS. The last build up of Aβ many not be well consolidated, and thus may more easily removed, flooding the brain with a toxic substance.

 

As for oleuropein, there are conflicting studies as to whether it actually passes the BBB. It also may not be the best olive oil polyphenol in that regard, but many others that do can generally be found in cheap olive leaf extracts. Like oleocanthal, which produces the burning at the back of the throat in good olive oils. Other polyphenols with good activity are myricetin (and possibly dihydromyricetin, sold for hangovers) and quercetin, all of which are available in caps.

 

Mice treatment for 4 weeks with oleocanthal significantly decreased amyloid load in the hippocampal parenchyma and microvessels. This reduction was associated with enhanced cerebral clearance of Aβ across the blood-brain barrier (BBB). Further mechanistic studies demonstrated oleocanthal to increase the expression of important amyloid clearance proteins at the BBB including P-glycoprotein and LRP1, and to activate the ApoE-dependent amyloid clearance pathway in the mice brains. 

https://www.ncbi.nlm...les/PMC4653763/

 

 

Myricetin at 5 or 10 mg/kg was intraperitoneally injected into rats over 21 days. Control rats were treated with 10 mL/kg saline. Behavioral test (the shuttle box test) was performed on day 22 to examine learning and memory in rats. Immediately after that, hematoxylin-eosin staining was performed to observe the morphological change in hippocampal CA3 pyramidal neurons. Myricetin greatly increased the number of hippocampal CA3 pyramidal neurons and improved learning and memory impairments in rats with Alzheimer's disease. 

https://www.ncbi.nlm...les/PMC5270437/

 

 

Our data show that quercetin decreases extracellular β-amyloidosis, tauopathy, astrogliosis and microgliosis in the hippocampus and the amygdala.

https://www.ncbi.nlm...les/PMC4387064/

 

Edited by Turnbuckle, 28 July 2018 - 10:25 AM.

[v_squared123]

Nicotinomide Riboside, a form of vitamin b3, reduces tau in tau-driven mouse models of AD. 

 

https://neuroscience...lzheimers-8448/

 

No reduction in Ab plaque. However, it is important to note these mice were designed to develop excess tau pathology. Perhaps it explains why no reduction in Abeta occured.

[v_squared123]

Dozens of brands of nicotinomide riboside on amazon. Ranging in price from $30 - $60 dollars per bottle. Perhaps brand name plays a role there. Nonetheless, it is easily accessible as opposed to Zileuton.

Edited by v_squared123, 28 July 2018 - 12:46 PM.

[Turnbuckle]

Nicotinomide Riboside, a form of vitamin b3, reduces tau in tau-driven mouse models of AD. 

 

https://neuroscience...lzheimers-8448/

 

No reduction in Ab plaque. However, it is important to note these mice were designed to develop excess tau pathology. Perhaps it explains why no reduction in Abeta occured.

 

NR is mostly broken down in the intestines into nicotinamide (NAM), and NAM is included in this protocol.

[v_squared123]

University of Iowa study shows nicotinomide riboside supplementation boosts levels of NAD+ safely in human subject

 

https://www.scienced...61010135418.htm

NR is mostly broken down in the intestines into nicotinamide (NAM), and NAM is included in this protocol.

Is there a nootropic effect behind taking nicotinamide riboside? ie stimulating or energizing? It appears to be marketed as such by some brands

[v_squared123]

Sulforaphane via upregulation of Heat Shocking Proteins clears away Abeta and tau pathology in mice.

 

https://www.ncbi.nlm...pubmed/29714053

 

Not sure the dose, but there are studies done in Autistic Spectrum Disorder individuals who have benefited from the use of sulforaphane supplementation ie reduction in ASD symptoms. It is believed this occured due to upregulation of the heat-shock protein which could also be associated with the phenomenom of asd symptoms abatting after children with ASD develop a fever as fevers upregulate heat-shock proteins. That study in particular was completed by Johns Hopkins University. Doses ranged from 50-150 nmols depends on weight. Supplementation wise, could be around 3-4 capsules for an adult given each capsule will produce 7-8 mg of sulforaphane assuming avg male adult is between 150-200 lbs. 

Edited by v_squared123, 28 July 2018 - 01:08 PM.

[v_squared123]

Just a FYI about heat shock proteins. They are molecular chaperones that play a critical role in preventing protein aggregation, damaged proteins, and the suppression of neuronal cell death. They have also shown to be protective against neurodegenerative diseases.

[v_squared123]

Sulforaphane, which is high in broccoli sprouts, clears away brain amyloid plaques and tau tangles and ameliorated memory defects in mice engineered to get Alzheimer’s disease.

The sulforaphane also increased heat shock proteins in the brain. Heat shock proteins play a role in disaggregating protein aggregates.

The precursor to sulforaphane is found in cruciferous vegetables but is highest in broccoli sprouts which can contain up to 100 times more than mature broccoli.

Edited by v_squared123, 29 July 2018 - 04:21 PM.

[resveratrol_guy]

Supplementation wise, could be around 3-4 capsules for an adult given each capsule will produce 7-8 mg of sulforaphane assuming avg male adult is between 150-200 lbs. 

 

Interesting. How did you arrive at that dose, based on the mouse study? Also what brand(s) provide 7-8 mg per capsule? I've seen only 2 mg.
 

[resveratrol_guy]

As for oleuropein, there are conflicting studies as to whether it actually passes the BBB. It also may not be the best olive oil polyphenol in that regard, but many others that do can generally be found in cheap olive leaf extracts. Like oleocanthal, which produces the burning at the back of the throat in good olive oils. Other polyphenols with good activity are myricetin (and possibly dihydromyricetin, sold for hangovers) and quercetin, all of which are available in caps.

 

Well in light of all that, it might make sense to make olive leaf extract a permanent supplement. It's not particularly expensive. Personally, I've never noticed anything from quercetin, but I never took it with HEPPS. I'm also not sure about myricetin, as the mice were intraperitonially injected, but it's worth some investigation.

[Turnbuckle]

More on dihydromyricetin--

 

Dihydromyricetin ameliorates behavioral deficits and reverses neuropathology of transgenic mouse models of Alzheimer's disease.

Dihydromyricetin (DHM) is a plant flavonoid and a positive allosteric modulator of GABAARs we developed recently (Shen et al. in J Neurosci 32(1):390-401, 2012 [1]). In this study, transgenic (TG2576) and Swedish transgenic (TG-SwDI) mice with AD-like pathology were treated with DHM (2 mg/kg) for 3 months. Behaviorally, DHM-treated mice show improved cognition, reduced anxiety level and seizure susceptibility. 

 

 

 

This was given orally at 2 gm/kg. And another paper--

Dihydromyricetin inhibits microglial activation and neuroinflammation by suppressing NLRP3 inflammasome activation in APP/PS1 transgenic mice

Taken together, our findings suggest that DHM prevents progression of AD-like pathology through inhibition of NLRP3 inflammasome-based microglia-mediated neuroinflammation and may be a promising therapeutic drug for treating AD.

 

 

 

In this case they were dosed by intraperitoneal injection, but that seems unnecessary in light of the previous paper.

[v_squared123]

Guys, what about marijuana? 

 

Cannabinoids remove plaque-forming Alzheimer's proteins from brain cells

https://www.scienced...60629095609.htm

 

Scientists have found preliminary evidence that tetrahydrocannabinol (THC) and other compounds found in marijuana can promote the cellular removal of amyloid beta, a toxic protein associated with Alzheimer's disease.

 

Medical Marijuana is very accessible in a lot of the US states. You just need a prescription from a marijuana clinic. I think over a dozen US states have allowed medical marijuana and over several have legal recreational use of it ie no prescription required. 

 

Its important to note that a low-dose thc strain would be best as indicated in the article. There are many high-cdb low thc strain available. In fact, low-dose thc strains would also mean the psycho-active component of marijuana would be very low so you wouldnt worry about getting high. Im talking about a 9-1 ratio of cdb to thc. 

 

I also understand that the purpose of this thread is a "quick-fix" approach.....smoking marijuana is by-far the fastest way to have the cannabinioids enter the body. Much faster than ingesting capsules or oils. 

 

 

The "quick fix" takes months, no matter the route of ingestion. A less problematical solution to intraneuronal Aβ (as opposed to Aβ plaques) is carnosine, as previously mentioned --

 

I dont know if this provides any evidence but take a look. Start at the 28:25 mark. It appears to have helped this individual. 

 

https://www.youtube....h?v=SVweDD2GTFE

 

FYI, its part 3 of CNNs Dr. Sanjay Guptas "Weed" documentary. 

 

I have watched the entire series and this is the only segment of the entire 4 part series that covers AD. 

Edited by v_squared123, 01 August 2018 - 07:24 AM.

[resveratrol_guy]

I think an update is in order, as I resumed HEPPS 6 days ago. As I said, I'm also on sirolimus and I've taken to consuming rather large amounts of grapefruit juice lately, although I've ceased consuming mushrooms since restarting, in order to better isolate the effects. Now, in addition to my previous anecdote, I've just this week recalled 2 other unique, unrelated, and meaningless names that were each lost for at least several months. I could elaborate, but  my point is just to suggest that this regimen is worth more rigorous analysis. Granted, maybe I'm just at the point in my sirolimus dosing where memory improvements suddenly start to occur, but the survey results on Longecity suggest to me that its those improvements are minimal, unless perhaps one has type 3 diabetes, which almost certainly doesn't apply in my case.

The timing is suspicious: I started HEPPS, got brain fog, then memory improved, then I quit and got brain fog again. Then I started it again, got brain fog yet again, and improved again. As I said, I think the brain fog is really just indicative of disaggregation in the absence of sufficient oleuropein (or oleocanthal, as the case may be) to bind up the monomers.

In addition to the aforementioned anomalous recall, I subjectively notice that I recall events in my day better. In particular, I've also been doing some video interviews for a project I'm working on. As part of the project, I need to replay them after uploading to ensure that they've been properly edited. I find, hours after the actual interview, that I can paraphrase what was said in the next sentence, which is then confirmed seconds later by YouTube. I've always been able to do this with my own words, more or less, because after all it's easier to remember one's own speech, but when it comes to others' speech, after but a single exposure, this strikes me as unprecedented in the last few years, if not longer.

It can get annoying, though. I feel like I'm overwhelmed by trivial recollections all day long, like how I adjusted the air conditioning while waiting at a stoplight. It's as though my brain has gotten used to working really hard to fill in the gaps with plausible experiences, but suddenly it needs to delete lots of trivial information in order to reinforce the important stuff.
 

[Turnbuckle]

Thanks for the update, resveratrol_guy. I might as well update the protocol as well, as the following appears to work without MB--

 

 

Updated Alzheimer's protocol — experimental

(a link to the latest update can always be found on my profile page by clicking on my avatar)

 

The following in powder form can be used in fruit juice--

 

HEPPS --  1 g (1/4 teaspoon)

Taurine -- 3 g (1 teaspoon)

Carnosine -- 3 g (1/2 teaspoon)

Vitamin C -- 2 g (1/4 teaspoon)

 

 

The following are best in capsules--

 

Olive Leaf extract 20% oleuropein (one 500 mg cap)

Olive Leaf extract 25% hydroxtyrosol (one 100 mg cap)

Dihydromyricetin (one 350 mg cap)

Nicotinamide (one 250 mg cap)

Magnesium theonate (one 667 mg cap, also available in flavored and unflavored powder) 

 

 

Optional, for chelation of metals--

 

Meriva curcumin (one 500 mg cap)

 

 

Notes--

 

Taken together every day or every other day for three months or as needed. Then once a week.

One might start with a lower level of HEPPS and ramp it up to 1g to avoid the initial rapid clearance of Aβ.

 

 

References for additions--

 

MgT [(magnesium-L-threonate] treatment reduced Aβ-plaque, prevented synapse loss and memory decline in the transgenic mice. Strikingly, MgT treatment was effective even when the treatment was given to the mice at the end-stage of their Alzheimer’s disease-like pathological progression. 

https://www.ncbi.nlm...les/PMC4172865/

 

 

 

Edited by Turnbuckle, 05 August 2018 - 09:59 AM.

[aribadabar]

Turnbuckle, what is your take on centrophenoxine?

Would it be beneficial to add it to this protocol ?