674 replies to this topic

[Turnbuckle]

Turnbuckle, what is your take on centrophenoxine?

Would it be beneficial to add it to this protocol ?

 

While nootropics may be useful for some individuals, there's no research I've seen that this one directly impacts the causes of Alzheimer's.

[Andey]

Looks like removing tau aggregates could bring cognitive benefit regardless of AD disease status

Therefore, the aim of this study was to investigate the implications of tau ablation on the mitochondrial function and cognitive abilities of a litter of young mice (3 months old). Our results showed that tau deletion had positive effects on hippocampal cells by decreasing oxidative damage, favoring a mitochondrial pro-fusion state, and inhibiting mitochondrial permeability transition pore (mPTP) formation by reducing cyclophilin D (Cyp-D) protein. More importantly, tau deletion increased ATP production and improved the recognition memory and attentive capacity of juvenile mice. Therefore, the absence of tau enhanced brain function by improving mitochondrial health, which supplied more energy to the synapses. Thus, our work opens the possibility that preventing negative tau modifications could enhance brain function through the improvement of mitochondrial health.

https://www.scienced...304695?via=ihub

There is also an overlap with mito fusion. Kudos  for Turnbuckle, as his ideas became a central theory of aging at least in my mind)

 

[Moumou]

Turnbuckle, have you though of delivering some "stuff" Intranasaly? Main issues would be overdosing and intraoccular pressure, but the captation by brain tissues would be greater and less submitted to gastric/intestine degradations.

[Moumou]

The present findings may provide direction for several avenues of scientific query and empirical exploration. For example, the lack of differential olfactory deficits in AD and PD may be reflective of the presence of pathological features in olfactory brain regions during the earliest stages of the disease process, so that by the time a definitive diagnosis of either disorder is made, distinguishing olfactory deficits may be obscured. These results may also implicate a similar dysfunction in olfactory brain regions existent in both illnesses.

 

From Meta Analysis :https://jamanetwork....larticle/773547

 

 

+ Early stage of AD, start from Limbic structures next to Olfactory Nerve System

 

https://www.degruyte...-013-0108-3.pdf

 

+ Plus a nasal adjuvent Protollin that breaks some bad peptides.

 

https://www.ncbi.nlm...les/PMC2747093/

 

[resveratrol_guy]

What about eicosanoyl-5-hydroxytryptamide (EHT) for tau cleanup? I've discussed this stuff before. At the time, it was uneconomic, but it's a promising supplement that's worth revisiting, especially in the context of a multifaceted AD protocol.

[Mr Spock]

@Turnbuckle. Thank you for this info.

 

I have started this protocol for my 92 year old mother. She's quite averse to taking supps/ prescription drugs generally, so it's difficult to persuade her to take too many things.She has slowly declined in the last year and half to two years.

 

As you know, HEPPS isn't available here in the UK ; in light of this, should one change the amounts of the other supps? Also, Can one replace the ascorbic acid, with another type of Vit C,that isn't so bitter?

 

Thanks

 

 

[Turnbuckle]

@Turnbuckle. Thank you for this info.

 

I have started this protocol for my 92 year old mother. She's quite averse to taking supps/ prescription drugs generally, so it's difficult to persuade her to take too many things.She has slowly declined in the last year and half to two years.

 

As you know, HEPPS isn't available here in the UK ; in light of this, should one change the amounts of the other supps? Also, Can one replace the ascorbic acid, with another type of Vit C,that isn't so bitter?

 

Thanks

 

With HEPPS you may see improvement very quickly. Without it I doubt you will get much. And while HEPPS is available in the UK, you will need to find someone in a company or university or doctor's office through which you can order it--or at least take delivery. In the US some chem supply companies will let you order with a personal card but then will cancel your order if they see the delivery address is a residence. Another alternative--if you know someone in the US who can take delivery from Amazon and then send it on to you. One of the vendors in the US selling through Amazon is Research Products International, which as its name suggests, takes international orders. But again you will have to direct the shipment to a business address. I don't know how particular they are, but I expect any business might do. 

 

I've not tried reshipping, but this might work when buying from Amazon in the US--https://www.reship.com/#/

They say, Your purchased goods arrive at our warehouse where they get forwarded to your home, anywhere in the world!

 

A reminder: This is HEPPS and not HEPES. Both are biochemical buffers with similar names and similar chemistry, but with opposite results. Amazon offers both, so it's easy to make a mistake.

Edited by Turnbuckle, 19 August 2018 - 12:14 PM.

[Andey]

 

I've not tried reshipping, but this might work when buying from Amazon in the US--https://www.reship.com/#/

They say, Your purchased goods arrive at our warehouse where they get forwarded to your home, anywhere in the world!

 

  I use reshipping all the time and it's definitely a working concept.

Can't recommend any though as my reshipper works only for US-Ukraine destination.

[Mr Spock]

Thank you 

[Mind]

Thought this might be relevant here: https://www.longecit...-reduce-amyloid

[Daniel Cooper]

I'm about to start taking HEPPS (which I obtained from Amazon - Research Products International brand).  They shipped to me with no questions.

 

Before I start I'm just wondering if anyone has had any adverse reactions to HEPPS.  I have no reason to believe there are any, but seems reasonable to ask.

 

 

[resveratrol_guy]

I'm about to start taking HEPPS (which I obtained from Amazon - Research Products International brand).  They shipped to me with no questions.

 

Before I start I'm just wondering if anyone has had any adverse reactions to HEPPS.  I have no reason to believe there are any, but seems reasonable to ask.

 

Have plenty of Curcubrain and olive leaf extract on hand in case, as seems likely, you'll end up with a headache (caused by disaggregating abeta monomers?) within a matter of days. Asprin would probably help as well, although of course that carries other risks, such as internal bleeding. It might also be a good idea to inform a local friend of your intentions, for safety's sake.

 

Apart from the foregoing, and some mild nausea, I had no problem with HEPPS other than the temporary brain fog that I mentioned previously.

[Turnbuckle]

I'm about to start taking HEPPS (which I obtained from Amazon - Research Products International brand).  They shipped to me with no questions.

 

Before I start I'm just wondering if anyone has had any adverse reactions to HEPPS.  I have no reason to believe there are any, but seems reasonable to ask.

 

 

As it appears that loosely agglomerated plaques can release a lot of amyloid beta initially, you might start with the other things first, then add in the HEPPS at a low dose, increasing it over a few days until you get to one gram.

Edited by Turnbuckle, 24 August 2018 - 09:08 AM.

[Fafner55]

Senolytic treatment with dasatinib and quercetin is reported to reduce tau tangles. “Tau Tangles Cleared by Senolytic Drugs in Alzheimer’s Mice” (2018) https://www.genengne...s-mice/81256162 “Tau transgenic mice with late-stage pathology were treated with senolytics to remove senescent cells,” the article noted. “Despite the advanced age and disease progression, MRI brain imaging and histopathological analyses indicated a reduction in total NFT density, neuron loss, and ventricular enlargement.” "The mice were 20 months old and had advanced brain disease when we started the therapy," says study senior author Miranda E. Orr, Ph.D., a pharmacologist at UT Health San Antonio. "After clearing the senescent cells, we saw improvements in brain structure and function. “The treatment seems to have stopped the disease in its tracks." "The fact we were able to treat very old mice and see improvement gives us hope that this treatment might work in human patients even after they exhibit symptoms of a brain disease," adds Nicolas Musi, M.D., the study's first author “Tau protein aggregation is associated with cellular senescence in the brain” (2018) https://www.biorxiv....ll.pdf html Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer’s disease, progressive supranuclear palsy, chronic traumatic encephalopathy and over twenty others Findings: Neurons with NFTs from human Alzheimer’s disease brain develop an expression profile consistent with cellular senescence. This complex stress response induces a near permanent cell cycle arrest, adaptations to maintain survival, cellular remodeling, and metabolic dysfunction. Moreover, senescent cells induce chronic degeneration of surrounding tissue through the secretion of pro-inflammatory, pro-apoptotic molecules termed the senescence-associated secretory phenotype (SASP). Using transgenic mouse models of tau-associated pathogenesis we found that NFTs induced a senescence-like phenotype including DNA damage, karyomegaly, mitochondrial dysfunction and SASP. Cdkn2a transcript level, a hallmark measure of senescence, directly correlated with brain atrophy and NFT load. We found this relationship extended to postmortem brain tissue from humans with progressive supranuclear palsy to indicate a phenomenon common to tau toxicity. Treatment of tau transgenic mice with drugs to remove senescent cells had decreased NFT burden, preserved neuronal and glial brain cells and improved brain structure and function.

[Turnbuckle]

One paper suggests that quercetin alone reduces hyperphosphorylated tau via upregulating AMPK--

 

Quercetin, a natural flavonoid abundantly found in onions, apples, tea, berries, cauliflower, and red wine, has been demonstrated to exert beneficial effect on Alzheimer's disease. We aimed to investigate its AMPK activity on hyperphosphorylation of tau and explore the underlying mechanism associated with Endoplasmic reticulum (ER) stress. Quercetin and quercetin-3-O-glucuronide suppressed ER stress with decreased phosphorylation of IRE1α and PERK, thereby inhibited TXNIP and NLRP3 inflammasome activation, ultimately attenuated tau phosphorylation in okadaic acid (OA) induced SH-SY5Y cells. However, the effect on tau phosphorylation was blocked by downregulation of AMPKα1/2 with SiRNA transfection. Moreover, administration of quercetin enhanced AMPK activity, inhibited IRE1α and PERK phosphorylation, NLRP3 expression and tau phosphorylation and improved cognitive disorder in mice exposed to high fat diets. AMPK may be a key player that links ER stress and tau phosphorylation and mediates quercetin's effect on cognitive disorder. Thus, quercetin and its AMPK activity may provide a potential therapeutic strategy for treatment of AD patients.

https://www.scienced...756464616000396

 

 

 

A key point they make is that AMPK activation of quercetin attenuates tau protein phosphorylation. But another paper asserts that activated AMPK may be responsible for hyperphosphorylated tau to begin with--

In summary, we show for the first time that activated AMPK is abnormally and massively accumulated in pre-tangle- and tangle-containing neurons in AD and in all the major primary tauopathies examined. Most regions where neuronal tau pathology occurred showed p-AMPK accumulation in the different cases examined. Granular p-AMPK immunoreactivity was also observed in AD and several other tauopathies in apparently normal neurons devoid of hyperphosphorylated tau, suggesting that AMPK accumulation is an early event preceding tau pathology. Furthermore, we found that AMPK phosphorylated tau in vitro at residues relevant to PHF formation. Together, these data indicate that AMPK activation, by co-occurring with tau pathology and by mediating tau phosphorylation, might represent a key event in the control of the neurodegenerative process in tauopathies.

https://www.ncbi.nlm...les/PMC3060560/

 

 

 

 

 

Edited by Turnbuckle, 25 August 2018 - 06:46 PM.

[Puppalupacus]

I've started the protocol as specified on post #179, having now built up to everything but the HEPPS with no issues.  Tomorrow, I will be adding the HEPPS. and I'm ready for the ensuing dumb.  I have both genes, but this is more experimental in preparation for introducing it to my father.  I have experienced a mental decline the past five years, but that could easily be something else (I'm 45).

[Empiricus]

I ordered some HEPPS from China.  What are things to look for in terms of taste, smell, texture, solubility, etc. to know it's the real thing?  

Edited by Empiricus, 29 August 2018 - 10:23 AM.

[Turnbuckle]

I ordered some HEPPS from China.  What are things to look for in terms of taste, smell, texture, solubility, etc. to know it's the real thing?  

 

Likely all the HEPPS being sold in the US is coming from China and given a huge markup. The stuff sold through RPI/Amazon is a nearly white powder with a slight crystalline appearance, like snow that's a bit compacted. The powder has a slight chemical taste that doesn't linger and is nearly tasteless in water. Very soluble. There's also a vague smell just after opening the container. A bit like casein but not objectionable.

 

By contrast, HEPES (which you don't want), is also a white powder, but much finer--at least with the sample I have from Sigma. It has no taste and a smell that's similar to HEPPS, but stronger.

Edited by Turnbuckle, 29 August 2018 - 10:57 AM.

[Puppalupacus]

No dumbness to report with the addition of HEPPS; maybe I'm at the bottom already.  I do feel a little off and have had some gastro issues, but that could be completely unrelated.  Will report back if things change for the worse or the better, but for now, I will be taking everything as specified for the next few months.

[Empiricus]

Turnbuckle, the stuff I received looks just like snow, as per your description.  

 

Now, I have a bad allergy to something in olive leaf, but I seem to be able to tolerate olive oil.  I was, therefore, not planning on taking the olive leaf supplement, but replacing it with extra capsules of Dihydromyricetin (maybe 1 gram) and wondering if possibly I should add Tudca.  I would be able to tolerate fresh olive oil, but not sure if that would be pointless.

 

Does this make sense?  Dropping concentrated olive leaf phenols, are there any other changes to the protocol you would make? (i.e. lower dosing of HEPPS, or something else worth adding) In order to make up for possibly slower "clearance" of the debris.  

 

Edited by Empiricus, 03 September 2018 - 09:39 AM.

[Turnbuckle]

Turnbuckle, the stuff I received looks just like snow, as per your description.  

 

Now, I have a bad allergy to something in olive leaf, but I seem to be able to tolerate olive oil.  I was, therefore, not planning on taking the olive leaf supplement, but replacing it with extra capsules of Dihydromyricetin (maybe 1 gram) and wondering if possibly I should add Tudca.  I would be able to tolerate fresh olive oil, but not sure if that would be pointless.

 

Does this make sense?  Dropping concentrated olive leaf phenols, are there any other changes to the protocol you would make? (i.e. lower dosing of HEPPS, or something else worth adding) In order to make up for possibly slower "clearance" of the debris.  

 

 

Don't use what you can't tolerate, certainly. Taurine is known to protect neurons from Aβ, and this paper says, "phenobarbital and melatonin also protect neurons against Aβ-induced neurotoxicity." There are many others as well. As for taurine, it reaches a blood peak at 1.5 hours and then drops by half by 3 hours. So dosing it again after several hours might be helpful. Starting with a lower dose of HEPPS would also make sense.

[Andey]

Turnbuckle, the stuff I received looks just like snow, as per your description.  

 

Now, I have a bad allergy to something in olive leaf, but I seem to be able to tolerate olive oil.  I was, therefore, not planning on taking the olive leaf supplement, but replacing it with extra capsules of Dihydromyricetin (maybe 1 gram) and wondering if possibly I should add Tudca.  I would be able to tolerate fresh olive oil, but not sure if that would be pointless.

 

 

Highly ironic that you have the Van Gogh`s Olive Tree as your avatar )

[William Sterog]

Uncaria rhynchophylla, a Chinese medicinal herb, has potent antiaggregation effects on Alzheimer's beta-amyloid proteins.
Fujiwara H, et al. J Neurosci Res. 2006.

Our study demonstrates that several of these herbs have potent inhibitory effects on fibril formation of both Abeta(1-40) and Abeta(1-42) in concentration-dependent manners; in particular, Uncaria rhynchophylla inhibited Abeta aggregation most intensively.

I have been searching a good source of this herb for years.

[Turnbuckle]

Uncaria rhynchophylla, a Chinese medicinal herb, has potent antiaggregation effects on Alzheimer's beta-amyloid proteins.
Fujiwara H, et al. J Neurosci Res. 2006.

Our study demonstrates that several of these herbs have potent inhibitory effects on fibril formation of both Abeta(1-40) and Abeta(1-42) in concentration-dependent manners; in particular, Uncaria rhynchophylla inhibited Abeta aggregation most intensively.

I have been searching a good source of this herb for years.

 

 

This is cat's claw, right? Cat's claw herb has good ratings on Amazon and is cheap. One extract trademarked PTI-00703 is sold on Amazon as Percepta. It's rather more expensive.

[William Sterog]

This is cat's claw, right? Cat's claw herb has good ratings on Amazon and is cheap. One extract trademarked PTI-00703 is sold on Amazon as Percepta. It's rather more expensive.

Not exactly, Cat Claw is usually a term applied to Uncaria tomentosa, a plant who lacks the compounds that would be interesting for us to use.

https://www.longecit...t-you-can-take/

Edited by William Sterog, 05 September 2018 - 02:49 PM.

[Turnbuckle]

Not exactly, Cat Claw is usually a term applied to Uncaria tomentosa, a plant who lacks the compounds that would be interesting for us to use.

https://www.longecit...t-you-can-take/

 

 

There are papers on the effects of uncaria tomentosa re AD-- 

 

The alkaloid components of

Uncaria tomentosa have also been shown to improve

memory function in mice with experimental amnesia

(Mohamed et al., 2000). More specific to AD, a proprietary

extract of Uncaria tomentosa, PTI-00703, potently

inhibits b-amyloid fibril formation and even solubilizes

pre-formed amyloid fibrils (Snow, 1999). An extract

enriched in the fibril-inhibiting factors was also shown to

diminish the amyloid plaque burden in an animal model

of AD analogous to the Tg2576 strain (Snow, 2001).

https://www.tandfonl...138802090893531

 

 

[William Sterog]

There are papers on the effects of uncaria tomentosa re AD--

Very interesting, I thought that the responsible of the effects was GSE, which isn't present in Tomentosa.

[Empiricus]

Thanks for the links, Turnbuckle.  The number of substances found to protective is not small.  I took 2 doses of 0.25 grams of HEPPS spaced 10 hours apart, along various possibly protective factors. After 48 hours I don't see improvement, but I suppose I shouldn't expect any this soon.   

Edited by Empiricus, 06 September 2018 - 08:31 AM.

[Meggo]

We need something like a group buy for HEPPS. It is very difficult to obtain inside the EU.

[Turnbuckle]

We need something like a group buy for HEPPS. It is very difficult to obtain inside the EU.

 

Look at post 187, or you might ask Empiricus how he got some from China.