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The Latest Alzheimer's Research


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#361 mag1

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Posted 21 March 2015 - 01:28 AM

I am not sure why everyone keeps talking of the Biogen phase 1 trial as a phase 1 trial: it was really a phase 2 trial that was called a phase 1.

It was randomized, had quite a few patients with a few different dosing arms, and it is still recruiting! I think that they should just keep on recruiting that trial.

They could turn it into a mini-phase 3 lead-in trial. I am sure there are now a whole bunch of people who want to sign up for it. Why not? Biogen does not intend to

start up the phase 3s for months. Patients would have no other way to access this promising drug candidate. And, of course, Biogen is now sitting on $50 billion of market capitalization

related to their AD drug.

 

Yet, I am not sure whether their product is really marketable. It requires an hour IV infusion once per month. How would they ever be able to IV dose millions of AD patients

and others who might want it? There are other powerful anti-amyloids in the pipeline that are orally dosed and are already in phase 3 trials.

 

Sure, calling the Biogen product a cure is being provocative, though one must consider that there has been a 100% failure rate in AD drugs up to this point. Before today it was not clear

whether a cure would emerge even within the next 20 years. It is now much more certain that such a time is approaching. For those who have family members that have been afflicted with

Alzheimer's, looking to the future was scary. Waiting for a neurodegenerative illness to begin unraveling one's neuro-anatomy takes much of the fun out of life.

 

With Biogen's antibody on the way, one could imagine taking low-dose treatments years before the point where the patients are being treated in the current trial. This would likely be safer and more effective.

 

This really is Biogen's day.

 

It is entirely fair to mention TauRx. Their product is neck and neck with Biogen's, maybe a little ahead (Taurx is dosing patients with moderate AD versus early stage with Biogen).

Combining a tau and an amyloid drug would make considerable sense. Hopefully, they will contact each other about doing such a trial sooner rather than later.  

 



#362 tunt01

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Posted 21 March 2015 - 01:39 AM

Typical market overreaction.



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#363 mag1

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Posted 21 March 2015 - 01:48 AM

I am not sure. The stock is only up 50% during the last year that does not seem unreasonable.

 

If they had not blown past the expectations today, there stock might have even been down.



#364 resveratrol_guy

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Posted 21 March 2015 - 01:49 PM

 

I have been wondering if actin sequestration is fundamentally more important to cellular metabolism than previously thought. With more actin the cells motility is vastly improved. If aggregated malformed proteins clog the cell as theorized actin allows the cell to build more room to accomodate. TB4 also increases phagocytosis, removing the malformed proteins.http://www.ncbi.nlm....pubmed/19631707

Combine this with increasing HSF1 with saunas over 19 minutes and you have a very potent cocktail for removing improperly folded proteins without the dangerous immune upregulation that comes with an amyloid vaccine.

 

"The peptide is also involved in lesion-induced neuroplasticity through microglia upregulation and it participates in the growth of neuronal processes." -- Wow! Sounds like a poor man's GMCSF. It might even be just as good, but only GMCSF has any sort of human trials for dementia, except for this snippet about TB4 causing improvements in diabetic neuropathy, which is only tangentially related to Alzheimer's.

 

But look, if you're right about TB4, then that would be hugely significant, because it appears to be much more accessible than GMCSF. However, the bar is very high: GMCSF causes microglia to attack protein aggregates, then increases synaptic density after the fact. My guess is that even if TB4 does the same thing, we won't know for many years, if ever, because (I assume) it's not patentable.

 

So I think you have a very compelling case here. But based on the dearth of studies, does this mean we need a TB4 group buy so we can test it ourselves? Even in that case, we would need several months for the putative cognitive effects to manifest.



#365 Nemo888

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Posted 21 March 2015 - 02:47 PM


I have been wondering if actin sequestration is fundamentally more important to cellular metabolism than previously thought. With more actin the cells motility is vastly improved. If aggregated malformed proteins clog the cell as theorized actin allows the cell to build more room to accomodate. TB4 also increases phagocytosis, removing the malformed proteins.http://www.ncbi.nlm....pubmed/19631707

Combine this with increasing HSF1 with saunas over 19 minutes and you have a very potent cocktail for removing improperly folded proteins without the dangerous immune upregulation that comes with an amyloid vaccine.

"The peptide is also involved in lesion-induced neuroplasticity through microglia upregulation and it participates in the growth of neuronal processes." -- Wow! Sounds like a poor man's GMCSF. It might even be just as good, but only GMCSF has any sort of human trials for dementia, except for this snippet about TB4 causing improvements in diabetic neuropathy, which is only tangentially related to Alzheimer's.

But look, if you're right about TB4, then that would be hugely significant, because it appears to be much more accessible than GMCSF. However, the bar is very high: GMCSF causes microglia to attack protein aggregates, then increases synaptic density after the fact. My guess is that even if TB4 does the same thing, we won't know for many years, if ever, because (I assume) it's not patentable.

So I think you have a very compelling case here. But based on the dearth of studies, does this mean we need a TB4 group buy so we can test it ourselves? Even in that case, we would need several months for the putative cognitive effects to manifest.


I took it for a host of TBI related problems and had very unexpected results. The first was an improved sense of smell. Followed by being able to dream again. http://www.alzheimer...and-alzheimers/ Though during the dosing period I slept and ate significantly more I noticed no cognitive improvements, in the following month as the neurons matured my ability to study dense subjects was like that of my teens. Cognitive boost lasted almost three months. Also helped with my peripheral neuropathy. Athletes are taking it for some reason, probably to promote healing, so it is widely available. Ususally get it from Genco peptide but any reliable US supplier should be fine. Being difficult to patent is a bit of a problem, Korean Gov just invested 7.2 million for phase 3 US trials for corneal dryness. Probably take sustained government investment to get this hormone to market.

If you have some spare cash and don't mind injections I would give it a try. 5mg to get circulating levels up and then 1mg/day for thirty days followed by at least a month the of physio type rehabilitation to train the new tissue. IIRC the safety levels tested in humans were in mg/kg so at that dose it should be safe.

Edited by Nemo888, 21 March 2015 - 02:50 PM.


#366 mag1

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Posted 21 March 2015 - 06:48 PM

Was the safety issue overlooked with the Biogen product? Were patients dosed up until efficacy was found even with the known problems of ARIA?

 

"In ApoE4 carriers, the incidence of ARIA-E was 5 percent in the 1 mg/kg and 3 mg/kg arms, 43 percent in the 6 mg/kg arm and 55 percent in the 10 mg/kg arm. In ApoE4 non-carriers, the incidence of ARIA-E was 9 percent, 11 percent and 17 percent in the 3 mg/kg, 6 mg/kg and 10 mg/kg aducanumab arms, respectively; no cases were reported in the 1 mg/kg arm."

 

Those who developed ARIA were then moved into a lower dose arm. Might this have skewed the results?

 

In the original trial with AN1792 they encountered ARIA in 6% of the patients and there was much concern. Will these high rates of ARIA now be overlooked? 



#367 Logic

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Posted 22 March 2015 - 08:58 PM

Wait-a-minute!?

I show a paper saying that a stack of 30 easily obtainable supps improves rats' learning/memory to better than that of young rats', and hardly anyone is interested!?

There's even a nice graph.  Perhaps graphs take too much brainpower to interpret!?   :)

http://www.longecity...ndpost&p=719909

 

is this because humanity is fixated on 'one supp to rule them all, One supp for finding, One supp to save us all and from the darkness hide us!'??

 

The physiciatrist in me is really interested to know!?

In one breath everyone gets told there are numerous reasons for aging and no one substance will do it for you.  In the next: "30 supps!  F-off!  I'm not even going to consider it!"

Are we all guilty of being blinded by our need for a simple solution?   :)


Edited by Logic, 22 March 2015 - 09:01 PM.

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#368 Nemo888

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Posted 24 March 2015 - 02:16 PM

Wait-a-minute!?

I show a paper saying that a stack of 30 easily obtainable supps improves rats' learning/memory to better than that of young rats', and hardly anyone is interested!?

There's even a nice graph.  Perhaps graphs take too much brainpower to interpret!?   :)

http://www.longecity...ndpost&p=719909

 

is this because humanity is fixated on 'one supp to rule them all, One supp for finding, One supp to save us all and from the darkness hide us!'??

 

The physiciatrist in me is really interested to know!?

In one breath everyone gets told there are numerous reasons for aging and no one substance will do it for you.  In the next: "30 supps!  F-off!  I'm not even going to consider it!"

Are we all guilty of being blinded by our need for a simple solution?   :)

There are a number of reasons. First it is mice. The control diet was total garbage. The study was very short. Supplements only work well if you have deficiencies. I think most of us take the majority of things on that list already. Though I do love the Life Extension Foundation they are horrible exaggerators. I say that even though I buy their products and have supported them for over 20 years. They really do pull conclusions out of their ass sometimes.


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#369 aribadabar

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Posted 30 March 2015 - 04:22 PM

Wait-a-minute!?

I show a paper saying that a stack of 30 easily obtainable supps improves rats' learning/memory to better than that of young rats', and hardly anyone is interested!?

There's even a nice graph.  Perhaps graphs take too much brainpower to interpret!?   :)

http://www.longecity...ndpost&p=719909

 

 

No, you are just late to the party- it has already been discussed here.



#370 Kalliste

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Posted 31 March 2015 - 03:37 PM

An international team of more than 18 research groups has demonstrated that the compounds they developed can safely prevent harmful protein aggregation in preliminary tests using animals. The findings raise hope that a new class of drugs may be on the horizon for the more than 30 diseases and conditions that involve protein aggregation, including diabetes, cancer, spinal cord injury, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). Proteins are necessary for almost every cellular process. However, when cell machinery doesn't clear out old proteins, they can clump, or aggregate, into toxic plaques that lead to disease.

The researchers call the compounds that they developed molecular tweezers because of the way they wrap around the lysine amino acid chains that make up most proteins. The compounds are unique in their ability to attack only aggregated proteins, leaving healthy proteins alone. To develop a new drug, researchers typically screen large libraries of compounds to find ones that affect a protein involved in a disease. This team used a fundamentally different approach to develop the molecular tweezers. "We looked at the molecular and atomic interactions of proteins to understand what leads to their abnormal clumping. Then, we developed a tailored solution. So unlike many other drugs, we understand how and why our drug works."

The team is in the process of testing multiple versions of the tweezers, each with a slightly different molecular makeup. For CLR01, one of the most promising versions, the researchers have demonstrated therapeutic benefits in two rodent models of Alzheimer's disease, two fish and one mouse model of Parkinson's disease, a fish model of spinal cord injury and a mouse model of familial amyloidotic polyneuropathy, a rare disease in which protein aggregation affects the nervous system, heart and kidneys. "Our data suggest that CLR01, or a derivative thereof, may become a drug for a number of diseases that involve protein aggregation. We also found a high safety window for CLR01." In one of the safety tests, mice receiving a daily CLR01 dose 250 times higher than the therapeutic dose for one month showed no behavioral or physiological signs of distress or damage. In fact, blood cholesterol in the mice dropped by 40 percent, a possible positive side effect of CLR01.

 

 

This is SENS-level stuff.


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#371 mag1

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Posted 01 April 2015 - 02:29 AM

The good news is finally starting to flow in AD. It has been a long time coming.

 

It must be clear to the research community that the finish line is now in sight. All the research that has been stored away

for future reference now needs to get out there. 

 

Biogen, TauRx, molecular tweezers-- things are starting to move forward.


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#372 tunt01

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Posted 01 April 2015 - 03:55 AM

CLR 01 sounds amazing. That needs to be looked at for a group buy.
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#373 ceridwen

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Posted 01 April 2015 - 04:16 AM

I would certainly like to get some. However with many of the group buys I've tried to join although I've paid the compound hasn't arrived


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#374 mag1

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Posted 01 April 2015 - 04:29 AM

I am very surprised by this idea of a group buy for CLR01.

 

Where could it possibly be bought?



#375 ta5

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Posted 11 April 2015 - 04:20 PM

Maybe melatonin would help:


Yes, maybe. The full text is available:

Int J Mol Sci. 2013 Jul 12;14(7):14575-93. 
Melatonin in Alzheimer's disease.
Lin L, Huang QX, Yang SS, Chu J, Wang JZ, Tian Q.
Department of Pathology and Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.

 

Another new study:

 

J Pineal Res. 2015 Apr 7. 
Ali T1, Kim MO.
College of Natural Sciences, Gyeongsang National University, Jinju, Republic of Korea.
Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disease, pathologically characterized by the accumulation of amyloid beta (Aβ) aggregation in the brain; and is considered to be the primary cause of cognitive dysfunction. Aβ aggregates lead to synaptic disorder, tau hyperphosphorylation and neurodegeneration. In this study, the underlying neuroprotective mechanism of melatonin against Aβ1-42 -induced neurotoxicity was investigated in the mice hippocampus. Intracerebroventricular (i.c.v.) Aβ1-42 -injection triggered memory impairment, synaptic disorder, hyperphosphorylation of tau protein and neurodegeneration in the mice hippocampus. After 24 hour of Aβ1-42 -injection the mice were treated with melatonin (10 mg/kg, intraperitonially) for 3 weeks, reversed the Aβ1-42 -induced synaptic disorder via increasing the level of pre-syanptic (Synaptophysin and SNAP-25) and postsynaptic protein (PSD95, p-GluR1 (Ser845), SNAP23 and p-CREB (Ser133)) respectively; and attenuated the Aβ1-42 -induced memory impairment. Chronic melatonin treatment attenuated the hyperphosphorylation of tau protein via PI3K/Akt/GSK3β signaling by activating the p-PI3K, p-Akt (Ser 473) and p-GSK3β (Ser9) in the Aβ1-42 -treated mice. Furthermore, melatonin decreased Aβ1-42 -induced apoptosis through decreasing the overexpression of caspase-9, caspase-3 and PARP-1 level. Additionally, evaluation of immunohistochemical analysis of caspase-3, Fluorojade-B and Nissl staining indicated that melatonin prevented neurodegeneration in Aβ1-42 -treated mice. Our results demonstrated that melatonin has neuroprotective effect against Aβ1-42 -induced neurotoxicity through decreasing memory impairment, synaptic disorder, tau hyperphosphorylation and neurodegeneration via PI3K/Akt/GSK3β signaling in the Aβ1-42 -treated mouse model of AD. On the basis of these results, we suggest that melatonin could be an effective, promising and safe neuroprotective candidate for the treatment of progressive neurodegenerative disorders, such as AD.
PMID: 25858697

Edited by ta5, 11 April 2015 - 04:22 PM.


#376 Logic

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Posted 12 April 2015 - 01:19 AM

p-Aminobenzoic acid derivatives as acetylcholinesterase inhibitors.

Abstract
Because Alzheimer's disease (AD) is a medical problem characterized by progressive loss of memory and cognition that is associated with a deficient cholinergic system, this work aims to evaluate some p-aminobenzoic acid (PABA) derivatives as acetylcholinesterase inhibitors in vitro, in continuation with our last studies. The assayed compounds are low toxic, simple-structured and low cost.

http://www.ncbi.nlm....pubmed/15935907

 

Thx to Lufega:

http://www.longecity...ndpost&p=493680

(The whole thread is worth a read when you consider the effect chronic low level infections have on longevity)

 

The effect of para-amino benzoic acid (PABA) on the virus of Herpes simplex (VHS-1, strain L2) was studied and it was shown to be active in vitro and in vivo. The action of PABA was virucidal in the culture of the cell-free virus-containing material. It lowered the death rate of the laboratory mice with experimental herpetic encephalitis (intraperitoneal contamination) at the average by 40 per cent and increased the mean life-span of the animals significantly decreasing the virus titre in the mouse brain. PABA was not toxic with respect to the Vero cells thus not preventing the virus-induced cytopathic effect in the cultures. However, PABA showed high ability to potentiate the antiherpetic action of acyclovir (Zovirax, acycloguanosine) in the infected cultures when acyclovir was used in inactive concentrations.

PMID: 8660116

 

I dont know about the derivatives, but from personal experience I can say that plain old PABA  F...s up fever blisters better than anything else I have tried, probably due to "...PABAs ability to induce interferon. Interferons are able to interfere with viral replication inside the host cell. That's very cool."  - Lufega

 

As HSV and similar virii are associated with Alzheimer's and cognitive decline, and as PABA is easily available; I thought it worth mentioning here.  I'm all for practical, easily available therapies!

 

http://www.longecity...-the-brain-and/

 

It may even return your grey hair to its original colour!   :)


Edited by Logic, 12 April 2015 - 01:26 AM.

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#377 ta5

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Posted 12 April 2015 - 11:19 PM

Curcumin again and a connection to HSV:

 

 
Virology. 2008 Apr 10;373(2):239-47. 
Kutluay SB1, Doroghazi J, Roemer ME, Triezenberg SJ.
Curcumin, a phenolic compound from the curry spice turmeric, exhibits a wide range of activities in eukaryotic cells, including antiviral effects that are at present incompletely characterized. Curcumin is known to inhibit the histone acetyltransferase activity of the transcriptional coactivator proteins p300 and CBP, which are recruited to the immediate early (IE) gene promoters of herpes simplex virus type 1 (HSV-1) by the viral transactivator protein VP16. We tested the hypothesis that curcumin, by inhibiting these coactivators, would block viral infection and gene expression. In cell culture assays, curcumin significantly decreased HSV-1 infectivity and IE gene expression. Entry of viral DNA to the host cell nucleus and binding of VP16 to IE gene promoters was not affected by curcumin, but recruitment of RNA polymerase II to those promoters was significantly diminished. However, these effects were observed using lower curcumin concentrations than those required to substantially inhibit global H3 acetylation. No changes were observed in histone H3 occupancy or acetylation at viral IE gene promoters. Furthermore, p300 and CBP recruitment to IE gene promoters was not affected by the presence of curcumin. Finally, disruption of p300 expression using a short hairpin RNA did not affect viral IE gene expression. These results suggest that curcumin affects VP16-mediated recruitment of RNA polymerase II to IE gene promoters by a mechanism independent of p300/CBP histone acetyltransferase activity.
PMID: 18191976
 
 
A new Med Hypothesis article:
 
Med Hypotheses. 2015 Mar 14. pii: S0306-9877(15)00119-X.
Mori I1.
Accumulating evidence has suggested that the reactivation of herpes simplex virus type 1 (HSV-1) in the brain is a potent risk factor of Alzheimer’s disease [1,2]. Amyloid-β (Aβ) is a major component of the senile plaques. It accumulates in the brain of elderly patients where it plays a significant role in the pathogenesis of Alzheimer’s disease. The internal amino acid sequence of HSV-1 gB is a homologue of the carboxyl-terminal of the Aβ peptide and it initiates and promotes the Aβ fibril formation [1].
PMID: 25804240
 
[2] Ball, M.J., Lukiw, W.J., Kammerman, E.M., Hill, J.M. Intracerebral propagation of Alzheimer’s disease: strengthening evidence of a herpes simplex virus etiology. Alzheimers Dement. 2013;9:169–175.

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#378 ta5

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Posted 12 April 2015 - 11:44 PM

Melatonin-Herpes connection:

 
Int J Dent. 2012;2012:491872.
Cengiz Mİ1, Cengiz S, Wang HL.
PMID: 22792106
 
From the full text:
 
Melatonin and Herpes Viral Infection
The benefical effects of melatonin in herpes infections of the oral cavity have been compared with Acyclovir. In this case, melatonin proved benefical in reducing the severity of herpes at least as effectively as the prescription drug. This is consistent with the actions of melatonin on other viral infections where it has also been found to reduce the severity of those infections. The benefits of melatonin in these situations seem to stem from the immunomodulatory actions of melatonin in the stimulation of IL-1B, which has antiviral effects. The suppressive actions of melatonin on herpes may also relate to its stimulation of NK, CD4 cells, and so forth. At this point, the precise mechanism where by melatonin may reduce the severity of herpes infections remains unknown.

 

References from the above article:

 

J Pineal Res. 2008 May;44(4):373-8.

Regression of herpes viral infection symptoms using melatonin and SB-73: comparison with Acyclovir.

Nunes Oda S1, Pereira Rde S.
PMID: 18410585
 
J Pineal Res. 2004 Mar;36(2):73-9.
Bonilla E1, Valero N, Chacín-Bonilla L, Medina-Leendertz S.
PMID: 14962057

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#379 Kalliste

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Posted 13 April 2015 - 06:43 AM

All very interesting, I have long suspected that many popular "antioxidants" are not so much antioxidants as they are low-level anti-virals, epigenetic manipulators.



#380 corb

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Posted 14 April 2015 - 02:17 PM

 

An international team of more than 18 research groups has demonstrated that the compounds they developed can safely prevent harmful protein aggregation in preliminary tests using animals. The findings raise hope that a new class of drugs may be on the horizon for the more than 30 diseases and conditions that involve protein aggregation, including diabetes, cancer, spinal cord injury, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). Proteins are necessary for almost every cellular process. However, when cell machinery doesn't clear out old proteins, they can clump, or aggregate, into toxic plaques that lead to disease.

The researchers call the compounds that they developed molecular tweezers because of the way they wrap around the lysine amino acid chains that make up most proteins. The compounds are unique in their ability to attack only aggregated proteins, leaving healthy proteins alone. To develop a new drug, researchers typically screen large libraries of compounds to find ones that affect a protein involved in a disease. This team used a fundamentally different approach to develop the molecular tweezers. "We looked at the molecular and atomic interactions of proteins to understand what leads to their abnormal clumping. Then, we developed a tailored solution. So unlike many other drugs, we understand how and why our drug works."

The team is in the process of testing multiple versions of the tweezers, each with a slightly different molecular makeup. For CLR01, one of the most promising versions, the researchers have demonstrated therapeutic benefits in two rodent models of Alzheimer's disease, two fish and one mouse model of Parkinson's disease, a fish model of spinal cord injury and a mouse model of familial amyloidotic polyneuropathy, a rare disease in which protein aggregation affects the nervous system, heart and kidneys. "Our data suggest that CLR01, or a derivative thereof, may become a drug for a number of diseases that involve protein aggregation. We also found a high safety window for CLR01." In one of the safety tests, mice receiving a daily CLR01 dose 250 times higher than the therapeutic dose for one month showed no behavioral or physiological signs of distress or damage. In fact, blood cholesterol in the mice dropped by 40 percent, a possible positive side effect of CLR01.

 

 

This is SENS-level stuff.

 

 

Did you know the researchers working on this had to resort to crowdfunding last year?
And the NIA supposedly has a 100,000,000$ budget just for Alzheimer's research. It's so sad it's kinda funny.
 



#381 Kalliste

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Posted 14 April 2015 - 04:27 PM

Thats crazy. We should fund them and ask for a group-buy in return ;)



#382 corb

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Posted 14 April 2015 - 05:57 PM

Thats crazy. We should fund them and ask for a group-buy in return ;)

 

They were asking for two million dollars, it was pretty obvious it was more of a protest than a real campaign but still, I think they weren't joking about the sum. That's a substantial amount of money for a small community like this.
I think the best thing we can do is try to get them publicity somehow.



#383 mrfixituk

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Posted 15 April 2015 - 07:09 AM

http://www.telegraph...stem-tweak.html



#384 niner

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Posted 15 April 2015 - 01:01 PM

They were asking for two million dollars, it was pretty obvious it was more of a protest than a real campaign but still, I think they weren't joking about the sum. That's a substantial amount of money for a small community like this.


I think the best thing we can do is try to get them publicity somehow.

 

Maybe they should ask the Solar Roads people for help...


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#385 corb

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Posted 15 April 2015 - 01:17 PM

 

They were asking for two million dollars, it was pretty obvious it was more of a protest than a real campaign but still, I think they weren't joking about the sum. That's a substantial amount of money for a small community like this.


I think the best thing we can do is try to get them publicity somehow.

 

Maybe they should ask the Solar Roads people for help...

 

 

I was thinking more among the lines of the ALS ice bucket challenge people. This can supposedly treat ALS as well so I don't see why not.



#386 Logic

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Posted 15 April 2015 - 01:30 PM

To add to the above Circumin info.

 

The effect of curcumin (turmeric) on Alzheimer's disease: An overview

"...Because of the lipophilic nature of curcumin, it crosses the blood brain barrier and binds to plaques. Curcumin was a better A-beta 40 aggregation inhibitor and it destabilizes the A-beta polymer... Due to various effects of curcumin, such as decreased Beta-amyloid plaques, delayed degradation of neurons, metal-chelation, anti-inflammatory, antioxidant and decreased microglia formation, the overall memory in patients with AD has improved..."

http://www.ncbi.nlm..../?log$=activity

 

Curcumin ameliorates the permeability of the blood-brain barrier during hypoxia by upregulating heme oxygenase-1 expression in brain microvascular endothelial cells.

http://www.ncbi.nlm....7?log$=activity

 



#387 Darryl

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Posted 17 April 2015 - 04:19 PM


The group did find CD11c microglia and arginase, an enzyme that breaks down arginine, are highly expressed in regions of the brain involved in memory, in the same regions where neurons had died.
 
Blocking arginase using the small drug difluoromethylornithine (DFMO) before the start of symptoms in the mice, the scientists saw fewer CD11c microglia and plaques develop in their brains. These mice performed better on memory tests.
 
“All of this suggests to us that if you can block this local process of amino acid deprivation, then you can protect — the mouse, at least — from Alzheimer’s disease,” Kan said.
 
The paper:
 
Kan MJ, Lee JE, Wilson JG, Everhart AL, Brown CM, Hoofnagle AN, Jansen M, Vitek MP, Gunn MD, Colton CA. Arginine deprivation and immune suppression in a mouse model of Alzheimer’s disease. J Neuroscience 2015. doi:10.1523/JNEUROSCI.4668-14.2015

We have previously described the unique CVN-AD mouse model of AD, in which immune-mediated nitric oxide is lowered to mimic human levels, resulting in a mouse model that demonstrates the cardinal features of AD, including amyloid deposition, hyperphosphorylated and aggregated tau, behavioral changes, and age-dependent hippocampal neuronal loss. Using this mouse model, we studied longitudinal changes in brain immunity in relation to neuronal loss and, contrary to the predominant view that AD pathology is driven by proinflammatory factors, we find that the pathology in CVN-AD mice is driven by local immune suppression. Areas of hippocampal neuronal death are associated with the presence of immunosuppressive CD11c+ microglia and extracellular arginase, resulting in arginine catabolism and reduced levels of total brain arginine. Pharmacologic disruption of the arginine utilization pathway by an inhibitor of arginase and ornithine decarboxylase protected the mice from AD-like pathology and significantly decreased CD11c expression. Our findings strongly implicate local immune-mediated amino acid catabolism as a novel and potentially critical mechanism mediating the age-dependent and regional loss of neurons in humans with AD.
 
Difluoromethylornithine (Eflornithine, Ornidyl) is an approved drug for facial hirsutism and sleeping sickness. Unfortunately, systemic DFMO has some fairly severe adverse effects in humans. However, they're dose related and reversible, suggesting that low dose ornidyl + arginine supplementation may be worth a trial.

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#388 ceridwen

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Posted 17 April 2015 - 07:00 PM

I'm not too impressed by this as HSV1 can be a cause of Alzheimers and that virus makes its cell wall out of arginine . I'm not sure that the above would not make the disease very much worse-in humans given that what do people think?



#389 mag1

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Posted 17 April 2015 - 07:17 PM

Depleting arginine is currently a strategy being pursued in a phase 3 cancer trial. https://clinicaltria...is group&rank=1

The substance that is being used depletes arginine levels in the blood to near zero.

 

It will be interesting to see whether this has any effect on cognitive status of the patients.


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#390 APBT

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Posted 22 April 2015 - 01:57 AM

http://www.theglobea...rticle24030398/

 

Follow the MIND diet to stave off Alzheimer’s

 

Most of us have heard about the heart-healthy Mediterranean and blood-pressure-lowering DASH diets that may also guard against dementia.

According to a study, a hybrid of these two eating plans – called the MIND diet – is associated with a significantly lower risk of developing Alzheimer’s disease. That’s true even if you don’t follow the diet strictly.

The newly created MIND diet (Mediterranean-DASH Intervention for Neurodegenerative Delay), developed by researchers from Rush University Medical Center in Chicago, was shown to reduce the likelihood of developing Alzheimer’s by 53 per cent in people who followed it rigorously and by 35 per cent in those who adhered to it only modestly.

Alzheimer’s disease, the most common cause of dementia, damages and kills brain cells, causing a steady deterioration in memory and thinking ability. It’s not a normal part of aging, but your risk for the irreversible disease increases greatly after 65.

Along with elements from the Mediterranean and DASH diets, the MIND diet includes specific foods and nutrients found in past studies to be linked to optimal brain health. The diet’s 10 “brain-healthy food groups” include green leafy vegetables, other vegetables, berries, nuts, beans, whole grains, fish, poultry, olive oil and wine.

The plan also advises that five unhealthy food groups – red meat, butter and stick margarine, cheese (because of its high saturated-fat content), pastries and sweets, and fried or fast food – be limited.

For the study, published last month in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, the researchers analyzed the food intake of 923 community-dwelling Chicago residents, ages 58 to 98. Participants were scored on how closely their food intake matched the MIND diet, the Mediterranean diet or the DASH diet. (DASH stands for Dietary Approaches to Stop Hypertension.)

During a follow-up period of 4 1/2 years, 144 participants developed Alzheimer’s disease.

All three diets, when closely followed, offered significant protection against Alzheimer’s. The Mediterranean diet lowered Alzheimer’s risk by 54 per cent, the MIND diet by 53 per cent and the DASH diet by 39 per cent.

Only the MIND diet, however, was shown to guard against Alzheimer’s when not followed strictly. Participants who followed the plan moderately well were 35-per-cent less likely to develop the disease compared with those with the lowest adherence scores.

The findings also hinted that the longer a person follows the MIND diet, the greater the protection from Alzheimer’s disease.

While this observational study shows promise for reducing the risk of Alzheimer’s, it doesn’t prove cause and effect. The results need to be confirmed by randomized controlled trials, the gold-standard evidence for a cause-and-effect relationship.

These new findings add to a growing body of evidence that strongly suggests your overall dietary pattern matters more than single nutrients when it comes to Alzheimer’s prevention.

Eating a combination of healthful foods that deliver a wide range of protective nutrients while, at the same time, minimizing your intake of foods that may harm brain cells is what counts.

 

The MIND diet for optimal brain health

While we wait for other studies to confirm the protective link between the MIND diet and Alzheimer’s risk, there’s no reason to delay adopting this brain-friendly eating pattern. Follow the food guide below to earn the highest MIND diet score.

Leafy green vegetables: At least 6 servings/week

One serving: ½ cup cooked or 1 cup raw (e.g., salad greens)

Eating plenty of vegetables has been linked to a slower rate of cognitive decline in older adults, but leafy greens (e.g., spinach, kale, Swiss chard, beet greens, collards, rapini, broccoli, arugula, Romaine lettuce, leaf lettuce) seem to offer the greatest protection. Leafy greens are excellent sources of vitamin K, folate, beta-carotene and lutein, nutrients thought to help preserve brain functioning. (You’ll get more beta-carotene and lutein if you eat your greens cooked rather than raw.)

Other vegetables: At least 1 serving/day

One serving: ½ cup cooked or raw vegetables

In addition to salad greens and green leafy vegetables, include other green vegetables (e.g., asparagus, green beans, green peppers), orange (e.g., carrots, sweet potato, butternut squash), yellow (e.g., yellow peppers), red (e.g., red peppers, tomato, beets), purple (e.g. eggplant, purple cabbage) and white/tan (e.g., onions, garlic, cauliflower, mushrooms) to consume a wide range of protective phytochemicals.

Berries: At least 2 servings/week

One serving: ½ cup

Berries are rich in polyphenols, phytochemicals that protect brain cells by fighting free-radical damage, reducing inflammation and removing toxic proteins that accumulate with age. Blueberries and strawberries appear to be most potent in terms of brain health.

Nuts: At least 5 servings/week

One serving: 1 ounce, about ¼ cup

Nuts (all types) help lower elevated blood pressure and LDL (bad) cholesterol and guard against Type 2 diabetes, factors that contribute to memory loss and Alzheimer’s disease. Nuts are a good source of vitamin E; higher vitamin E levels are linked to less cognitive decline as we age.

Walnuts may be the king of nuts when it comes to brain health. Research suggests eating more walnuts can help improve memory, concentration and the speed at which your brain processes information. Walnuts deliver polyphenols (like berries) and an omega-3 fatty acid called alpha linolenic acid.

Legumes: At least 4 servings/week

One serving: ½ cup cooked

Lentils and beans (e.g., kidney beans, black beans, chickpeas), packed with low glycemic carbohydrates, provide a steady stream of fuel (glucose) to the brain. Plus, adding beans to your diet can help lower blood pressure and cholesterol.

Whole grains: At least 3 servings/day

One serving: 1 slice 100-per-cent whole-grain bread, ½ cup cooked brown rice, quinoa, whole-grain pasta, oatmeal, 1 cup 100-per-cent whole-grain, ready-to-eat breakfast cereal

Foods that promote a healthy cardiovascular system, such as whole grains, are also good for your brain. That’s because your heart and blood vessels supply nutrient- and oxygen-rich blood to the brain. If your brain doesn’t get the blood flow it needs, it can impair your memory and thinking abilities.

Fish: At least 1 serving/week

One serving: 3 ounces cooked

Oily fish such as salmon, trout, sardines and herring are plentiful in DHA, an omega-3 fatty acid essential for brain function. A higher intake of DHA is thought to slow brain aging and improve memory and thinking skills. It may also help prevent the build-up of an Alzheimer’s-related protein called beta amyloid.

Poultry: At least 2 servings/week

One serving: 3 ounces cooked

As part of a healthy eating pattern, eating more poultry – and less red meat – is associated with a lower risk of Alzheimer’s disease.

Olive oil: Use as your primary cooking oil

Olive oil is a rich source of monounsaturated fat, the type that helps reduce inflammation and prevents blood-vessel dysfunction. Extra-virgin olive oil also contains oleocanthal, a phytochemical that may boost production of two key enzymes believed to be critical in removing beta-amyloid from the brain.

Wine: One serving/day

One serving: 5 ounces

Studies suggest that one glass of wine per day helps preserve memory and reduces Alzheimer’s risk. Low levels of alcohol are thought to have anti-inflammatory effects in the brain. Too much alcohol, however, can damage the brain.

Limit ‘brain-unfriendly foods’

To get a top MIND diet score you must also limit butter/margarine to less than 1 tablespoon/day, fast or fried food less than once/week, red meat fewer than four times/week, cheese less than once/week and pastries and sweets less than five times/week.

 

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