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All,

 

This new study [1] (science press coverage) appears like it might be a significant breakthrough in the treatment of Alzheimer's disease. Researchers appear to have discovered a small molecule that at least in rodents is safe, crosses the blood-brain barrier, and is effective at breaking up beta amyloid plaques, thought to play an important role in the neuronal death associated with Alzheimer's disease. From the article linked above:

 

The Korean scientists, led by YoungSoo Kim of the Brain Science Institute at the Korea Institute of Science and Technology (KIST) in Seoul, investigated the ability of EPPS [4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid] to attach to amyloid-beta clumps and convert them into simpler, smaller molecules.

Through a series of experiments, they found that EPPS could break apart plaque in a living mammal. They also found the molecule could be added to drinking water yet still travel in the blood to the brain and cross the blood-brain barrier, which otherwise prevents foreign material from entering the brain. EPPS could penetrate the barrier because it is a relatively small molecule, Kim said.

The scientists found that doses between 30 and 100 milligrams per kilogram of body weight per day were effective in breaking up the amyloid beta. Further tests demonstrated that EPPS appears to have no toxic effects in mice up to 2,000 mg/kg per day.

From the full text, not only did mice treated with EPPS show a reduction in beta amyloid plaques in their hippocampus and other brain areas in a dose dependent manner, they also showed less cognitive impairment relative to control mice using several measures of cognitive performance.

 

The lead author is quite optimistic about this compound's potential:

 

"I strongly believe these drug candidates [based on EPPS] will halt the neurodegeneration and rescue patients from death," Kim said.

Here's hoping human trials prove that he's right!

 

--Dean

 

------

[1] Nat Commun. 2015 Dec 8;6:8997. doi: 10.1038/ncomms9997.

EPPS rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by

disaggregation of amyloid-β oligomers and plaques.

 

Kim HY(1,)(2,)(3), Kim HV(1,)(2), Jo S(4), Lee CJ(4), Choi SY(1), Kim DJ(1), Kim

Y(1,)(2).

 

Full text: http://www.nature.com.sci-hub.io/ncomms/2015/151208/ncomms9997/abs/ncomms9997.html

 

Alzheimer's disease (AD) is characterized by the transition of amyloid-β (Aβ)

monomers into toxic oligomers and plaques. Given that Aβ abnormality typically

precedes the development of clinical symptoms, an agent capable of disaggregating

existing Aβ aggregates may be advantageous. Here we report that a small molecule,

4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS), binds to Aβ

aggregates and converts them into monomers. The oral administration of EPPS

substantially reduces hippocampus-dependent behavioural deficits, brain Aβ

oligomer and plaque deposits, glial γ-aminobutyric acid (GABA) release and brain

inflammation in an Aβ-overexpressing, APP/PS1 transgenic mouse model when

initiated after the development of severe AD-like phenotypes. The ability of EPPS

to rescue Aβ aggregation and behavioural deficits provides strong support for the

view that the accumulation of Aβ is an important mechanism underlying AD.

 

PMCID: PMC4686862

PMID: 26646366

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Great news. I'm surprised I missed that study! Let's hope Phase I trials start soon (and that the researchers stratify the results by APOE genotype, which, amazingly, is still not always done, even though it almost always proves worth it/relevant).

 

Zeta

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We used to use HEPES buffer frequently in the lab.  I thought that their model system the way they did it seemed to be not too close to what happens in patients.  Just a few days after injecting the agent into brains and treating with HEPES before and during for a few days seems to be quick.  Maybe that's how things are done, I do not know.

 


 

Human platelet calcium mobilisation in response to beta-amyloid (25-35): buffer dependency and unchanged response in Alzheimer's disease.

Hedin HL, Eriksson S, Fowler CJ.

Neurochem Int. 2001 Feb;38(2):145-51.

PMID: 11137883


 

Abstract

 

In the present study, the effects of beta-amyloid (25-35) (Abeta (25-35)) upon calcium signalling by the human platelet has been investigated. When assays were conducted using HEPES buffers, Abeta (25-35), but not the inactive peptide Abeta (35-25), produced a robust increase in intracellular calcium that remained after removal of extracellular calcium but was abolished by the phospholipase C inhibitor U-73122. There was no significant difference between the calcium response to Abeta (25-35) in platelets from patients with Alzheimer's disease and from age-matched controls. In contrast to the robust effects on calcium mobilisation in HEPES buffers, very little calcium response to Abeta (25-35) was seen when Krebs (pH 7.8) buffer was used.

 

 

Phosphate and HEPES buffers potently affect the fibrillation and oligomerization mechanism of Alzheimer's Aβ peptide.

Garvey M, Tepper K, Haupt C, Knüpfer U, Klement K, Meinhardt J, Horn U, Balbach J, Fändrich M.

Biochem Biophys Res Commun. 2011 Jun 10;409(3):385-8. doi: 10.1016/j.bbrc.2011.04.141. Epub 2011 May 7.

PMID: 21575606


 

Abstract

 

The oligomerization of Aβ peptide into amyloid fibrils is a hallmark of Alzheimer's disease. Due to its biological relevance, phosphate is the most commonly used buffer system for studying the formation of Aβ and other amyloid fibrils. Investigation into the characteristics and formation of amyloid fibrils frequently relies upon material formed in vitro, predominantly in phosphate buffers. Herein, we examine the effects on the fibrillation and oligomerization mechanism of Aβ peptide that occur due solely to the influence of phosphate buffer. We reveal that significant differences in amyloid fibrillation are observed due to fibrillation being initiated in phosphate or HEPES buffer (at physiological pH and temperature). Except for the differing buffer ions, all experimental parameters were kept constant. Fibril formation was assessed using fluorescently monitored kinetic studies, microscopy, X-ray fiber diffraction and infrared and nuclear magnetic resonance spectroscopies. Based on this set up, we herein reveal profound effects on the mechanism and speed of Aβ fibrillation. The three histidine residues at positions 6, 13 and 14 of Aβ(1-40) are instrumental in these mechanistic changes. We conclude that buffer plays a more significant role in fibril formation than has been generally acknowledged.

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PS:

 

EPPS rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by disaggregation of amyloid-β oligomers and plaques.
Kim HY, Kim HV, Jo S, Lee CJ, Choi SY, Kim DJ, Kim Y.
Nat Commun. 2015 Dec 8;6:8997. doi: 10.1038/ncomms9997.
PMID: 26646366 Free PMC Article
 
Abstract
 
Alzheimer's disease (AD) is characterized by the transition of amyloid-β (Aβ) monomers into toxic oligomers and plaques. Given that Aβ abnormality typically precedes the development of clinical symptoms, an agent capable of disaggregating existing Aβ aggregates may be advantageous. Here we report that a small molecule, 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS), binds to Aβ aggregates and converts them into monomers. The oral administration of EPPS substantially reduces hippocampus-dependent behavioural deficits, brain Aβ oligomer and plaque deposits, glial γ-aminobutyric acid (GABA) release and brain inflammation in an Aβ-overexpressing, APP/PS1 transgenic mouse model when initiated after the development of severe AD-like phenotypes. The ability of EPPS to rescue Aβ aggregation and behavioural deficits provides strong support for the view that the accumulation of Aβ is an important mechanism underlying AD.

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PS:

 

EPPS rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by disaggregation of amyloid-β oligomers and plaques.
Kim HY, Kim HV, Jo S, Lee CJ, Choi SY, Kim DJ, Kim Y.
Nat Commun. 2015 Dec 8;6:8997. doi: 10.1038/ncomms9997.
PMID: 26646366 Free PMC Article

 

Al,

 

Did you notice this is the same paper I referenced in the opening post of this thread?

 

--Dean

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All,

 

This seems like a pretty big deal, worthy of inclusion in this "Big Alzheimer's Breakthrough!?" thread.

 

It appears from [1] (press release, popular press article) researchers have developed a non-invasive technique to image both beta-amyloid and tau tangles, both in Alzheimer's patients and asymptomatic controls, and use the information to predict cognitive status. Here is an image from their new brain scanning technique:

 

Early-diagnosis-staging-of-Alzheimers-di

 

 

Pretty impressive. They think it can be used as both for diagnosis and early detection, and as a research tool to understand the cause and development of AD. Hopefully on the road to finding a cure...

 

--Dean

 

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[1] Neuron Volume 89, Issue 5, 2 March 2016, Pages 971–982 

doi:10.1016/j.neuron.2016.01.028

 
PET Imaging of Tau Deposition in the Aging Human Brain
 
Michael Schöll1, 2, 6, Samuel N. Lockhart1, 6, Daniel R. Schonhaut3, James P. O’Neil4, Mustafa Janabi4, Rik Ossenkoppele1, 3, 5, Suzanne L. Baker4, Jacob W. Vogel1, Jamie Faria4, Henry D. Schwimmer1, Gil D. Rabinovici1, 3, 4, William J. Jagust1, 4, , 
 
Summary
Tau pathology is a hallmark of Alzheimer’s disease (AD) but also occurs in normal cognitive aging. Using the tau PET agent 18F-AV-1451, we examined retention patterns in cognitively normal older people in relation to young controls and AD patients. Age and β-amyloid (measured using PiB PET) were differentially associated with tau tracer retention in healthy aging. Older age was related to increased tracer retention in regions of the medial temporal lobe, which predicted worse episodic memory performance. PET detection of tau in other isocortical regions required the presence of cortical β-amyloid and was associated with decline in global cognition. Furthermore, patterns of tracer retention corresponded well with Braak staging of neurofibrillary tau pathology. The present study defined patterns of tau tracer retention in normal aging in relation to age, cognition, and β-amyloid deposition.
 
Keywords
tau; amyloid; PET; aging; memory

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Dean, I reposted the reference because the paper was free full-text directly, as I indicated, instead of via the Sci-Hub portal which sometimes is down and some here like Michael prefer not to use.

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Guest T. Ronald Theodore

            Re:        “EPPS rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by disaggregation of amyloid-β oligomers and plaques” Kim et al, Nature Communications 8 December 2015

     HEPES, Zwitterions, and the “Good” Buffers as   Biological Response Modifiers

In reference to the article “EPPS rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by disaggregation of amyloid-β oligomers and plaques” Kim et al, Nature Communications 8 December 2015, we note some important omissions.

Kim et al state specific effects of EPPS affecting Alzheimer’s disease. We would point out that EPPS is also referenced as HEPPS.1 HEPPS has been accepted as a “Good” buffer and a zwitterion. The authors attribute the effects of EPPS to anti-inflammatory action.  The authors omit reference that EPPS (HEPPS) is a listed “Good” buffer and a zwitterion.1  The anti-inflammatory effects of zwitterions and “Good” buffers have been previously described.3,4  The effects of these zwitterions as biological response modifiers with effects on neurological diseases including Alzheimer’s have been previously noted.4,5  ( HEPES has been used preferentially based on Good’s original data showing HEPES has the highest ability to increase the rate of mitochondrial oxidative phosphorylation). Kim et al attribute the effects of EPPS to anti-inflammatory actions. The anti-inflammatory effects of the buffers are well known.3,4   We would suggest that anti-inflammatory effects of the buffers may be singular, synergistic or combined effects of other biological responses that have been noted including mitochondrial and other actions.4,5,6,7  Prior literature and data would certainly anticipate the findings of Kim et al. It is noted that all these zwitterionic buffers have effects on the neurological system.

What is important is that further research to determine the effects of these zwitterionic buffers as biological response modifiers on neurological diseases including Alzheimer’s is continued. The ability of the zwitterionic buffers on brain and other organ injury are currently under review.

 

T. Ronald Theodore

Integrated Biologics, LLC

rtheodore@integratedbiologics.com

 

1.        Merck Index, 15th Edition, Feb 2015. 

2.        Norman E. Good et al., Hydrogen Ion Buffers for Biological Research,  Biochemistry vol.5, No. 2, Feb. 1966.

3.        "Effects of In-vivo Administration of Taurine and HEPES on the Inflammatory Response in Rats” Pharmacy and Pharmacology, vol. 46, No. 9, Sept. 1994.

4.        Theodore et al., Zwitterionic Compositions and Methods as Biological Response Modifiers, US Patent No. 6,071,919. 

5.        Garvey et al., Phosphate and HEPES buffers potently affect the fibrillation and oligomerization mechanism of Alzheimer's Aβ peptide, Biochemical and Biophysical Research Communications,  06/2011; 409(3):385-8. DOI: 10.1016/j.bbrc.2011.04.141.

6.        Theodore et al., Pilot Ascending Dose Tolerance Study of Parenterally Administered 4-(2 Hydroxyethyl)-l-piperazine Ethane Sulfonic Acid (TVZ-7) in Dogs, Cancer Biotherapy & Radiopharmaceuticals, Volume 12, Number 5, 1997.

7.        Theodore et al., Preliminary Evaluation of a Fixed Dose of Zwitterionic Piperazine (TVZ-7) in Clinical Cancer, Cancer Biotherapy and Radiopharmaceuticals, Volume 12, Number 5, 1997.

 

 

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Perhaps we can bring everyone's favorite oil to discuss EVOO and see if there is a connection with Alzheimer's disease PMC3689195 (caveat: study in mice):

 

Olive-Oil-Derived Oleocanthal Enhances β-Amyloid Clearance as a Potential Neuroprotective Mechanism against Alzheimer’s Disease: In Vitro and in Vivo Studies

 

"Oleocanthal, a phenolic component of extra-virgin olive oil, has been recently linked to reduced risk of Alzheimer’s disease (AD), a neurodegenerative disease that is characterized by accumulation of β-amyloid (Aβ) and tau proteins in the brain. However, the mechanism by which oleocanthal exerts its neuroprotective effect is still incompletely understood. Here, we provide in vitro and in vivo evidence for the potential of oleocanthal to enhance Aβ clearance from the brain via up-regulation of P-glycoprotein (P-gp) and LDL lipoprotein receptor related protein-1 (LRP1), major Aβ transport proteins, at the blood-brain barrier (BBB). Results from in vitro and in vivo studies demonstrated similar and consistent pattern of oleocanthal in controlling Aβ levels."

 

Again, this is mice, but considering that the Mediterranean diet is supposed to be protective against AD, perhaps EVOO might play a role. In any case, if you know someone to be vulnerable to AD (or are yourself), incorporating EVOO as a fatty acid in your diet might be worth a shot.

Edited by TomBAvoider

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Thanks Tom,

 

Very interesting! 

 

From the full text (my emphasis):

 

While both Aβ peptide species, Aβ40 and Aβ42, have been implicated in the pathogenesis of AD,32 Aβ40 was used in this work because it is practically feasible as it has much faster clearance rate than Aβ42 (ref).

 

That is significant, because Michael used it to criticize one of the natto / nattokinase studies I dug up that showed natto was beneficial for AD because it was able to clear amyloid-beta. He said:

 

Dean Pomerleau, on 22 Nov 2015 - 6:54 PM, said:

It [nattokinase] also breaks up amyloids, implicated in a bunch of degenerative diseases, including Alzheimer's disease [1].

 

Ye-e-eah. First, the amyloids they looked at were beta-amyloid(1-40) (which is widely considered to be the much less harmful and possibly harmless or in some cases beneficial Abeta species: it's the much more aggregate-prone Abeta(1-42) that appears to do the harm));

 

I wonder if he'll have the same criticism when compound in question is derived from his precious EVOO? ☺

 

Speaking of derived - it's interesting to see that Oleocanthal derived from EVOO (also in olive leaf extract) was effective in vivo at clearing beta-amyloid despite the fact that it was removed from it's olive oil carrier, and isolated from all the other compounds naturally occurring alongside it in EVOO, something Michael criticized olive leaf extract for in this post.  

 

I'm still not taking the OLE, based on your and Michael's cautions that OLE and EVOO are very different.

 

--Dean

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https://vimeo.com/59243534

 

The video shows the newer testing method and how it correlates with types of olives and harvest time, stress etc.

 

Oleocanthol has a definite back of the throat burn similar to ibuprofen. Chew and swallow an ibuprofen and you will definitely get the idea! :)

Of course the olive oil won't burn as much, but the stuff I currently use definitely has a noticeable back of the throat burn when swallowed by itself.

I buy it from:

 

http://www.amphoranueva.com

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Alzheimer's Breakthrough for Real This Time?

 

As we've seen repeatedly in this thread, reports about a "Big Alzheimer's Disease Breakthrough" seem to be a dime-a-dozen. But this one [1] looks like it might actually be the real deal. Why do I say that? Partly because of the results themselves, partly because of the enthusiasm it's getting from other researchers in the field, partly from the fact that it was published in Nature, and partly because of the amazing coverage the study it's getting in Nature, MIT Technology Review, Science Daily, Scientific Americanand last and least (but with surprisingly good coverage) the Daily Mail.

 

It basically was a test on an antibody, Aducanumab (ADB), that the body already makes but in small amounts that researchers hoped with break up Amyloid Beta (Aβ) plaques. They tested in both mice and people. The human study lasted a year, and basically involved intravenous infusion of various amounts of ADB or a placebo in patients with early signs of alzheimer's disease. The study was small (only 103 people received the drug at varying dosages), but the results were quite striking. Using the recently developed technique (described above) for imaging Aβ levels, the researchers got these before/after pictures from humans in the placebo group (top) and from people receiving increasing dosages of ADB:

 

3F8EBE99-8A0B-461C-9E4A45A1D00EDDC0.jpg

 

Pretty remarkable improvement, with pretty strong hints of a dose/response relationship, which makes it even more exciting. It is perhaps the first compound that shows real promise of being able to cross the blood-brain barrier and break up Aβ plaques.

 

Of course, there is quite a substantial fraction of the AD research community who think Aβ plaques are a consequence of AD, and not the cause. But there were some pretty strong hints at cognitive improvements from ADB, with hints again of a dose/response relationship, suggesting the treatment might be having benefits beyond simply breaking up the plaques.

 

Here are some enthusiastic quotes from experts in the field, ironically, from of all places, the Daily Mail article:

 

The importance of this first step cannot be understated - Professor Richard Morris, of Edinburgh University
 
These findings could be a “game-changer” - Professor David Allsop, of the University of Lancaster
 
These results are the most detailed and promising that we’ve seen for a drug that aims to modify the underlying causes of Alzheimer’s disease. - Dr James Pickett, head of research at the Alzheimer’s Society
 
These results provide tantalising evidence that a new class of drug to treat the disease may be on the horizon. - Dr David Reynolds, chief scientific officer of Alzheimer’s Research UK
 
These new data are tantalising - Professor John Hardy, University College London
 
This is the best news I’ve had in my 25 years of doing Alzheimer’s research. - Professor Stephen Salloway (CORR), of the Butler Hospital in Rhode Island
 
The effect of this drug is unprecedented. - Professor Roger Nitsch (CORR), of the University of Zurich
 
Of course, considering the source those quotes should be taken with a grain of salt. Nonetheless, it appears pretty exciting. 
 

On the downside, at the two highest dosages there appeared to be a significant risk of micro-hemorrhages in the brain, sufficiently severe for some of the subjects to drop out. Unfortunately, this bleeding was more common in ApoE ε4 carriers, the folks at highest risk of AD.

 

It looks like they are already in the process of starting a new trial with 2000+ mild AD patients, so it shouldn't be too long until we know a whole lot more.

 

--Dean

 

--------

[1] NATURE | 50 | VOL 537 | 1 SEPTEMBER 2016

 

The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease

 

Jeff Sevigny1*, Ping Chiao1*, Thierry Bussière1*, Paul H. Weinreb1*, Leslie Williams1, Marcel Maier2, Robert Dunstan1, Stephen Salloway3, Tianle Chen1, Yan Ling1, John O’Gorman1, Fang Qian1, Mahin Arastu1, Mingwei Li1, Sowmya Chollate1, Melanie S. Brennan1, Omar Quintero-Monzon1, Robert H. Scannevin1, H. Moore Arnold1, Thomas Engber1, Kenneth Rhodes1, James Ferrero1, Yaming Hang1, Alvydas Mikulskis1,  Jan Grimm2, Christoph Hock2,4, Roger M. Nitsch2,4§ & Alfred Sandrock

 

Free full text: http://www.nature.com/articles/nature19323.epdf

 

Abstract

 

Alzheimer’s disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating—Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.

 

PMID: not available

doi:10.1038/nature19323

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