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Amyloid Plaques: Barking Up the Wrong Tree?
Lane Simonian
Posted: Thursday, April 4, 2013 12:09 PM
Joined: 12/12/2011
Posts: 4845


The findings of this study may be among the most important ever made in regards to Alzheimer's disease. 

 

The consistent conclusion of our study, taken together with other studies is that behavioral decline, neuronal cell death, and inflammatory cell activation precede plaque formation, providing a strong indication that neurodegenerative processes are occurring independent of AB [amyloid plaque] formation.  Fundamentally, this means that AD [Alzheimer's Disease] progressive decline may occur well before plaque deposition in AD. 

 

From PLOS ONE: Neuroinflammation and Neuronal Loss Precede AB deposition in the hAPP-J20 Mouse Model of Alzheimer's Disease 

 

All of this makes a great deal of sense.  Peroxynitrite formation precedes the formation of amyloid plaques.  Indeed it is what causes plaques to aggregate.  Peroxynitrites mediate inflammation and neuronal cell death in Alzheimer's disease and contribute to behavioral problems as well. 

 

The plaques may cause the additional formation of peroxynitrites (through the incorporation of heavy metals), but only at a level which causes neuronal damage and not death.  This explains why all the drug trials designed to lower plaque levels have failed so far and why they will not prevent Alzheimer's disease and why every peroxynitrite scavenger ever tested has partially ameliorated Alzheimer's disease either in vivo, in animals, or in human beings. 


Lane Simonian
Posted: Thursday, April 4, 2013 12:20 PM
Joined: 12/12/2011
Posts: 4845


If this study receives a great deal of attention, it could be a huge step in the right direction.  The fixation on amyloid plaques might be broken.  Now if researchers next move to tau proteins--that would be more of a side step than a step in the right direction.  On the other hand, if researchers begin to study the role of nitration in the aggregation of amyloid plaques and tau tangles that would be a huge step in the right direction.  One writer aptly described the current approach to Alzheimer's disease as being stuck in an "intellectual cul-de-sac." After nine years of studying this disease, I am beginning to see the light at the end of the cul-de-sac.


Myriam
Posted: Thursday, April 4, 2013 4:51 PM
Joined: 12/6/2011
Posts: 3326


Thanks so much, Lane.  Let's hope the light at the end of the cul de sac leads to a driveway that leads to a street that leads to a super highway to a cure!
Myriam
Posted: Thursday, April 4, 2013 6:02 PM
Joined: 12/6/2011
Posts: 3326


Here's an article from sciencedaily.com: 

 

(Source: ScienceDaily) - Amyloids -- clumps of misfolded proteins found in the brains of people with Alzheimer's disease and other neurodegenerative disorders -- are the quintessential bad boys of neurobiology. They're thought to muck up the seamless workings of the neurons responsible for memory and movement, and researchers around the world have devoted themselves to devising ways of blocking their production or accumulation in humans.

But now a pair of recent research studies sets a solid course toward rehabilitating the reputation of the proteins that form these amyloid tangles, or plaques. In the process, they appear poised to turn the field of neurobiology on its head.

The first study, published in August, showed that an amyloid-forming protein called beta amyloid, which is strongly implicated in Alzheimer's disease, could reverse the symptoms of a multiple-sclerosis-like neurodegenerative disease in laboratory mice.

The second study, to be published yesterday, extends the finding to show that small portions of several notorious amyloid-forming proteins (including well-known culprits like tau and prion proteins) can also quickly alleviate symptoms in mice with the condition -- despite the fact that the fragments can and do form the long tendrils, or fibrils, previously thought harmful to nerve health.

Go to full story:
http://www.sciencedaily.com 


Lane Simonian
Posted: Thursday, April 4, 2013 7:52 PM
Joined: 12/12/2011
Posts: 4845


Thanks, Myriam, for these studies and for your hopeful thoughts and great imagery.  I am thinking that once the amyloid paradigm is broken the chances for a cure or at least an effective treatment greatly increase. 
Lane Simonian
Posted: Friday, April 5, 2013 9:49 AM
Joined: 12/12/2011
Posts: 4845


"Sydney's Garvan Institute of Medical Research announced a discovery that will transform the way doctors diagnose and treat Alzheimer's disease.   

 

They found plaques on the brain, long considered a sign of the disease, is one of the last events to occur in a person with Alzheimer's.    

 

A mouse model revealed significant nerve cell loss and brain inflammation began early in the disease, when subtle memory problems appeared. Plaque occurred much later in the process. 

 

PhD student Amanda Wright and Dr Bryce Vissel said plaque has been considered a marker of the disease since 1906.  This discovery shows brain inflammation and cell loss may be an earlier indicator of disease pathology than plaque and an alternative treatment for the disease." 

 

I am hoping for many more stories like this one.  Peroxynitrites via nitration are what cause amyloid to aggregate into plaques and via the nitration of NMDA receptors leads to the efflux of glutamate which causes inflammation and the influx of calcium which kills neurons.  Peroxynitrite scavengers inhibit and partially reverse all these processes.  They also chelate heavy metals out of amyloid plaques lessening the contribution of amyloid plaques to the production of peroxynitrites.  Once the cause of a disease is known, the steps to prevent and treat it become much easier to identify.   


Lane Simonian
Posted: Friday, April 5, 2013 8:45 PM
Joined: 12/12/2011
Posts: 4845


I will post the study itself (had troubles before): 

 

http://www.plosone.org/article/infooi/10.1371/journal.pone.0059586 

 

Peroxynitrites appear to be almost a prerequisite for the formation of plaques so it makes sense that the damage to the brain begins before the appearance of plaques. 

 

2011 Sep 8;71(5):833-44. doi: 10.1016/j.neuron.2011.07.001.

Nitration of tyrosine 10 critically enhances amyloid β aggregation and plaque formation.

Source

Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.

Abstract

Part of the inflammatory response in Alzheimer's disease (AD) is the upregulation of the inducible nitric oxide synthase (NOS2) resulting in increased NO production. NO contributes to cell signaling by inducing posttranslational protein modifications. Under pathological conditions there is a shift from the signal transducing actions to the formation of protein tyrosine nitration by secondary products like peroxynitrite and nitrogen dioxide. We identified amyloid β (Aβ) as an NO target, which is nitrated at tyrosine 10 (3NTyr(10)-Aβ). Nitration of Aβ accelerated its aggregation and was detected in the core of Aβ plaques of APP/PS1 mice and AD brains. NOS2 deficiency or oral treatment with the NOS2 inhibitor L-NIL strongly decreased 3NTyr(10)-Aβ, overall Aβ deposition and cognitive dysfunction in APP/PS1 mice. Further, injection of 3NTyr(10)-Aβ into the brain of young APP/PS1 mice induced β-amyloidosis. This suggests a disease modifying role for NOS2 in AD and therefore represents a potential therapeutic target.

 

Eugenol in various essential oils is just one example of a peroxynitrite scavenger that inhibits inflammation and neuronal cell death even before the appearance of amyloid plaques (by de-nitrating the NMDA receptor). 

 

If you inhibit the formation of peroxynitrites (with phenolic compounds in a Mediterranean diet and with omega 3-fatty acids such as fish oil), you can delay the onset of Alzheimer's disease.  Methoxyphenols and various other peroxynitrite scavengers that not only inhibit but partially reverse tyrosine nitration willl partially reverse the disease. 

 

 


Lane Simonian
Posted: Friday, April 19, 2013 10:39 PM
Joined: 12/12/2011
Posts: 4845


This is a very good editorial exposing the misplaced direction of much of current research on Alzheimer's disease. 

 

 

 Sharon Begley

The Scandal That is Alzheimer's Research

Of all the columns I’ve written, no topic has brought more agonized, heartfelt and desperate-sounding emails than Alzheimer’s disease. Back in 2004, I wrote three columns (when I was at The Wall Street Journal) on how one particular theory of what causes this awful disease—and therefore the best approach for treating it—has had the field in a headlock, censoring competing theories. That closed-mindedness, I quoted scientists as saying, had a lot to do with why there is not only no cure or preventive for Alzheimer’s, but not even a treatment that slows down the inexorable cognitive decline.
 

The emails, as you might expect, told me about loved ones who had been lost to Alzheimer’s, and expressed frustration, anger and fury that part of the reason for the lack of progress might be that scientists were not open-minded about any but their pet hypothesis.
 

This all came rushing back to me this week when Myriad Genetics, Inc., reported that a Phase 3 clinical trial (the last one before a company seeks FDA approval for a new drug) it had been testing for an experimental Alzheimer’s drug had failed. The drug, Flurizan, is called a “selective amyloid lowering agent,” or SALA. Amyloid is a peptide (part of a protein). The amyloid known as Aβ42 is—according to the dogma—the “primary initiator of neurotoxicity and amyloid plaque development in the brains of Alzheimer’s disease patients,” as Myriad puts it. And indeed, in human cells growing in lab dishes as well as in lab animals, Flurizan reduces levels of Aβ42.
 

But when Myriad gave it to people with early-stage Alzheimer’s, it didn’t help them a bit. We don’t know why. Maybe Flurizan did not reduce Aβ42 in the patients. Or maybe—and this would be disastrous for the field—it did reduce Aβ42 but that had no beneficial effect. If the latter, it is more proof that the amyloid dogma—Aβ42 causes Alzheimer’s, therefore get rid of Aβ42 and you’ll cure the disease—is wrong. I call it “disastrous” because a huge majority of the research and drug-development efforts in Alzheimer’s assumes that Aβ42 causes the disease and that getting rid of Aβ42 is the holy grail.
 

At the risk of being obnoxiously self-referential, let me re-cycle some of what I said about the amyloid dogma back in 2004:
 

“Beliefs about what causes this merciless disease have taken on such a religious fervor that one group is called tauists, after a protein called tau that forms 'neurofibrillary tangles' inside the neurons and, say these scientists, kills neurons responsible for memory and thought. Another is called baptists, after the [Aβ42] that forms plaques around brain neurons and, say its accusers, causes neuron-killing tau tangles or kills neurons directly, or both. Apostates think amyloid plaques sop up neurotoxic proteins along with poisonous metals such as zinc and copper, and that eliminating plaques could therefore harm patients. . . . [But] there are growing doubts that amyloid is guilty as charged. Autopsies of people with early-stage Alzheimer's show that the tangles form first, before plaques, in brain regions initially affected by the disease. 'If you look at the evidence, it's the tangles that cause neuronal degeneration, and they come first, before the amyloid,' says neurologist Patrick McGeer of the University of British Columbia. Another problem for the amyloid dogma, ... adds neurobiologist Nikolaos Robakis of Mount Sinai School of Medicine, New York City, is that autopsies of the brains of Alzheimer's victims show that 'plaques don’t correlate with neuronal death. The amyloid is here and the dead neurons are somewhere else.' . . .  'If amyloid were the answer,' says Dr. McGeer, 'the disease would have been solved by now.'

I’m afraid that’s still where things stand, four years after I wrote that. Now let me share a note I just got from a scientist who has long questioned the amyloid dogma:
 

“I couldn’t resist contacting you....not with glee [about the Myriad failure], instead sadness at how scientific narcissism [he means the focus on the amyloid hypothesis to the near-exclusion of everything else] fails every damn time. . . . As far as Flurizan is concerned, I am sure the amyloid contingent will make their excuses: blame the drug, the placebo group (for not falling fast enough!), the timing (clearly we need to start anti-amyloid therapy in utero!) and, ultimately, the species (humans simply are not as good responders as mice). However, at this stage, I sense that the heads are beginning to drop and the swagger has disappeared. . . . While my hope is that this will open the field to all manner of crazy hypotheses, my fear is that the excuses will be persuasive enough. At this point, everything that lowers amyloid in mice/cells has failed in human trials. Perhaps a coincidence? Maybe. However, the alternate is never really considered. All of this is not to say that I was right [that amyloid is not the cause of Alzheimer’s and therefore cannot be the target of drugs to treat it]. I still don't know exactly how amyloid fits into the puzzle. But betting the house on 00 in roulette is no way to conduct science. Trouble is, we mostly are not gambling with our own money or lives.”

No, they are gambling with the lives of patients now and in the future whose lives are being taken by Alzheimer's. On that depressing note, Happy 4th.

 


Lane Simonian
Posted: Saturday, April 20, 2013 12:16 AM
Joined: 12/12/2011
Posts: 4845


Amyloid plaques/oligomers are likely not just a byproduct of Alzheimer's disease but neither are they the main cause.  Heme in amyloid oligomers in conjunction with hydrogen peroxide can contribute to tyrosine nitration, but most likely on a limited scale. 

 

http://www.ncbi.nlm.nih.gov/pubmed/17109254 

 

As Alzheimer's disease progresses, hydrogen peroxide levels decrease so this route to tyrosine nitration (which can lead to either damage or death to neurons) is cut off. 

 

http://www.ncbi.nlm.nih.gov/pubmed/16141213 

 

http://www.ncbi.nlm.nih.gov/pubmed/21487307 

 

The entombment of zinc and copper in amyloid plaques limits the conversion of superoxide anions into hydrogen peroxide.  The net effect of this on tyrosine nitration is difficult to gauge: less nitration via heme/hydrogen but more superoxide anions available to combine with inducible nitric oxide to form peroxynitrites.

   

 

In any case, immunotherapy strategies against amyloid oligomers/plaques will fail because they are not the main source of peroxynitrite formation and subsequent tyrosine nitration.