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Amyloid plaques found in older adults w no symptoms
LDDaughter
Posted: Sunday, January 5, 2020 5:28 PM
Joined: 12/22/2011
Posts: 1065


This is such an important article.  Another view for considering that trying to get rid of amyloid plaque is probably the wrong drug target as well as confirmation that Dale Bredesen, author of the End of Alzheimer's is on the right track trying to define the different kinds of Alzheimer's causes. 

https://www.cnn.com/2020/01/03/opinions/diagnosing-treating-alzheimers-opinion-devi/index.html


BadMoonRising
Posted: Thursday, January 9, 2020 11:23 AM
Joined: 4/22/2017
Posts: 323


The article is a bit (unintentionally) misleading for readers who are unfamiliar with the continuum of Alzheimer's Disease. The author does, however, provides helpful links, including one that begins by stating:

"Alzheimer’s disease is a heterogenous disorder with multiple phenotypes and genotypes, although they eventually converge to a final common clinicopathological endpoint. However, Alzheimer’s disease drug trials do not account for the heterogeneity of the disease in trial design, impeding development of effective drugs."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300886/

Dr. Devi is describing patients who have symptoms of Alzheimer's and actually test both biologically (plaques and/or tau) and neurocognitively for Alzheimer's Disease. However, their ability to function without assistance rules out a diagnosis of dementia.

My understanding is that scientists believe that neuroinflammation IS a major factor associated with AD. As far as Bredesen, IMO, he needs to either put up or shut up. IOW, he has had ample opportunity to publish a valid study yet he has not yet done so.


Lane Simonian
Posted: Thursday, January 9, 2020 10:55 PM
Joined: 12/12/2011
Posts: 4845


I think Dr. Bredesen largely has it right: there are multipe factors that can cause Alzheimer's disease.  Amyloid oligomers, hyperphosphorylated tau proteins, and inflammation are just three of them.  They all also happen to be secondary triggers, meaning that they don't occur unless some other factor leading to oxidation in the brain (unhealthy diet, environmental toxins, stress in life, etc.) are present in the first place.  That is the reason why anti-amyloid drugs, anti-tau drugs, and anti-inflammatory drugs have very little effect on the progression of the disease.

The Bredesen approach involves trying to identify those factors that are damaging the brain and then remove then.  He also recommends a variety of antioxidants.  I put it a bit differently: inibit or if possible prevent the formation of oxidants that are damaging the brain, remove those oxidants, and reverse the damage that they are doing to the brain and you can largely stabilize Alzheimer's disease.


LDDaughter
Posted: Friday, January 10, 2020 5:04 PM
Joined: 12/22/2011
Posts: 1065


Here's an interesting article talking about a perceived bias in the scientific world towards amyloid plaque being the only cause of Alzheimer's disease even though hundreds of these medications have failed in trials. It shines a light on how difficult it still is for other theories to get funded for trials and published. Some of these scientists have similar ideas to Bredesen, that  neuroinflammation, infections and viruses may be possible causes. Bredesen has through decades of research, identified multiple contributing factors to Alzheimer's, but this goes against the prevailing school of thought, which is difficult to penetrate. Having a comprehensive lifestyle tailored approach for each person also is outside the box for how treatments and trials get approved.  He mentions this in his book when explaining how he was turned down by the IRB's for a trial.  

https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarted-progress-toward-cure/ 


Lane Simonian
Posted: Friday, January 10, 2020 6:48 PM
Joined: 12/12/2011
Posts: 4845


Yes, if your idea fits outside the view that either amyloid, tau, or inflammation are the cause of Alzheimer's disease it is hard to get funding.  And if you are suggesting using multiple compounds from natural products to treat the disease that makes it harder yet.

Here is one of the reasons why amyloid plaques are not the cause of Alzheimer's disease or even a contributing cause.

Mature amyloid fibrils [deposited as plaques] derived from Aβ-(1–40) did not generate hydrogen peroxide. We conclude that hydrogen peroxide formation during the early stages of protein aggregation may be a common mechanism of cell death in these (and possibly other) neurodegenerative diseases.

http://www.jbc.org/content/280/43/35789.full

Amyloid oligomers attact copper and zinc and the enzyme which converts superoxide anions into hydrogen peroxide requires copper and zinc.  By contrast, amyloid plaques entomb copper and zinc so superoxide anions are no longer being coverted into hydrogen peroxide.  The problem, though, is that superoxide anions combine with inducible nitric oxide to form peroxynitrite and peroxynitrite then kills neurons.

The inhibition of inducible nitric oxide formation in mice basically stops an Alzheimer's like disease:

Brains from subjects who have Alzheimer's disease (AD) express inducible nitric oxide synthase (iNOS). We tested the hypothesis that iNOS contributes to AD pathogenesis. Immunoreactive iNOS was detected in brains of mice with AD-like disease resulting from transgenic expression of mutant human beta-amyloid precursor protein (hAPP) and presenilin-1 (hPS1). We bred hAPP-, hPS1-double transgenic mice to be iNOS(+/+) or iNOS(-/-), and compared them with a congenic WT strain. Deficiency of iNOS substantially protected the AD-like mice from premature mortality, cerebral plaque formation, increased beta-amyloid levels, protein tyrosine nitration, astrocytosis, and microgliosis. Thus, iNOS seems to be a major instigator of beta-amyloid deposition and disease progression. Inhibition of iNOS may be a therapeutic option in AD.

https://www.ncbi.nlm.nih.gov/pubmed/16260491

Various phenolic compounds from plants both inhibit inducible nitric oxide formation, scavenge peroxynitrite, and partially reverse oxidation and nitration in the brain.

Phenolic compounds from plants as nitric oxide production inhibitors.

Author information

1 Department of Pharmaceutical Sciences, University of Calabria, I-87036 Rende (CS), Italy. filomena.conforti@unical.it

Abstract

Nitric oxide (NO) is a diatomic free radical produced from L-arginine by constitutive and inducible nitric oxide synthase (cNOS and iNOS) in numerous mammalian cells and tissues. Nitric oxide (NO), superoxide (O2-) and their reaction product peroxynitrite (ONOO-) may be generated in excess during the host response against viral and antibacterial infections and contribute to some pathogenesis by promoting oxidative stress, tissue injury and, even, cancer. Oxidative damage, caused by action of free radicals, may initiate and promote the progression of a number of chronic diseases, including cancer, cardiovascular diseases, Alzheimer's disease, diabetes and inflammation. The mechanism of inflammation injury is attributed, in part, to release of reactive oxygen species from activated neutrophils and macrophages. ROS propagate inflammation by stimulating release of mediators such as NO and cytokines. The interest of the research is motivated by the current need to find new substances of natural origin which have demonstrated effectiveness in the described fields of application and low degree of toxicity for humans. Natural products provide a vast pool of NO inhibitors that can possibly be developed into clinical products. This article reviews some plenolic secondary metabolites from plants with NO inhibitory properties and their structure-activity relationship studies that can be focused for drug development programs.

https://www.ncbi.nlm.nih.gov/pubmed/21291370

Good luck, though in getting anybody to fund such studies in the United States.



LDDaughter
Posted: Sunday, January 12, 2020 3:18 PM
Joined: 12/22/2011
Posts: 1065


Lane Simonian wrote:

Good luck, though in getting anybody to fund such studies in the United States.

Thanks for your reply, though the explanation was beyond my laywoman's level-and too late i the day to tackle. 

I'm curious if you know anything about how the sequence of events that led to the DASH diet lifestyle approach being accepted for hypertension?  I can't seem to find the ordinator's name, but thought it was an academic in CA back in the 90's. Somehow he got this idea to catch on and studies were then done, but I think only on the dietary part of it.  Could their approach to getting acceptance be a guideline for others to follow that have more complex theories?  


Lane Simonian
Posted: Sunday, January 12, 2020 9:34 PM
Joined: 12/12/2011
Posts: 4845


This is the limited information that I have found so far for the history behind the DASH diet:

The prevalence of hypertension led the U.S. National Institutes of Health (NIH) to propose funding to further research the role of dietary patterns on blood pressure. In 1992 the NHLBI [National Heart, Lung, and Blood Institute] worked with five of the most well-respected medical research centers in different cities across the U.S. to conduct the largest and most detailed research study to date. The DASH study used a rigorous design called a randomized controlled trial (RCT), and it involved teams of physicians, nurses, nutritionists, statisticians, and research coordinators working in a cooperative venture in which participants were selected and studied in each of these five research facilities. The chosen facilities and locales for this multi-center study were: (1) Johns Hopkins University in Baltimore, Maryland, (2) Duke University Medical Center in Durham, North Carolina, (3) Kaiser Permanente Center for Health Research in Portland, Oregon, (4) Brigham and Women's Hospital in Boston, Massachusetts, and (5) Pennington Biomedical Research Center in Baton Rouge, Louisiana.

There is probably a lesson somewhere in this history for receiving federal funding to study diet and the use of natural products for the treatment of Alzheimer's disease, but I am not sure at this point what it is.


LDDaughter
Posted: Wednesday, January 15, 2020 1:19 PM
Joined: 12/22/2011
Posts: 1065


Lane Simonian wrote:

This is the limited information that I have found so far for the history behind the DASH diet:

The prevalence of hypertension led the U.S. National Institutes of Health (NIH) to propose funding to further research the role of dietary patterns on blood pressure. In 1992 the NHLBI [National Heart, Lung, and Blood Institute] worked with five of the most well-respected medical research centers in different cities across the U.S. to conduct the largest and most detailed research study to date. The DASH study used a rigorous design called a randomized controlled trial (RCT), and it involved teams of physicians, nurses, nutritionists, statisticians, and research coordinators working in a cooperative venture in which participants were selected and studied in each of these five research facilities. The chosen facilities and locales for this multi-center study were: (1) Johns Hopkins University in Baltimore, Maryland, (2) Duke University Medical Center in Durham, North Carolina, (3) Kaiser Permanente Center for Health Research in Portland, Oregon, (4) Brigham and Women's Hospital in Boston, Massachusetts, and (5) Pennington Biomedical Research Center in Baton Rouge, Louisiana.

There is probably a lesson somewhere in this history for receiving federal funding to study diet and the use of natural products for the treatment of Alzheimer's disease, but I am not sure at this point what it is.

 Thanks Lane! Yes, there's a lesson in there somewhere.