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In Healthy Brains, Does Aβ Really Matter?
Serenoa
Posted: Friday, August 23, 2013 5:59 PM
Joined: 4/24/2012
Posts: 484


The more I know, the less I understand.

 

  

 In Healthy Brains, Does Aβ Really Matter?

 

18 November 2011. Amyloid plaque buildup in the brain is one of the hallmarks of Alzheimer's disease. But one perplexing aspect of amyloid pathology, known for decades from autopsy findings (see Crystal et al., 1988), is that many cognitively normal people are walking around with heads full of amyloid and seem to suffer no ill effects. The advent of imaging technologies that illuminate amyloid deposition among the living illustrates the point even more. The finding begs the question: Are plaques themselves actually harmful?

 

 

http://www.alzforum.org/new/detail.asp?id=2969

 

 

Curbing Innate Immunity Boosts Synapses, Cognition

 

8 August 2013. New research suggests that the innate immune system affects cognition by regulating synapse formation and maintenance. What role might this process play in Alzheimer’s, where immune cells become activated? At the Alzheimer's Association International Conference (AAIC), held July 14-18 in Boston, Massachusetts. Qiaoqiao Shi, working with Cynthia Lemere at Brigham and Women’s Hospital, Boston, reported that AD mice lacking a key component of the complement system have worse amyloid β (Aβ) pathology, but better memory, than their intact littermates. It is not yet clear why, but intriguingly, the mice with deficient complement systems retain more neurons and synapses as they age than their immune-competent brethren. In humans, brain amyloid load correlates poorly with cognition, whereas synaptic density shows a tight relationship with mental skills (see ARF related news story; DeKosky and Scheff, 1990). 

 

 

http://www.alzforum.org/new/detail.asp?id=3558

 

 


Lane Simonian
Posted: Friday, August 23, 2013 8:46 PM
Joined: 12/12/2011
Posts: 4833


"The more I know, the less I understand." Serenoa, I know the feeling. 

 

Based on your information and that provided by Geo, I am beginning to rethink.  I used to think the death of neurons in Alzheimer's disease was merely a function of mitochondrial failure.  But the final blow may be provided by the complement system. 

 

"We were surprised to see neurons express C1q, which flags them as injured cells," says Dr. Pinsky. C1q activates the complement proteins, leading to the destruction of the injured neurons. Dr. Pinsky believes the discovery may have relevance for the treatment of neurodegenerative diseases, such as Alzheimer's disease, that also destroy neurons.

 

http://www.newswise.com/articles/injured-neurons-saved-after-stroke 

 

 

Peroxynitrites appear to play a role in mitochondrial failure and the activation of the complement system.   

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2438280/ 

 

http://www.ncbi.nlm.nih.gov/pubmed/23646980 

 

Fas/FasL signal transduction pathway and C3 may affect and reinforce apoptosis mediated by ONOO–.

 

http://www.cmj.org/ch/reader/view_abstract.aspx?file_no=201181756141780&flag=1 

 

And a list of plants that are complement inhibitors (some of which are recommeded for the treatment of Alzheimer's disease). 

 

http://www.hindawi.com/journals/cdi/2012/534291/tab2/ 

 

Ok, up to this point, I don't have to speculate.  Now I have to speculate.  Could amyloid actually be playing a positive role by binding to C1q and lessening its role in destroying neurons?  Could it be that people who are healthy but have significant amounts of amyloid in their brain have strong antioxidant systems in their bodies that reduce the oxidation and inflammation from various stressors (sugar, pollutants, etc.)?  In any case, amyloid does not seem to be signicantly correlated to cognitive decline if correlated at all. 

 

 

 

 

 

 


Serenoa
Posted: Saturday, August 24, 2013 7:47 AM
Joined: 4/24/2012
Posts: 484


OK, I'm starting to process all this new information and starting to make some new connections. But, all these recent leads seem to be taking us down several different paths. The question is will these new insights and clues leads us back to a workable hypothesis again. I wish I could add something meaningful to this discussion now but I think I have to let all these clues stew for a while in my brain, and keep reading. Thank you all so much for all the good information.

 

 


Lane Simonian
Posted: Saturday, August 24, 2013 11:23 AM
Joined: 12/12/2011
Posts: 4833


You are welcome, Serenoa.  My new working hypothesis is that peroxynitrites damage neurons and synaptic proteins and C3 finishes them off. 

 

http://www.ncbi.nlm.nih.gov/pubmed/16111817 

 

During development, brain cell connections (synapses) undergo remodeling as inactive or excess synapses are pruned and remaining synapses are strengthened. Later in life, during neurodegenerative diseases such as Alzheimer’s disease and glaucoma, synapses are lost as brain cells die. While we traditionally think of synaptic activities as neural processes, innate immune cells called microglia play a potentially significant role. Microglia are the only immune cells that reside in the brain,  The Boston researchers discovered that certain proteins (called C1q and C3) involved in immune system functions are found at synapses in both the developing and degenerating brain. They hypothesize that these proteins coat and tag certain synapses to be eaten (“phagocytosed”) by immune microglial cells.

 

http://www.dana.org/grants/imaging/detail.aspx?id=35086 

 

What I am not able to understand is what role amyloid plaques play in this.  By incorporating copper and zinc, amyloid would reduce the amount of superoxides converted to hydrogen peroxide so perhaps that increases the production of peroxynitrites (assuming that there is still some inducible nitric oxide left for them to combine with).  And does the C3 incorporation into plaques in any way limit their role in the death of neurons and synaptic proteins?  Does amyloid play both a positive and negative role in Alzheimer's disease?  The old thinking was C3 activation was neuroprotective because it helped remove the plaques but that does not seem to be the case.  So maybe amyloid plaques simply don't have much role in Alzheimer's disease (although it may take a few more drug trials to confirm that). 

 


Lane Simonian
Posted: Saturday, August 24, 2013 10:28 PM
Joined: 12/12/2011
Posts: 4833


This may be part of the explanation for why amyloid could help those with multiple sclerosis: 

 

1995;426(6):603-10.

Complement activation in amyloid plaques in Alzheimer's disease brains does not proceed further than C3.

Source

Department of Neuropathology, Free University Hospital, Amsterdam, The Netherlands.

Abstract

In Alzheimer's disease (AD) patients, the complement components Clq, C4 and C3 can be detected in different types of beta/A4 plaques, one of the hallmarks of AD. Contradictory findings on the presence of late complement components in AD brains have been reported. Nevertheless, it was suggested in recent studies that in AD brain complement activation results in complement membrane attack complex (MAC) formation and that complement activation may act as an intermediate between beta/A4 deposits and the neurotoxicity observed in AD. In the present study the presence of a number of complement components and regulatory proteins in AD temporal cortex and, for comparison, in glomerulonephritis (GN) was analysed. In GN kidneys, besides Clq, Clr, Cls and C3, the late components and the C5b-9 complex are also associated with capillary basement membrane and mesangial immune complex deposits. In AD temporal cortex Clq, C4 and C3 are co-localized with beta/A4 deposits. However, in contrast to the GN kidney, the late complement components C5, C7 and C9, as well as the C5b-9 membrane attack complex cannot be detected in beta/A4 positive plaques. The absence of the cytolytic C5b-9 complex in AD brain suggests that in AD, the complement MAC does not function as the proposed inflammatory mediator between beta/A4 deposits and the neurofibrillary changes.

 

 

http://www.ncbi.nlm.nih.gov/pubmed/7655742 

 

In this paper we review evidence from pathological, animal model and human functional and genetic studies, implicating activation of complement in MS...

Complement plays a central role in the innate immune system, providing an important defence against infection and immune complex disease. The system consists of approximately 30 circulating and membrane expressed proteins which collaborate to provide protection from infection [,]. The physiological actions of C are mediated through production of opsonins (molecules that enhance the ability of macrophages and neutrophils with C receptors to phagocytose material – C3b, iC3b, C4b, etc.), anaphylatoxins (peptides that induce local and systemic inflammatory responses, increasing the permeability of blood vessels and attracting neutrophils through their chemotactic properties – C3a, C4a and C5a) and through direct killing of organisms by the terminal complement complex (TCC/C5b–9) which disrupts and forms pores in the phospholipid bilayer of a target cell. Although the C components in plasma are synthesized mainly by hepatocytes in the liver, within the CNS it is clear that glial cells and neurones can produce the majority of C proteins and expression is increased in response to inflammation [].

 

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2675242/ 

 

http://med.stanford.edu/ism/2013/april/a-beta.html 

 

There are some contradictory reports of C9 being present in some plaques, so even here plaques may not be all good or all bad.  However, it is likely that most of the C9 activity occurs outside of plaques and that it is in part a function of peroxynitrite formation. 

 

 


Lane Simonian
Posted: Saturday, August 24, 2013 10:34 PM
Joined: 12/12/2011
Posts: 4833


This may be the diagram and caption that explains Alzheimer's disease and other neurodegenerative diseases. 

 

 

FIGURE 6 | Pathophysiological triggers of poly(ADP-ribose) polymerase (PARP) activation and interacting pathways of injury.

 

From the following article:

Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors 

Prakash Jagtap & Csaba Szabó

Nature Reviews Drug Discovery 4, 421-440 (May 2005) 

doi:10.1038/nrd1718 

 

 

Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors 

 

The reduction of oxygen supply during ischaemia alters mitochondrial function, which leads to the production of reactive oxidant species. In heart failure, cardiotoxic drugs or inefficient working of the heart leads to the production of oxidants and free radicals from various sources (such as the mitochondria, xanthine oxidase or NADPH oxidase). During stroke, oxidant and free-radical generation is triggered primarily by N-methyl-D-aspartate (NMDA)-receptor activation. In inflammatory states, various pro-inflammatory pathways are stimulated in response to autoimmune responses and/or pro-inflammatory microbial components. The corresponding isoforms of nitric oxide synthase (NOS; brain NOS in the central nervous system, endothelial NOS in the cardiovascular system and inducible NOS under inflammatory conditions) produce NO (but under conditions of L-arginine depletion NOS can also produce superoxide). Under low pH conditions (such as tissue hypoxia/acidosis), nitrite can also be converted to NO. Superoxide (which is produced from various cellular sources, including mitochondria) and NO react to yield peroxynitrite. Peroxynitrite and hydroxyl radical induce single-strand breaks in DNA, which, in turn, activate PARP. This rapidly depletes the cellular NAD+ and ATP pools. Cellular energy exhaustion triggers the further production of reactive oxidants. Depletion of NAD+ and ATP leads to cellular dysfunction. Depletion of NADPH leads to reduced endothelial NO formation (endothelial dysfunction). The cellular dysfunction is further enhanced by the promotion of pro-inflammatory gene expression by PARP, through the promotion of nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP1) and mitogen-activated protein (MAP) kinase activation. PARP can also promote complement activation. The oxidant-induced pro-inflammatory molecule and adhesion-molecule expression, along with the endothelial dysfunction, induce neutrophil recruitment and activation, which initiates positive-feedback cycles of oxidant generation, PARP activation and cellular injury. For instance, tissue-infiltrating mononuclear cells produce additional oxidants and free radicals. PARP is also involved in triggering the release of mitochondrial cell-death factors, such as apoptosis-inducing factor (AIF). There are many oxidative and nitrosative injury pathways that are triggered by oxygen- and nitrogen-centred oxidants and free radicals, which act in parallel or in synergy with PARP-mediated pathways of cell injury. The relative contribution of cell necrosis versus inflammatory cell injury, as well as the relative role of the various pathways shown in the figure, depends on the specific pathophysiological conditions in question.

 

This just about ties everything together. 


Lane Simonian
Posted: Monday, August 26, 2013 10:17 AM
Joined: 12/12/2011
Posts: 4833


This is starting to make some sense.  The complement membrane attack complex (the last stages in the complement system pathway) not only tags certain injured and dying cells for elimination (by phagocytes), it also pokes holes in cell membranes.  This may explain why amyloid plaques begin within cells and ends up outside of cells. 

 

 

The presence of the membrane attack complex in people with Alzheimer's disease seems to be highly variable although somewhat localized. 

 

http://www.ncbi.nlm.nih.gov/pubmed/8062101 

 

A few but not all amyloid plaques appear to play a role in this process.  The ones that do may contribute to neurodegeneration; those that don't are in a way neuroprotective. 

 

The role of peroxynitrites in this process is also variable.  By upregulating PARP (poly ribose adp polymerase), peroxynitrites contribute to the depletion of cellular injury and these wounded neurons and other brain cells are targets of the complement membrane attack complex.  However by nitrating binding sites for early complements (C1q and C3) on immunoglobulin peroxynitrites inhibit the activation of the complement system pathway.  So what you end up with is a partially constrained inflammatory process rather than a full blown inflammatory process. 

 

 

Through the complement system, immunglobulin may help remove amyloid plaques including some of those involved in the membrane attack complex, but it may also to a certain degree increase the complement membrane attack complex. 

 

http://www.ncbi.nlm.nih.gov/pubmed/16003929 

 

Ironically, in the case of multiple sclerosis activation of part of the complement system is neuroprotective via the phosphatiylinositol 3 kinase/Akt pathway but this pathway is blocked in Alzheimer's disease. 

 

http://www.jimmunol.org/content/176/5/3173.full.pdf 

 

Interesting, some of the same compounds which scavenge peroxynitrites also inhibit the complement membrane attack complex. 

A natural scavenger of peroxynitrites, rosmarinic acid, protects against impairment of memory induced by Abeta(25-35).

http://www.ncbi.nlm.nih.gov/pubmed/17420060 

 

Inhibition of complement by covalent attachment of rosmarinic acid to activated C3b.

 http://www.researchgate.net/publication/12946178_Inhibition_of_complement_by_covalent_attachment_of_rosmarinic_acid_to_activated_C3b?citationList=incoming 

 

A variety of phenolic compounds inhibit the death of neurons both by scavenging peroxynitrites and inhibiting the development of the complement membrane attack complex. 


Lane Simonian
Posted: Monday, August 26, 2013 3:10 PM
Joined: 12/12/2011
Posts: 4833


This is a fairly concise summary of "plaque complement and cognitive loss in Alzheimer's disease." I have not seen many more recent studies, so the exact role of this inflammatory process in Alzheimer's disease may take some more time to unravel. 

 

http://www.medscape.com/viewarticle/581465 


Cindy322
Posted: Monday, August 26, 2013 3:13 PM
Joined: 8/6/2012
Posts: 8


I'm new to this...and totally lost!  My husband is on Exelon and Namenda.  I hope they are helping but I truly have no idea if they are - or not?  For all of the seemingly great information on this page...is any of it something that will help my husband now...or is this something that will help future generations?
Serenoa
Posted: Monday, August 26, 2013 9:19 PM
Joined: 4/24/2012
Posts: 484


Yes, there are things out there that can help now. It's good you are doing the research. Knowledge is power. There is no miracle cure here yet but there are drugs currently available to treat other diseases being tested for Alzheimer's. If they work you can get them prescribed off label before FDA approval. But, there are many other things that will help that we discuss all the time here.
Lane Simonian
Posted: Monday, August 26, 2013 9:58 PM
Joined: 12/12/2011
Posts: 4833


I agree with Serenoa, there are treatments available now that help with Alzheimer's disease and likely other treatments that will be available in the near future. 

 

You probably read these on the coconut oil post but here are the results of various compounds from natural products that have been effective in small-scale clinical trials. 

 

Eugenol in rosemary essential oil, geraniol in lemon essential oil, and lavender and orange to offset the stimulating effects of eugenol and geraniol via aromatherapy. 

 

Results: All patients showed significant improvement in personal orientation related to cognitive function on both the GBSS-J and TDAS after therapy. In particular, patients with AD showed significant improvement in total TDAS scores. Result of routine laboratory tests showed no significant changes, suggesting that there were no side-effects associated with the use of aromatherapy. Results from Zarit's score showed no significant changes, suggesting that caregivers had no effect on the improved patient scores seen in the other tests.

 

Conclusions: In conclusion, we found aromatherapy an efficacious non-pharmacological therapy for dementia. Aromatherapy may have some potential for improving cognitive function, especially in AD patients.

 

http://onlinelibrary.wiley.com/doi/10.1111/j.1479-8301.2009.00299.x/full 

 

Eugenol and ferulic acid in lemon balm (Melissa officinalis) via tincture.  Aromatherapy is likely just as effective and safer than a tincture.  Lemon balm essential oil, though, is quite expensive.  It should not be used in conjunction with anti-anxiety medications (too much sedation). 

 

RESULTS:

At four months, Melissa officinalis extract produced a significantly better outcome on cognitive function than placebo (ADAS-cog: df = 1, F = 6.93, p = 0.01; CDR: df = 1, F = 16.87, p < 0.0001). There were no significant differences in the two groups in terms of observed side effects except agitation, which was more common in the placebo group (p = 0.03).

CONCLUSIONS:

Melissa officinalis extract is of value in the management of mild to moderate Alzheimer's disease and has a positive effect on agitation in such patients.

 

http://www.ncbi.nlm.nih.gov/pubmed/12810768 

 

Ferulic acid, vanillic acid, and syringic acid in heat-processed ginseng.  Heat-processed ginseng is the result of a complicated process of steaming and the use of dry heat (and it is very expensive about $700  for a month's supply), but steaming white (Asian panax) ginseng for about three to four hours produces a similar concentration of compounds. 

 
 

RESULTS:

The treatment groups showed significant improvement on the MMSE and ADAS. Patients with higher dose group (4.5 g/day) showed improvements in ADAS cognitive, ADAS non-cognitive, and MMSE score as early as at 12 weeks, which sustained for 24-week follow-up.

DISCUSSION:

These results demonstrate the potential efficacy of a heat-processed form of ginseng on cognitive function and behavioral symptoms in patients with moderately severe AD.

 

 

http://www.ncbi.nlm.nih.gov/pubmed/22780999 

 

There are many other things that can help including various spices (curcumin in turmeric, ginger, garlic), a Mediterranean diet, exercise, pet therapy, music, art, gardens, social interactions to name just a few. 


Lane Simonian
Posted: Monday, August 26, 2013 11:48 PM
Joined: 12/12/2011
Posts: 4833


This writer adds some more insight as to the role of amyloid in Alzheimer's disease.  The almost inescapable conclusion is that amyloid is not required for Alzheimer's disease.  Amyloid without peroxynitrites is not a problem;  and amyloid is only a minor contributor to peroxynitrite formation in the context of Alzheimer's disease.

 

Alzheimer's: Still Barking Up the Wrong Tree?

 

I was intrigued, and a bit alarmed, by a study in this month’s . The study used an imaging agent called Pittsburgh Compound B (so-named because it was discovered at the University of Pittsburgh; it detects brain deposits ) to examine the brains of 43 people, age 65 to 88, who had neither Alzheimer’s disease nor mild cognitive impairment. Of the 43, 9 showed evidence of these brain deposits, called amyloid plaques, in at least one brain area.

 

Uh oh, you might think. But think again. Here is what caught my attention in the paper describing the study: “Neurocognitive performance was not significantly worse among amyloid-positive compared with amyloid-negative participants. . . . [A]myloid deposition was not associated with worse cognitive function, suggesting that an elderly person with a significant amyloid burden can remain cognitively normal.”

So here’s the reason for my alarm: since Pittsburgh Compound B has, since its discovery, been treated like the Second Coming, do we really want to screen people with this technique, telling them omigod you have amyloid plaques—when the cause-and-effect link between the plaques and Alzheimer’s is, shall we say, on shaky ground? Or as the scientists, led by Howard Jay Aizenstein and William E. Klunk of the University of Pittsburgh School of Medicine, write, we’ll need more research to figure out whether “amyloid deposition is not sufficient to cause Alzheimer disease.”

 

The amyloid hypothesis of Alzheimer’s disease has had the field in a stranglehold for decades, as I’ve written about before. In 2006, for instance, Zaven Khachaturian, who oversaw Alzheimer’s funding at the National Institute on Aging from 1977 to 1995, told me that the theory that amyloid plaques cause AD has become a pernicious “orthodoxy,” and that “having one view prevail is harmful; it becomes a belief system, not science.” And Robert Mahley, president of the J. David Gladstone Institutes, San Francisco, told me that “where the field made its mistake was in trying to make everything fit one common [amyloid] pathway. We’ve got to realize there are multiple ways you can wind up with [Alzheimer’s].”

 

They, and others, are most upset about what the amyloid orthodoxy has meant for basic research--namely, that scientists with other ideas struggled to get funded. As a result, alternatives have hardly been pursued, and we are no closer to treating, let alone preventing or curing, AD than we were 25 years ago. That’s a tragedy, and perhaps a crime.

 

But what will the amyloid orthodoxy mean for patients? If it is moved into the clinic with the use of Pittsburgh Compound B, and healthy adults are screened for amyloid plaques with this technique, we'll face a problem just as serious as focusing on a single theory of AD. Doctors will identify these brain deposits in millions of people, and scare them out of their wits by telling them that they have what looks like the cause of a terrifying disease—when the whole idea that the plaques cause AD may be wrong?

 

Klunk put it this way: “The good news is it appears the brain can tolerate these plaques for years before the effects are apparent. The bad news is that by the time the symptoms emerge, the disease has had perhaps a 10-year head start. We suspect that people with amyloid deposits and normal brain functioning have a high risk of developing Alzheimer’s disease in the future, but we do not yet have proof of this.” No kidding.

 

http://www.sharonlbegley.com/alzheimer-s-still-barking-up-the-wrong-tree 

 


Vita99
Posted: Tuesday, August 27, 2013 6:15 AM
Joined: 9/4/2012
Posts: 469


This thread gets more interesting every day.  My aromatherapy is not going very well.  I must find a different way of doing it. I am using too much oil.  In the Japanese study ( Lane's last link) they used lemon oil and rosemary.  I have not seen lemon oil used before, only lemon balm.  Lemon essentials oil is another one that is easy to find and inexpensive.
Lane Simonian
Posted: Tuesday, August 27, 2013 10:08 AM
Joined: 12/12/2011
Posts: 4833


I did not think of the evaporation problem, but I should have as the advice is to always put the cap back on the essential oil bottles after using.  Essential oils should also be kept out of direct sunlight. 

 

I am beginning to think that direct inhalation may be even better than a diffuser because more of the essential oil gets directly to the brain that way and you don't need much of the essential oil to get to the brain.  Either, though, should lead to positive results in most cases. 

 

I am not sure how close scopolamine-induced dementia is to real dementia but here are two interesting studies regarding lemon essential oil and lavender essential oil in helping to reverse scopolamine-induced dementia. 

 

http://www.ncbi.nlm.nih.gov/pubmed/19356307 

 

http://www.ncbi.nlm.nih.gov/pubmed/23351960 

 

Jimbo and colleagues chose good essential oils for their clinical trial on aromatherapy for dementia. 


Vita99
Posted: Friday, August 30, 2013 7:38 AM
Joined: 9/4/2012
Posts: 469


Hi Lane.  I tried smelling the oils directly from the bottle and did not get the pleasant aroma such as I did get from a wide mouth cup.  Of course the effectiveness may have been as much from the bottle as from the cup. I am still experimenting.
Lane Simonian
Posted: Friday, August 30, 2013 5:34 PM
Joined: 12/12/2011
Posts: 4833


My dear mother used to sometimes say after sniffing the essential oil directly from the bottle, "That almost knocked me out."  Admittedly it can be a strong and not always a pleasant smell.  There is no blueprint for how to do this so keep experimenting.  In a way everyone who tries this now is providing a blueprint for those who try it later.