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Amyloid Plaques do not cause Alzheimer's disease
Lane Simonian
Posted: Sunday, May 7, 2017 9:19 AM
Joined: 12/12/2011
Posts: 4984

Amyloid plaques are a reflection of oxidative stress not its cause.  Individuals exposed to high levels of oxidative stress over a relatively short-term have plaques within their brains but not Alzheimer's disease (children exposed to high levels of pollution in Mexico City). Individuals exposed to oxidative stress throughout their life-times but have kept that stress checked through diet and exercise (the nuns in the nun study) have plaques in their brain but do not have Alzheimer's disease.

Amyloid oligomers contribute to Alzheimer's disease through the activation of protein kinase C alpha but they are one of dozens of factors that do so (others include high glucose levels, nicotine, mercury, various pesticides, air pollutants, Down syndrome, overuse of acetaminophen, various industrial solvents, and psychological stress).

"Malinow’s team found that when mice are missing the PKC alpha gene, neurons functioned normally, even when amyloid beta was present. Then, when they restored PKC alpha, amyloid beta once again impaired neuronal function. In other words, amyloid beta doesn’t inhibit brain function unless PKC alpha is active."


If you remove amyloid beta, you remove only once source that activates protein kinase C alpha.  This explains why drugs that remove amyloid beta only appear to slightly slow down the progression of Alzheimer's disease early on.  At this stage one would be better off inhibiting protein kinase C alpha activity (one possible candidate is riluzole).

Due to oxidation, protein kinase C activity declines.  So removing amyloid beta after the early stages of the disease does not good at all.

The key to the progression of the disease can be found in the attached chart.

Protein kinase C activation leads to the activation of NMDA receptors and NMDA receptors lead to the formation of peroxynitrite (ONOO- in chart).  Peroxynitrite inhibits the transport and removal of glutamate which ensure perpetual NMDA receptor activation and the continual production of peroxynitrite.  Peroxynitrite and caspase-3 kill neurons, and peroxynitrite through oxidation and nitration inhibit neurotransmissions, limit the synthesis and release of neurotransmitters needed for the retrieval of short-term memory, sleep, balanced mood, social recognition, and alertness, and prevent the regeneration of neurons.

The following is the key to treating Alzheimer's disease.

Mechanism of Oxidative Stress and Synapse Dysfunction in the Pathogenesis of Alzheimer’s Disease: Understanding the Therapeutics Strategies

We suggest that oxidative stress mediated through NMDAR and their interaction with other molecules might be a driving force for tau hyperphosphorylation and synapse dysfunction. Thus, understanding the oxidative stress mechanism and degenerating synapses is crucial for the development of therapeutic strategies designed to prevent AD pathogenesis.

In conclusion, through this review, we have tried to give our perspective on the wide variety of interaction between NMDAR-mediated oxidative stresses with the etiology of Alzheimer’s disease. NMDAR-mediated oxidative stress mechanisms are likely to play an important role in the synapse dysfunction in the pathogenesis of AD. Moreover, mitochondrial-mediated oxidative stress and apoptosis are also suggested to be contributing factors in AD pathogenesis. Furthermore, oxidative stress-mediated kinase and tau phosphorylation provides a connection of synapse dysfunction in AD. As we are not getting complete remedies from antioxidant therapy or known NMDAR antagonist drug used for AD pathology, should we go for combinational therapy? Or are there so many intermediate molecules between NMDAR to neurodegeneration? Should we go for target intermediate molecules? Therefore, understanding the role of oxidative stress-associated molecule and kinases in synapse dysfunction during AD pathogenesis may also lead to the development of mechanism-based therapeutics and better constructive strategies.

Namenda/memantine is not a particularly good NMDA receptor antagonist.  Its inventor, Stuart Lipton, is now working on another NMDA receptor antagonist--nitro-memantine.  Anavex is working on a drug that blocks an intermediate molecule (neuronal nitric oxide synthase) and at 41 weeks in a small trial saw some initial improvements occurred that were maintained.  The peroxynitrite scavenger Korean red ginseng lead to improvements at 24 weeks that were sustained for two years. Maybe better treatments based on understanding the pathways that lead to Alzheimer's disease and its progression will be forthcoming.

Lane Simonian
Posted: Saturday, October 14, 2017 10:32 AM
Joined: 12/12/2011
Posts: 4984

The amyloid precursor protein and amyloid oligomers stimulate g protein-coupled receptors (which leads to the activation of protein kinase C, NMDA receptors, and the formation of peroxynitrite), but amyloid plaques do not.  The question of why this is the case has puzzled me, but this may be the answer why.  The amyloid precursor protein and amyloid oligomers attract zinc, but amyloid plaques entomb zinc, and it appears that zinc is what stimulates a particular g protein-coupled receptor:

G-Protein Coupled Receptor 83 (GPR83) Signaling Determined by Constitutive and Zinc(II)-Induced Activity

memory and inflammatory conditions (GPR83)

Excessive amounts of the amyloid precursor protein due to a genetic mutation always leads to Alzheimer's disease because it overactivates GPR83 but the age of onset varies.  Other factors such as mercury exposure, pesticide exposure, or high intake of high fructose corn syrup activates other g protein-coupled receptors and thus can lead to earlier onset of Alzheimer's disease.

Amyloid oligomers are a product of oxidative stress and early in Alzheimer's disease they also contribute to that stress.  That stress, too, is caused by many different factors so removing amyloid oligomers may delay the onset of the disease and slightly slow down its early progression, but no more than that.

Amyloid plaques do not activate g protein-coupled receptors and therefore are no factor in Alzheimer's disease.

To sum up more than 25 years focusing on preventing the formation and removing amyloid beta for the treatment of Alzheimer's disease has largely been wasted.

Lane Simonian
Posted: Saturday, October 14, 2017 10:45 AM
Joined: 12/12/2011
Posts: 4984

An additional clue:

A role for GPR83, a newly deorphanized G protein-coupled receptor, in stress-induced neuroimmune modulation


GPR83 is a recently deorphanized G-protein coupled receptor (GPCR) found to be widely expressed throughout the brain and immune system of mice. Analysis of expression reveals high levels in discrete brain regions, such as nucleus accumbens, hypothalamus, amygdala and hippocampus, regions known to be involved in stress modulation, anxiety, depression, and memory. Previous studies have reported that GPR83 is regulated by the stress hormone corticosterone and that GPR83 knockout mice are resistant to stress-induced anxiety, despite having similar increases in plasma corticosterone as wild type mice.

In part this may explain why psychological stress increases the risk for Alzheimer's disease.  In mice designed to have an Alzheimer's-like disease, the forced production of amyloid and stress are two factors that can lead to memory impairment, but in humans multiple factors can induce Alzheimer's disease.

Lane Simonian
Posted: Sunday, October 15, 2017 5:11 PM
Joined: 12/12/2011
Posts: 4984

Amyloid oligomers by attracting zine appear to increase oxidative stress through more than one type of g protein-coupled receptor:

Amyloid-β Induces Chemotaxis and Oxidant Stress by Acting at Formylpeptide Receptor 2, a G Protein-coupled Receptor Expressed in Phagocytes and Brain*

If you remove amyloid oligomers, you remove only one source  of oxidative stress, but if you prevent amyloid oligomers from causing oxidative stress they do no damage to the brain (via activation of g protein-coupled receptors and or receptor tyrosine kinases--protein kinase C alpha activation--NMDA receptor activation--peroxynitrite--caspase-3).

Malinow’s team found that when mice are missing the PKC alpha gene, neurons functioned normally, even when amyloid beta was present. Then, when they restored PKC alpha, amyloid beta once again impaired neuronal function. In other words, amyloid beta doesn’t inhibit brain function unless PKC alpha is active.

So to treat Alzheimer's disease early on, you have to remove all the factors causing oxidative stress, block the pathways by which these factors cause oxidative stress, and/or remove the oxidants (this is largely what the Bredesen protocol does via a healthy diet, antioxidant supplements, and ending exposure to environmental toxins).  As the disease progresses, removing the oxidants and reversing part of the damage they cause is what is likely needed (aromatherapy, panax ginseng, and CBD oil, for instance).

Posted: Monday, October 16, 2017 5:03 AM
Joined: 4/6/2014
Posts: 640

Lane, very interesting  to read .  My wife had a amyloid pet scan that shower no plaques.  Does mean that she does not have Alzheimer's  but some other type of dementia? She was diagnosed with Alzheimer's 4 years ago.

Keep It 100
Posted: Monday, October 16, 2017 7:29 AM
Joined: 2/26/2017
Posts: 583


Don, you may want to read this:

My husband has had an amyloid pet, but I haven't yet seen the results, and won't until his clinical trial ends. I am very curious. But he had a lumbar before the trial at another university, and the very low ABeta levels with very high tau levels in his CSF indicate that there are probably plenty of plaques and tangles to be found in there.....

My husband was always very healthy and athletic. His father did have alz at older age, as did one of his aunts, so I think there was always that genetic risk. However, his very young and aggressive onset is a mystery. When I met him nearly two decades ago, he was in the earlier stages of a very ugly divorce from a woman I can find no kinder words to use to describe her other than she is a true narcissistic psychopath. For many years I would lament that she is "killing him" with the stress she induced. Perhaps there is truly something to that?

Lane Simonian
Posted: Monday, October 16, 2017 10:24 AM
Joined: 12/12/2011
Posts: 4984

Donr, the cases in which a person would have diffuse plaques but not Alzheimer's disease are fairly common, but the cases in which one would have no plaques and have Alzheimer's disease are probably rare. It is probably more likely that your wife has another form of dementia.

Diffuse plaques are a sign of oxidative stress that has not progressed too far; dense core plaques are a sign of oxidative stress that is well advanced.  The later is well-correlated with Alzheimer's disease not because it is a cause of the disease but because it is a reflection of the disease (tyrosine nitration which causes the aggregation of plaques).

It appears that pet scans can tell the difference between the two types of plaques, so that there should now be fewer false positives with amyloid scans.  

I have been trying to think for awhile now where a person would have no plaques and still have Alzheimer's disease.  So far this is all I can come up with.  The first cut in the amyloid precursor protein requires the release of intracellular calcium, but several compounds such as caffeine and heparin can limit this release.  Intracellular calcium release also contributes to oxidative stress, but is not essential for it.  This might also explain PART(primary age related tauopathy) because intracellular calcium release contributes to the formation of tau tangles, but it is not essential for it either (tyrosine nitration also plays a role in misforming tau which inhibits neurotransmissions).  Maybe a doctor could determine whether it is Alzheimer's disease without plaques or another form of dementia.

I had forgotten about PART--the link was much appreciated.

Keep It 100, I am almost certain that stress is a risk factor for Alzheimer's disease.  Perhaps if you combine stress with the ApoE4 gene or some other risk factor such as a traumatic brain injury, it might help explain cases of early onset Alzheimer's disease that are not the result of determinant genes.

Best wishes to both of you and to your spouses.  I see bits of glimmer and hope in some of the non-amyloid clinical trials--maybe enough clues will be revealed from these trials to make further progress.

Posted: Monday, October 16, 2017 11:45 AM
Joined: 4/22/2017
Posts: 334


Dementia without plaques indicates your wife does not have Alzheimer's. The ongoing IDEAS study is finding that a large number of individuals diagnosed as having MCI or Alzheimer's have no plaques. Your wife's physician needs to dig a little deeper for a proper diagnosis.

Lane Simonian
Posted: Monday, October 16, 2017 3:41 PM
Joined: 12/12/2011
Posts: 4984

It is good to have discussions on this forum.

The title of the article Keep It 100 linked to is:

P.A.R.T. Dementia is Alzheimer's without the Plaque

 And from another article:

Alzheimer’s Disease Without Amyloid Plaques

 in medicinebiology

Amyloid plaques have long been thought to be the cause of neuron loss in Alzheimer’s disease.  Now researchers report that excess of mutated amyloid precursor protein (APP) inside the neurons is sufficient to induce neuron death.  The report challenges the notion that amyloid deposits outside of the cells are necessary for neuron death in Alzheimer’s disease.

Different forms of amyloid can contribute to neuronal cell death and to the formation of tau tangles but amyloid beta is not required for either.  Without oxidative stress, amyloid does no damage to the brain.  Prevent, limit, and reverse part of the damage that oxidation and nitration do to the brain and you are well on your way to solving the disease:

Several lines of evidence suggest that the balance between ROS (reactive oxygen species) and antioxidant defenses is particularly fragile in brain neurons. More importantly, perturbations of this delicate equilibrium are suspected to play a crucial role in many neurodegenerative diseases, first in Alzheimer’s disease and more recently in other tauopathies. 

The hippocampi – the brain centres for learning and memory – are one of the earliest regions to be sabotaged by Alzheimer’s pathology. Our data revealed that GSH [the antioxiodant glutathione] levels plummet in the hippocampi of patients with Alzheimer’s as well as those with MCI. The frontal cortices – brain CEOs responsible for a variety of executive functions – are chronologically affected later in Alzheimer’s. GSH levels mimic this chronology with no changes in the cortices of MCI patients, but significant reduction in those of Alzheimer’s patients. Interestingly, GSH remains unaffected in the cerebellum – a brain region unaffected by Alzheimer’s till late stages. It appears GSH decline is not ubiquitous but rather a region-specific phenomenon that appears to precisely map the progression of Alzheimer’s in our brains.

We suggest that oxidative stress mediated through NMDAR and their interaction with other molecules might be a driving force for tau hyperphosphorylation and synapse dysfunction. Thus, understanding the oxidative stress mechanism and degenerating synapses is crucial for the development of therapeutic strategies designed to prevent AD pathogenesis.

Clinical trials with over-the-counter supplements have concentrated on items which suppress inflammation, or on antioxidants which scavenge oxygen derived free radicals.  Most of these have proved to be worthless in the treatment of Alzheimer's disease.  Similarly most drugs used to treat Alzheimer's disease do little to slow down the deterioration, but instead offer a mild temporary symptom relief.  However, evidence has been accumulation that the primary driver of Alzheimer's disease is a nitrogen derived free radical called peroxynitrite, which may mediate both amyloid and tau accumulation as well as their toxicity.  Excellent results have been obtained with peroxynitrite scavengers, with reversals of Alzheimer's disease in human clinical trials being repeatedly demonstrated...