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amyloid oligomers and zinc
Lane Simonian
Posted: Wednesday, August 19, 2015 11:00 AM
Joined: 12/12/2011
Posts: 4845


The role of amyloid oligomers and zinc in Alzheimer's disease has always puzzled me. It appears, though, that zinc can attract oligomers to NMDA receptors and that zinc phosphorylation of NMDA receptors activates these receptors leading to calcium influx, peroxynitrite formation, and the death of neurons.

2009 Apr 1;29(13):4004-15. doi: 10.1523/JNEUROSCI.5980-08.2009.

A role for synaptic zinc in activity-dependent Abeta oligomer formation and accumulation at excitatory synapses.


http://www.ncbi.nlm.nih.gov/pubmed/19339596

The release of intracellular zinc by peroxynitrites leads to the further activation of NMDA receptors.

2004 Nov 24;24(47):10616-27.

Peroxynitrite-induced neuronal apoptosis is mediated by intracellular zinc release and 12-lipoxygenase activation.


http://www.ncbi.nlm.nih.gov/pubmed/15564577

Eugenol in various essential oils via aromatherapy inhibits tyrosine phosphorylation and activation of NMDA receptors and scavenges peroxynitrites, thus stopping the death of neurons. Ferulic acid in Korean red ginseng does the same. And so far aromatherapy and Korean red ginseng are the only two substances that have partially reversed Alzheimer's disease.



Lane Simonian
Posted: Friday, August 21, 2015 9:39 AM
Joined: 12/12/2011
Posts: 4845


One of the keys to Alzheimer's disease is the peroxynitrite-mediated tyrosine nitration of NMDA receptors--this is what allows the disease to progress even when other pathways that initially triggered the disease are cut off.

Peroxynitrite interacts with the NMDA receptor leading to nitration of the tyrosine residues present on the NMDA receptor subunits. This nitration is an irreversible reaction that leads to a constant potentiation of synaptic currents, calcium influx, and ultimately excitotoxicity [97;98; 99]. [the reaction may actually be reversible].

I can now make this point with almost absolute certainty, if you scavenge peroxynitrites and in the process inhibit NMDA receptor activation, you effectively treat Alzheimer's disease.

Eugenol in rosemary and other essential oils (lemon balm bay laurel, clove, etc.) via aromatherapy.

Neurosci Lett. 1997 Apr 4;225(2):93-6.

Eugenol protects neuronal cells from excitotoxic and oxidative injury in primary cortical cultures.


http://www.ncbi.nlm.nih.gov/pubmed/9147382

In Vitro Activity of the Essential Oil of Cinnamomum zeylanicum and Eugenol in Peroxynitrite-Induced Oxidative Processes


http://pubs.acs.org/doi/abs/10.1021/jf050183e?journalCode=jafcau

Effect of aromatherapy on patients with Alzheimer's disease

Methods:  After a control period of 28 days, aromatherapy was performed over the following 28 days, with a wash out period of another 28 days. Aromatherapy consisted of the use of rosemary and lemon essential oils in the morning, and lavender and orange in the evening.

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

Korean Red Ginseng Extract Inhibits Excitotoxic and Aβ-induced Apoptotic Cell Death in the Cultured Neurons


http://www.ncbi.nlm.nih.gov/pubmed/24882407

Improvement of Cognitive Deficit in Alzheimer’s Disease Patients by Long Term Treatment with Korean Red Ginseng
A 24-week randomized open-label study with Korean red ginseng (KRG) showed cognitive benefits in patients with Alzheimer’s disease. To further determine long-term effect of KRG, the subjects were recruited to be followed up to 2 yr. Cognitive function was evaluated every 12 wk using the Alzheimer’s Disease Assessment Scale (ADAS) and the Korean version of the Mini Mental Status Examination (K-MMSE) with the maintaining dose of 4.5 g or 9.0 g KRG per d. At 24 wk, there had been a significant improvement in KRG-treated groups. In the long-term evaluation of the efficacy of KRG after 24 wk, the improved MMSE score remained without significant decline at the 48th and 96th wk. ADAS-cog showed similar findings. Maximum improvement was found around week 24. In conclusion, the effect of KRG on cognitive functions was sustained for 2 yr follow-up, indicating feasible efficacies of long-term follow-up for Alzheimer’s disease.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659550/

Evaluation of the peroxynitrite scavenging activity of heat-processed ginseng [heat processed ginseng is Korean red ginseng steamed at a higher temperature]


To ascertain the principal active peroxynitrite (ONOO(-)) scavenging components of heat-processed Panax ginseng C.A. Meyer (sun ginseng [SG]), the ONOO(-) scavenging activities of fractions and components of SG were compared. The results demonstrated that the ONOO(-) scavenging ability of SG was due to its ether fraction containing phenolic compounds. High-performance liquid chromatography analysis and ONOO(-) scavenging activity tests of the phenolic acids contained in SG identified vanillic acid, ferulic acid, p-coumaric acid, syringic acid, and maltol as the main active ONOO(-) scavenging components of SG. The ONOO(-) scavenging activities of phenolic acids and maltol were dependent on the degrees of their proton donating ability.

Heat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer's disease.


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


Potent protection of ferulic acid against excitotoxic effects of maternal intragastric administration of monosodium glutamate at a late stage of pregnancy on developing mouse fetal brain.


Effect of ferulic acid and Angelica archangelica extract on behavioral and psychological symptoms of dementia in frontotemporal lobar degeneration and dementia with Lewy bodies.


Results: Treatment with Feru-guard led to decreased scores on the Neuropsychiatric Inventory in 19 of 20 patients and significantly decreased the score overall. The treatment also led to significantly reduced subscale scores on the Neuropsychiatric Inventory ("delusions", "hallucinations", "agitation/aggression", "anxiety", "apathy/indifference", "irritability/lability" and "aberrant behavior"). There were no adverse effects or significant changes in physical findings or laboratory data.

CONCLUSION:

Feru-guard may be effective and valuable for treating the behavioral and psychological symptoms of dementia in frontotemporal lobar degeneration and dementia with Lewy bodies.


Serenoa
Posted: Monday, August 24, 2015 6:05 AM
Joined: 4/24/2012
Posts: 484


Thank you for all the great info Lane. I like it when they describe specific pathway implications involved with the benefits of herbals/essential oils. This is from the Korean Red Ginseng article:

"KRG extract inhibited neuronal damage and generation of intracellular reactive oxygen species (ROS) induced by excitatory amino acids, such as glutamate and N-methyl-D-aspartate (NMDA), or by Aβ(25-35). To elucidate possible mechanism(s) by which KRG extract exerts neuroprotective action, its effects on apoptosis and apoptosis-related signaling molecules in neurons were assessed. KRG extract markedly increased phosphorylation of Bad at Ser 112 and inhibited Bax expression and caspase 3 activity. It also inhibited DNA fragmentation induced by NMDA or Aβ(25-35). These results indicate that KRG extract protects cultured neurons from excitotoxicity and Aβ(25-35)-induced toxicity through inhibition of ROS generation and apoptotic cell death."

This has lead me to thinking more about antioxidants and the body's own endogenous antioxidant system and things like glutathione, glucosamine, phosphorylation, etc. As always, the complexity of these things is mind blowing.

Lane Simonian
Posted: Sunday, January 31, 2016 10:11 AM
Joined: 12/12/2011
Posts: 4845


A bit more on the role of copper and zinc, amyloid oligomers and plaques, and antioxidants in Alzheimer's disease.  Copper and zinc increase production of amyloid oligomers.

For instance, ionic zinc and copper are able to accelerate the aggregation of A and to promote its neurotoxic redox activity by induction of oxidative cross-linking of the peptide into stable oligomers [49].

The nitration of oligomers by peroxynitrite into plaques leads to the entombment of copper and zinc and stops the production of hydrogen peroxide.

Ultrastructural studies with both peptides revealed that structures resembling "soluble oligomers" or "protofibrils" were present during this early phase of hydrogen peroxide formation. Mature amyloid fibrils derived from Abeta-(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.

The plaques, however, do not stop the production of peroxynitrite so the disease continues to progress.

Here is some general information on antioxidants for Alzheimer's disease:

Is Modulation of Oxidative Stress an Answer? The State of the Art of Redox Therapeutic Actions in Neurodegenerative Diseases

Concerning redox homeostasis, several antioxidant strategies are under study and aim not only at reducing the deleterious activities of ROS, but also at promoting the regenerative capacity of the adult brain [46] (Table 1). These drugs have been experimented in rodent models of AD and include garlic extracts, curcumin, melatonin, resveratrol, Gingko biloba extracts, green tea, and vitamin C. Although the clinical value of these antioxidants for the prevention of AD is often elusive, some of these compounds can be recommended based upon epidemiological evidence and already known benefits for prevention of other pathologies [47, 48].

And more specifically for Korean red ginseng:

Ginseng is one of the most widely used herbal medicines in the world. It has been used in the treatment of various ailments and to boost immunity for centuries; especially in Asian countries. The most common ginseng variant in traditional herbal medicine is ginseng, which is made from the peeled and dried root of Panax Ginseng. Ginseng has been suggested as an effective treatment for a vast array of neurological disorders, including stroke and other acute and chronic neurodegenerative disorders. Ginseng’s neuroprotective effects are focused on the maintenance of homeostasis. This review involves a comprehensive literature search that highlights aspects of ginseng’s putative neuroprotective effectiveness, focusing on stroke. Attenuation of inflammation through inhibition of various proinflammatory mediators, along with suppression of oxidative stress by various mechanisms, including activation of the cytoprotective transcriptional factor Nrf2, which results in decrease in reactive oxygen species, could account for its neuroprotective efficacy...Thus, ginseng can support neuronal survival and further promote neuronal growth and differentiation, which plays an important role in the diminution of Alzheimer disease pathology. 

http://journal.frontiersin.org/article/10.3389/fncel.2014.00457/full