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A pathway to Alzheimer's disease
Lane Simonian
Posted: Monday, October 29, 2012 3:09 PM
Joined: 12/12/2011
Posts: 4813


I found this nifty pathway for Alzheimer's disease.   

 

   

 

The pathway to the center left is the one that likely leads to Alzheimer's disease.  The pathway to the right largely protects against Alzheimer's disease. 

 

The activation of protein kinase C by phospholipase C gamma and beta leads to the production of inducible nitric oxide and superoxide anions which combine to form the chief oxidant in Alzheimer's disease--peroxynitrites. 

 

The activation of protein kinase C leads to secretion of the amyloid precursor protein which is cleaved by a calcium dependent enzyme to form amyloid plaques. 

 

Amyloid plaques increase the production of peroxynitrites and peroxynitrites increase the formation of amyloid plaques, but it is possible to have plaques without peroxynitrites and peroxynitrites without plaques.  It is not the plaques per se but the peroxynitrites that are the likely cause of Alzheimer's disease. 

 

Phenolic compounds in various fruits, vegetables, spices, herbs, teas, cocao, and essential oils (among others) inhibit the activation of phospholipase C gamma and polyunsaturated fats inhibit the ability of phospholipase C gamma and beta to activate Protein kinase C and to increase intracellular calcium levels.  Thus a Mediterranean diet high in these components or the predominant diet in India likely reduces the risk for Alzheimer's disease (one study on the Mediterranean diet said that it reduced the risk of Alzheimer's disease by 38% and the incidence of Alzheimer's disease in rural India is one percent).   

 

Peroxynitrites oxidize (damage) receptors involved in short-term memory (muscarinic acetylcholine), alertness (dopamine), mood (serotonin and opioid), sleep (melatonin), social recognition (oxytocin), smell (olfactory), and brain growth (adrenergic).  Peroxynitrites also nitrate NMDA receptors leading to the efflux of glutamate and the influx of calcium which kills brain cells.  Phenols (particularly methoxyphenols  such as eugenol in clove, bay laurel, basil, nutmeg, rosemary, and cinnamon leaf essential oils and ferulic acid, coumaric acid, syringic acid, and vanillic acid in heat-processed ginseng) detoxity/scavenge and reverse part of the oxidative damage (and perhaps part of the nitration damage) done by peroxynitrites.  They can be used to help improve cogntive (and non-cognitve) function in people with Alzheimer's disease and perhaps in some other forms of dementia. 

 

The "pathway" to the prevention and treatment of Alzheimer's disease is probably right there at the top of this page.  Now we have to get someone to act upon it.     

 

 

 


Serenoa
Posted: Monday, October 29, 2012 10:26 PM
Joined: 4/24/2012
Posts: 484


Thank you very much for laying this out in such detail. I think you are definitely on to something. And I think the only people who can, as you say, "act upon it" are us. The research is there but the doctors don't care (until the FDA approves it). I know it's just the nature of the system, but it really does leave people like us to put it all together and hopefully find our own treatments based on all the good research that is taking place.
Lane Simonian
Posted: Monday, October 29, 2012 10:45 PM
Joined: 12/12/2011
Posts: 4813


I am very appreciative of your comments, Serenoa.  It is easier to understand the scientific pathway that leads to Alzheimer's disease than it is to find the human pathway to get it treated.  I have come to the conclusion that the effective treatment for Alzheimer's disease is going to be discovered (actually has already been discovered) by scientists working abroad, by forward looking administrators and nurses in care facilities, and by individuals.  Eventually the weight of evidence and experience may change the course of how we seek to treat Alzheimer's disease. 
Lane Simonian
Posted: Saturday, November 10, 2012 8:50 PM
Joined: 12/12/2011
Posts: 4813


Sometimes, I catch up with the science and sometimes the science catches up with me.  I have been looking for a few years now to support the contention that phospholipase C is at least initially involved in Alzheimer's disease and here finally it is for phospholipase C gamma: 

 

2012 Sep 18. pii: S2212-4926(12)00092-9. doi: 10.1016/j.jbior.2012.09.008. [Epub ahead of print]

Phospholipase C-γ1 involved in brain disorders.

Source

School of Nano-Bioscience and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea; Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.

Abstract

Phosphoinositide-specific phospholipase C-γ1 (PLC-γ1) is an important signaling regulator involved in various cellular processes. In brain, PLC-γ1 is highly expressed and participates in neuronal cell functions mediated by neurotrophins. Consistent with essential roles of PLC-γ1, it is involved in development of brain and synaptic transmission. Significantly, abnormal expression and activation of PLC-γ1 appears in various brain disorders such as epilepsy, depression, Huntington's disease and Alzheimer's disease. Thus, PLC-γ1 has been implicated in brain functions as well as related brain disorders. In this review, we discuss the roles of PLC-γ1 in neuronal functions and its pathological relevance to diverse brain diseases.

 

I am hoping some day soon, when I ask what more do I need to find the answer will be nothing.   

 

 


Lane Simonian
Posted: Friday, November 23, 2012 8:02 PM
Joined: 12/12/2011
Posts: 4813


Phospholipase C (gamma or beta) via protein kinase C leads to the formation of peroxynitrites which causes Alzheimer's disease.  Phospholipase C also leads to the formation of amyloid plaques because it triggers the release of intracellular calcium which stimulates an enzyme that cleaves the amyloid precursor protein into plaques. 

 

 

PLC-mediated hydrolysis of PtdIns(4,5)P2  [PIP2] promotes amyloidogenesis by stimulating γ-secretase activity and PtdIns(4,5)P2 has been shown to directly inhibit γ-secretase activity. 

 

http://www.nature.com/nrn/journal/v12/n5/fig_tab/nrn3012_F2.html 

 

Interesting, though, this process takes place in phospholipids with saturated fatty acids and not in phospholipids with unsaturated fatty acids.  This is likely why a diet high in polyunsaturated fats (such as fish low in mercury and various nuts) delays the onset of Alzheimer's disease.  Phenolic compounds inhibit the activation of phospholipase C gamma and the subsequent formation of peroxynitrites via phospholipase C gamma and beta. 

 

http://www.ncbi.nlm.nih.gov/pubmed/16266772   

 

 

Methoxyphenols (such as eugenol in various essential oils) scavenge peroxynitrites and repair part of the damage that they do to critical receptors and proteins in the brain.  In general this is the route to both the prevention and treatment of Alzheimer's disease. 

 


Lane Simonian
Posted: Friday, November 23, 2012 10:48 PM
Joined: 12/12/2011
Posts: 4813


One last piece of the puzzle.  The protein kinase C activation of MAPK leads to the formation of peroxynitrites. 

 

Our results suggest that activated p38 MAPK may serve as a potential signaling molecule in ONOO(-) generation through dual regulatory mechanisms, involving iNOS induction and NADPH oxidase activation.

 

http://www.ncbi.nlm.nih.gov/pubmed/18289732 

 

If you put myo-inositol above PIP2 (phoshatidylinositol 4,5 biphosphate) and peroxynitrites under MAPK in the chart at the beginning of this thread and the pathway to Alzheimer's disease is complete.  Anything that increases myo-inositol levels, increases phospholipase C gamma or beta activity, or inhibits the phosphatidylinositol-3 kinase increases the risk for Alzheimer's disease.  Anything that scavenges peroxynitrites and repairs part of their damage can effectively treat Alzheimer's disease.  We are almost there.  


Lane Simonian
Posted: Monday, February 4, 2013 11:19 AM
Joined: 12/12/2011
Posts: 4813


Phospholipase C is the enzyme which leads to high acetylcholinesterase activity early in Alzheimer's disease (and thus the symptomatic relief provided by acetylcholinesterases Aricept and Exelon early in the disease), and via the release of calcium stimulates the two enzymes responsible for the processing of amyloid plaques: BACE1 and y-secretase. 

 

Phenolic compounds will inhibit phospholipase C gamma and thus limit BACE1 and y-secretase activity and the subsequent formation of amyloid plaques. 

 

Inhibition of phospholipase C gamma 1 by the prenylated flavonoids from Sophora flavescens.

 

flavonoids from Sophora flavescens against BACE1 and cholinesterases.
 

http://www.unboundmedicine.com/medline/citation/9225612/Inhibition_of_phospholipase_C_gamma_1_by_the_prenylated_flavonoids_from_Sophora_flavescens_

 

http://scholar.qsensei.com/content/1v2nnk 

 

We show that activation of phospholipase C may affect APP processing by either of two pathways, one involving an increase in protein kinase C and the other an increase in cytoplasmic calcium levels. The effects of calcium on APP processing appear to be independent of protein kinase C activation. The observed effects of calcium on APP processing may be of therapeutic utility.

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC43811/ 

 

The phospholipase C triggered activation of BACE1 and y-secretase and the subsequent formation of amyloid plaques is one pathway that leads to the production of peroxynitrites.  The other is via phospholipase C, protein kinase C, and MAPK p38.  By inhibiting both pathways, phenolic compounds can almost certainly delay the onset of Alzheimer's disease especially when combined with polyunsaturated fats which inhibit the actions of both phospholipase C gamma and beta. 

 

While the free radical scavenging and antioxidant properties of phenolics are well established, emerging literature reports suggest that their chemopreventive effects may also be ascribed to their ability to modulate components of cell signaling pathways

 

signaling components including, MAPK, protein kinase C (PKC), phospholipase C-γ (PLC ...  

 

http://onlinelibrary.wiley.com/doi/10.1002/biof.5520270103/abstract 

 

Now if you use BACE-1 and y-secretase inhibitors or antibodies and vaccines against amyloid plaques you only treat one pathway to peroxynitrites and you do nothing to reverse the damage already done by peroxynitrites.  At the very best, you only slow down the progression of the disease.  But if you use peroxynitrite scavengers (which also inhibit the production and reverse part of the damage done by peroxynitrites) you not only stop the progression of Alzheimer's disease you partially reverse it, as all studies using peroxynitrite scavengers have shown. 


Lane Simonian
Posted: Tuesday, February 5, 2013 10:34 AM
Joined: 12/12/2011
Posts: 4813


This is close to it.  I am going to repost the chart from the top of the post, so that the following abstract makes a little more sense. 

 

      
   

In a previous report, we characterized several oxidative stress parameters during the course of amyloid beta (Aβ) peptide/Fe2+-induced apoptotic death in neuronal cells. In extending these findings, we now report a marked decrease in protein kinase C (PKC) isoforms, reduced Akt serine/threonine kinase activity, Bcl 2-associated death promoter (BAD) phosphorylation and enhanced p38 mitogen-activated protein kinase (MAPK) and caspase-9 and -3 activation, 12 h after addition of both 5 µm Aβ and 5 µm Fe2+. These activities reminiscent for a pro-apoptotic cellular course were blocked in the presence of the iron chelator deferroxamine. Aβ alone, increased PKC isoform levels between three- and four-fold after 12 h, enhanced Akt activity approximately eight-fold and Ser136 BAD phosphorylation two-fold, suggesting that by itself is not toxic. Fe2+ alone transiently enhanced p38 MAPK and caspase-9 and -3 enzymes indicative for cell damage, but was not sufficient to cause cell death as previously indicated. GF, a PKC inhibitor or wortmannin, a blocker of the Akt pathway enhanced Aβ/Fe2+-induced toxicity, while SB, a p38 MAPK inhibitor, prevented cell damage and apoptosis. These findings further support the hypothesis that metal ion chelation and inhibitors of pro-apoptotic kinase cascades may be beneficial for Alzheimer's disease therapy.

 

http://onlinelibrary.wiley.com/doi/10.1046/j.1471-4159.2003.01831.x/full 

 

The critical points are these.  

 

Amyloid plaques absent iron are not toxic. 

 

Amyloid plaques in associaton with iron are toxic. 

 

Iron ions stimulate p38MAPK (which increases the formation of peroxynitrites). 

 

The damage done by amyloid plaques combined with iron ions damages neurons but does not kill them. 

 

And then based on other studies. 

 

The PI3/Akt pathway is neruoprotective.  Anything that inhibits this pathway (presenilin gene mutations, the APOE4 gene, bisphosphonate osteoporosis drugs) leads to or increases the risk for Alzheimer's disease. 

 

Phospholipase C activity leads to the formation of amyloid plaques via the release of intracellular calcium.  Amyloid plaques in conjunction with iron ions lead to the activation of MAPK p38 and the formation of peoxynitrites. 

 

Phospholipase C activity also leads to the formation of peroxynitrites via protein kinase C alpha and MAPK p38. 

 

Anything that increases phospholipase C activity--high glucose levels, high blood pressure, mercury, aluminium fluoride, organophosphate pesticides, stress, chronic bacterial and viral infections, etc. increase the risk for Alzheimer's disease. 

 

Anything that decreases phospholipase C activity--including a Mediterranean diet or a diet from India high in phenolic compounds and polyunsaturated fats reduces the risk for Alzheimer's disease. 

 

Removing amyloid plaques and chelating metal ions does not stop the peroxynitrite-mediated killing of neurons.  It only slows it down because there is a non-amyloid pathway to the formation of peroxynitrites.  So the people who say amyloid plaques are the cause of Alzheimer's disease and those who say it has nothing to do with Alzheimer's disease are both half right. 

 

Use methoxyphenols to inhibit the formation of peroxynitries and scavenge peroxnitrite and you can treat Alzheimer's disease.  This includes the methoxyphenol eugenol in various essential oils (bay laurel, rosemary, clove, basil, nutmeg, for instance) and the methoxyphenols ferulic acid, vanillic acid, syringic acid, and coumaric acid in heat-processed ginseng. 

 

 


Lane Simonian
Posted: Sunday, March 3, 2013 8:38 PM
Joined: 12/12/2011
Posts: 4813


Closing in...Closing in.  Inhibit p38 MAPk and scavenge peroxynitrites and you not only prevent the future death of neurons you partially restore cognitive functions. 

 

 
Abstract:
Mammalian p38 mitogen-activated protein kinases (MAPKs) are activated by various cellular stresses, as well as in response to inflammatory cytokines. In the central nervous systems (CNS), activation of the p38 MAPK pathway constitutes a key step in the development of several diseases, and the molecular mechanisms mediated by p38 MAPK signaling have been defined. Activation of this cascade releases pro-inflammatory cytokines that are known to be involved in cerebral ischemia, Alzheimers disease (AD), Parkinsons disease (PD), multiple sclerosis (MS), neuropathic pain and depression. In AD, stimulated p38 MAPK may trigger the hyperphosphorylation of a neural microtubule-associated protein, tau. In addition, we have recently revealed that activation of p38 MAPK signaling decreases dendritic spine number, which may be associated with memory impairment after epileptic seizures. Thus, p38 MAPK can serve as a target for novel drug development for neural diseases. p38 MAPK inhibitors have been studied extensively in both preclinical experiments and clinical trials for inflammatory diseases. New p38 MAPK inhibitors are now being tested in phase II clinical trials for neuropathic pain and depression. Here, we review current and possible future applications of p38 MAPK inhibitors as therapeutic agents in neural diseases.
 
2013 Feb 1;70(1):116-125. doi: 10.1016/j.phrs.2013.01.007. [Epub ahead of print]

PI3 k/akt inhibition induces apoptosis through p38 activation in neurons.

Source

Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Centros de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Institut de Biomedicina (IBUB), Universitat de Barcelona,. Nucli Universitari de Pedralbes,. 08028 Barcelona, Spain.

Abstract

Accumulating evidence suggests that the PI3K/AKT pathway is a pro-survival signalling system in neurons. Therefore, the inhibition of this pathway may be implicated in the degeneration of neurons in Parkinson's disease (PD), Alzheimer's disease (AD), and other neurological disorders. Here we study the participation of the mitogen-activated protein kinase (MAPK) pathway on apoptosis induced by PI3K/AKT inhibition in cultured cerebellar granule cells (CGCs). LY294002, a specific PI3K/AKT inhibitor, selectively activated the p38 MAPK kinase pathway and enhanced c-Jun phosphorylation, but did not activate JNK. The pharmacological inhibitors SB203580 (p38 inhibitor) and SP600125 (a JNK inhibitor) protected primary cultures of rat CGCs from LY294002-induced apoptosis. Furthermore, both compounds decreased the phosphorylation of c-Jun and lowered mRNA levels of the pro-apoptotic gene dp5, a direct target of c-Jun. Taken together, our data demonstrate that PI3K/AKT inhibition induces neuronal apoptosis, a process that is mediated by the activation of p38 MAPK/c-Jun/dp5.

 

Once you know the pathway that leads to a disease it is much easier to figure out how to prevent and treat that disease.  We essentially know the pathway that leads to Alzheimer's disease (shown in the chart in the above post).   It is just a matter of finding the best inhibitors/scavengers for the molecule (myo-inositol), enzymes (phospholipase C gamma and beta, protein kinase C alpha, p38 MAPK, NADPH oxidase, and IKK/Nuclear factor kappa b), and oxidant (peroxynitrites) that trigger and cause Alzheimer's disease. 

 

 


Lane Simonian
Posted: Sunday, March 3, 2013 9:57 PM
Joined: 12/12/2011
Posts: 4813


Maybe it is helpful to repost some of the p38 MAPK inhibitors and peroxynitrite scavengers found useful in the treatment of Alzheimer's disease. 

 

p38 MAPK inhibitors 

 

Salvianolic acid 

 

Addition of preincubated Sal B with Abeta1-42 significantly reduces its cytotoxic effects on human neuroblastoma SH-SY5Y cells. These results suggest that Sal B has therapeutic potential in the treatment of AD, and warrant its study in animal models.

 

http://www.ncbi.nlm.nih.gov/pubmed/17964692 

 

Reishi mushroom (lingzhi) 

 

2008 Jan 23;1190:215-24. Epub 2007 Nov 13.

Antagonizing beta-amyloid peptide neurotoxicity of the anti-aging fungus Ganoderma lucidum.

Source

Laboratory of Neurodegenerative Disease, Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong.

Abstract

Ganoderma lucidum (Leyss. ex Fr.) Karst. (Lingzhi) is a medicinal fungus used clinically in many Asian countries to promote health and longevity. Synaptic degeneration is another key mode of neurodegeneration in Alzheimer's disease (AD). Recent studies have shown the loss of synaptic density proteins in each individual neuron during the progression of AD. It was recently reported that beta-amyloid (Abeta) could cause synaptic dysfunction and contribute to AD pathology. In this study, we reported that aqueous extract of G. lucidum significantly attenuated Abeta-induced synaptotoxicity by preserving the synaptic density protein, synaptophysin. In addition, G. lucidum aqueous extract antagonized Abeta-triggered DEVD cleavage activities in a dose-dependent manner. Further studies elucidated that phosphorylation of c-Jun N-terminal kinase, c-Jun, and p38 MAP kinase was attenuated by G. lucidum in Abeta-stressed neurons. Taken together, the results prove a hypothesis that anti-aging G. lucidum can prevent harmful effects of the exterminating toxin Abeta in AD.

 

http://www.ncbi.nlm.nih.gov/pubmed/18083148 

 

Astragalus 

 

Key results:

A. mongholicus extract (1 g kg−1 day−1 for 15 days, p.o.) reversed Aβ(25-35)-induced memory loss and prevented the loss of axons and synapses in the cerebral cortex and hippocampus in mice. Treatment with Aβ(25-35) (10 μM) induced axonal atrophy and synaptic loss in cultured rat cortical neurons. Subsequent treatment with A. mongholicus extract (100 μg/ml) resulted in significant axonal regeneration, reconstruction of neuronal synapses, and prevention of Aβ(25-35)-induced neuronal death.

Conclusion and implications:

A. mongholicus is an important candidate for the treatment of memory disorders and the main active constituents may not be the known astragalosides.

 

 

http://onlinelibrary.wiley.com/doi/10.1038/sj.bjp.0706865/full 

 

Lonciera japonica flower 

 

Abstract

 

Background:

We previously reported that the extracts of several Korean medicinal plants showed neuroprotective activity in glutamate-injured primary culutres of rat cortical cells.

Objective:

Among them, the effect of the methanolic extract of Lonicera japonica flower on the glutamate-induced neuronal cell death and its potential mechanism of action was investigated.

Results:

Treatment by the methanolic extract of L. japonica flower significantly protected neuronal cells against glutamate-induced excitotoxicity. It decreased the calcium influx that accompanies the glutamate induced excitotoxicity of neuronal cells, and inhibited the subsequent overproduction of nitric oxide, reactive oxygen species and peroxide to the level of control cells. In addition, it preserved cellular activity of superoxide dismutase, an antioxidative enzyme reduced by glutamate insult.

Conclusions:

According to this data, the methanolic extract of L. japonica flower significantly protected neuronal cells against glutamate excitotoxicity via antioxidative activity.

 

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3261061/ 

 

Peroxynitrite Scavengers 

 

Eugenol (in rosemary and lemon balm essential oils, for instance). 

 

Eugenol (4-allyl-2-methoxyphenol) is a fragrant compound that is commonly contained in various sorts of plants, especially in spices and medicinal herbs. Eugenol has been used for dental analgesic, which also has anticonvulsive and anti-microbial activities. Besides, anti-inflammatory and antioxidative activities of eugenol are known. A body of evidence suggests that eugenol can be used as a drug for treatment of Alzheimer's disease (AD). According to recent reports, the extract of a medicinal plant Rhizoma Acori Graminei (RAG) alleviates neurotoxicity induced by amyloid beta peptides (Aβ) in vitro and the active constituent of RAG is eugenol. Eugenol inhibits Aβ-induced excessive influx of calcium ion into neurons that causes neuronal death.

 

http://www.ingentaconnect.com/content/ben/cbc/2006/00000002/00000001/art00005 

 

Abstract

  1. Top of page  
  2. Abstract  
  3. INTRODUCTION  
  4. METHODS  
  5. RESULTS  
  6. DISCUSSION  
  7. ACKNOWLEDGMENTS  
  8. REFERENCES 

Objective: Recently, the importance of non-pharmacological therapies for dementia has come to the fore. In the present study, we examined the curative effects of aromatherpay in dementia in 28 elderly people, 17 of whom had Alzheimer's disease (AD).

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. To determine the effects of aromatherpay, patients were evaluated using the Japanese version of the Gottfries, Brane, Steen scale (GBSS-J), Functional Assessment Staging of Alzheimer's disease (FAST), a revised version of Hasegawa's Dementia Scale (HDS-R), and the Touch Panel-type Dementia Assessment Scale (TDAS) four times: before the control period, after the control period, after aromatherpay, and after the washout period.

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 

 

CONCLUSIONS:

Melissa officinalis [lemon balm] 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 (which may increase blood flow in the brain and inhibit protein kinase C--an enzyme which has been linked to neuropsychatric problems; the following findings may therefore be applicable to Alzheimer's disease). 

 

Abstract  

AIM:

The behavioral and psychological symptoms of dementia place a heavy burden on caregivers. Antipsychotic drugs, though used to reduce the symptoms, frequently decrease patients' activities of daily living and reduce their quality of life. Recently, it was suggested that ferulic acid is an effective treatment for behavioral and psychological symptoms. We have also reported several patients with dementia with Lewy bodies showing good responses to ferulic acid and Angelica archangelica extract (Feru-guard). The present study investigated the efficacy of Feru-guard in the treatment of behavioral and psychological symptoms in frontotemporal lobar degeneration and dementia with Lewy bodies.

METHODS:

We designed a prospective, open-label trial of daily Feru-guard (3.0 g/day) lasting 4 weeks in 20 patients with frontotemporal lobar degeneration or dementia with Lewy bodies. Behavioral and psychological symptoms of dementia were assessed at baseline and 4 weeks after the start of treatment, using the Neuropsychiatric Inventory. The Neuropsychiatric Inventory scores were analyzed using the Wilcoxon rank sum test.

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.

 

http://www.ncbi.nlm.nih.gov/pubmed/21272180 

 

Sinapic acid 

 

Abstract  

Sinapic acid (SA) is a phenylpropanoid compound with anti-inflammatory and neuroprotective activities. The neuroprotective effects of SA in a mouse model of amyloid β (Aβ)(1-42) protein-induced Alzheimer's disease (AD) were investigated. Mice received a bilateral injection of Aβ(1-42) protein into the hippocampus to verify the efficacy of SA. Mice were treated with SA (10mg/kg/day, p.o.) for 7days beginning immediately after Aβ(1-42) protein injection, and an acquisition trial of the passive avoidance task was conducted 1h after the last administration of SA. Retention trial was conducted 24h after the acquisition trial, and mice were sacrificed for immunohistochemistry immediately after the retention trial. SA rescued neuronal cell death in the hippocampal CA1 region and also attenuated the increase of iNOS expression, glial cell activations and nitrotyrosine expressions induced by Aβ(1-42) protein. SA significantly attenuated memory impairment in the passive avoidance task. These results suggest that SA ameliorated Aβ(1-42) protein-related pathology including neuronal cell death and cognitive dysfunction via its anti-oxidative and anti-inflammatory activities, and may be an efficacious treatment for AD.

 

http://www.ncbi.nlm.nih.gov/pubmed/22971592 

 

Ferulic acid, syringic acid, vanillic acid, and p-coumaric acid in heat-processed ginseng 

 

Abstract

OBJECTIVES:

Ginseng has been reported to improve cognitive function in animals and in healthy and cognitively impaired individuals. In this study, we investigated the efficacy of a heat-processed form of ginseng that contains more potent ginsenosides than raw ginseng in the treatment of cognitive impairment in patients with moderately severe Alzheimer's disease (AD).

METHODS:

Forty patients with AD were randomized into one of three different dose groups or the control group as follows: 1.5 g/day (n = 10), 3 g/day (n = 10), and 4.5 g/day (n = 10) groups, or control (n = 10). The Alzheimer's Disease Assessment Scale (ADAS) and Mini-Mental State Examination (MMSE) were used to assess cognitive function for 24 weeks.

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 

 

A dozen or more similar compounds and plants have produced essentially the same results.  There is no real excuse anymore for not effectively treating this disease. 

 

 
 
 
 

Myriam
Posted: Sunday, March 3, 2013 11:59 PM
Joined: 12/6/2011
Posts: 3326


Awesome work, Lane!
Lane Simonian
Posted: Monday, March 4, 2013 10:07 AM
Joined: 12/12/2011
Posts: 4813


Sometimes I feel like I am a voice in the wilderness, so I always appreciate the friendly shout backs. With each new study I read and with each day that someone on and off these boards continues to do well with a combination of drugs, diet, and herbs/aromatherapy or with a variety of natural products by themselves, I grow in confidence that this disease can be held in check and at least partially reversed. 
Lane Simonian
Posted: Sunday, March 24, 2013 1:15 AM
Joined: 12/12/2011
Posts: 4813


To make sense of this article look at the chart that starts this thread. 

 

2013 Apr;70(1):116-25. doi: 10.1016/j.phrs.2013.01.007. Epub 2013 Feb 1.

PI3 k/akt inhibition induces apoptosis through p38 activation in neurons.

Source

Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Centros de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Institut de Biomedicina (IBUB), Universitat de Barcelona,. Nucli Universitari de Pedralbes,. 08028 Barcelona, Spain.

Abstract

Accumulating evidence suggests that the PI3K/AKT pathway is a pro-survival signalling system in neurons. Therefore, the inhibition of this pathway may be implicated in the degeneration of neurons in Parkinson's disease (PD), Alzheimer's disease (AD), and other neurological disorders. Here we study the participation of the mitogen-activated protein kinase (MAPK) pathway on apoptosis induced by PI3K/AKT inhibition in cultured cerebellar granule cells (CGCs). LY294002, a specific PI3K/AKT inhibitor, selectively activated the p38 MAPK kinase pathway and enhanced c-Jun phosphorylation, but did not activate JNK. The pharmacological inhibitors SB203580 (p38 inhibitor) and SP600125 (a JNK inhibitor) protected primary cultures of rat CGCs from LY294002-induced apoptosis. Furthermore, both compounds decreased the phosphorylation of c-Jun and lowered mRNA levels of the pro-apoptotic gene dp5, a direct target of c-Jun. Taken together, our data demonstrate that PI3K/AKT inhibition induces neuronal apoptosis, a process that is mediated by the activation of p38 MAPK/c-Jun/dp5.

 

 

The presenilin 1 gene mutation, the APOE4 gene, and bisphosphonate osteoporosis drugs inhibit the PI3K/AKT pathway.  All three are risk factors for Alzheimer's disease in descending order. 

 

http://www.jbc.org/content/280/36/31537.long 

 

http://www.ncbi.nlm.nih.gov/pubmed/16973905 

 

http://www.ncbi.nlm.nih.gov/pubmed/16100524 

 

Protein kinase C activates p38 MAPK which produces peroxynitrites which in turn increases the production of p38 MAPK.  

 

http://www.jbc.org/content/278/36/33753.full 

 

http://www.ncbi.nlm.nih.gov/pubmed/18289732 

 

http://www.ncbi.nlm.nih.gov/pubmed/19393619 

 

For Alzheimer's patients without behavioral problems, p38 MAPK inhibitors and peroxynitrite scavengers can be used to treat Alzheimer's disease (see thread peroxynitrite scavengers treat Alzheimer's disease for some of these inhibitors and scavengers).  In some but not all patients with Alzheimer's disease, protein kinase C levels remain high and this is likely the cause of hallucinations and agitation.  

 

http://whyfiles.org/shorties/163stress_memory/ 

 

 

Lowering myo-inositol levels--the precursor to protein kinase C activation--may help lessen behavioral problems.  Ferulic acid and glucuronolactones appear to lower myo-inositol levels as well as scavenge peroxynitrites and thus may potentially be useful in treating Alzheimer's disease.   

 

 

 

 


Myriam
Posted: Sunday, March 24, 2013 3:17 PM
Joined: 12/6/2011
Posts: 3326


I started looking for ferluic acid to see if it's available as a supplement.  Am still looking, but found that it is a natural chemical found in the cell walls of plants.  So wouldn't eating a mostly vegetarian diet be a solution? 

 

As an aside, in my search I ran into this from The Telegraph newspaper in England:  

 

http://www.telegraph.co.uk/health/elderhealth/9784141/A-glimmer-of-hope-for-dementia-sufferers.html 

 

Here is an excerpt: 

Another product, due to be launched at the end of this month, is said to improve the memory of those with Alzheimer’s but is not a tablet and doesn’t require a prescription. Scientists at Massachusetts Institute of Technology (MIT) have spent 15 years developing a once-daily drink that, they claim, helps the body maintain synapses – the connections between neurones, which are gradually lost in Alzheimer’s.  

 

The rationale behind the drink, called Souvenaid, is that the amyloid causes damage to the neurone membranes, which results in the loss of synapses and symptoms of poor memory. The scientists – led by Richard Wurtman, professor of neuroscience and neuropharmacology at MIT – reasoned that if the body was able to repair the damage done to the membranes, this might help the symptoms. They realised that for this to happen, the brain would need higher concentrations of the building blocks, such as fatty acids, antioxidants and vitamins, required to make new membranes. They examined metabolic pathways used by the body to make neurone membranes and developed a drink that included them in concentrations far higher than are found in a regular diet.  


Lane Simonian
Posted: Monday, March 25, 2013 5:22 PM
Joined: 12/12/2011
Posts: 4813


Yes, ferulic acid can be found in rice bran and in a number of other foods. 

 

http://en.wikipedia.org/wiki/Ferulic_acid 

 

Ferulic acid along with Angelica archangelica had a very positive effect on behavior in patients with lewy body dementia and frontoltemporal lobe dementia. 

 

2011 Jul;11(3):309-14. doi: 10.1111/j.1447-0594.2010.00687.x. Epub 2011 Jan 28.

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

Source

Division of Clinical Research, National Hospital Organization Kikuchi Hospital, Kumamoto, Japan. tkimura@kikuti.hosp.go.jp 

 

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.

 

Hopefully, a similar study will be done for Alzheimer's disease.  Ferulic acid's impact on memory in Alzheimer's disease is limited because it does not enter fatty tissues in the brain well.   Some scientists are trying to find a better version but like curcumin no definitive results as of yet. 

 

Souvenaid has promise as well partially for the reasons the scientists note.  I am not sure if they contain the best antioxidants for Alzheimer's disease but it may do some good, nevertheless. 


Lane Simonian
Posted: Monday, March 25, 2013 5:38 PM
Joined: 12/12/2011
Posts: 4813


The following may be critical findings in regards to which Mild Cognitive Impairment patients proceed to Alzheimer's disease. 

 

VIENNA, Austria -- March 12, 2013 -- Myo-Inositol and N-acetylaspartate are sensitive biomarkers for clinical conversion from mild cognitive impairment (MCI) to Alzheimer’s disease (AD), according to a study presented here at the 25th Annual European Congress of Radiology (ECR).

 

Conversion from MCI to AD can be detected through various clinical tests and imaging methods. However, there remains the need for earlier predictors because only 20% of patients with MCI convert to AD.

 

Comparison of patients with stable disease versus progressive disease for the left frontal cingulate gyrus showed a significantly lower myo-inositol-to-water ratio with stable disease (20%, P =.034). There was no significant difference for the right side.

 

Comparison of patients with progressive disease versus those who developed AD for the cingulate gyrus showed the increased myo-inositol-to-water ratio to be 72% predictive for dementia; similarly for the hippocampus, it was 70% predictive for dementia.

 

http://www.docguide.com/myo-inositol-n-acetylaspartate-are-sensitive-biomarkers-conversion-mci-alzheimers-disease?tsid=5 

 

The three main risk factors for high levels of myo-inositol are high glucose levels, high blood pressure (due to high salt levels), and Down syndrome.  Whether lowering glucose and sodium levels would be enough to prevent the progression from MCI to Alzheimer's disease is an open question. 

 

In the chart at the beginning of the thread, myo-inositol is the precursor to PIP2 (phosphatidylnositol 4,5 biphosphate) and impedes the activation of the PI3 (phosphatidyinositol 3) kinase/AKT which is neuroprotective.  Early intervention in the top tier of the chart (lower myo-inositol levels, increase AKT activity, decrease phospholipase C gamma and/or beta activity with various fruits, vegetables, teas, red wine, spices, essential oils, and fish oil) may help prevent the progression from MCI to Alzheimer's disease in some cases and delay it in others.  


Lane Simonian
Posted: Monday, March 25, 2013 9:34 PM
Joined: 12/12/2011
Posts: 4813


This link contains almost all the major studies regarding ferulic acid and dementia. 

 

http://www.perpetualcommotion.com/a/Ferulic_Acid.html

 

Once the absoption issues are worked out, ferulic acid and curcumin should both provide effective means to treat Alzheimer's disease. 


Lane Simonian
Posted: Thursday, April 25, 2013 12:54 AM
Joined: 12/12/2011
Posts: 4813


For such a seemingly incomprehensible disease, Alzheimer's disease is actually deceptively simple.  Look at the chart at the beginning of this threat to put this research into context. 

 

2013 Apr;70(1):116-25. doi: 10.1016/j.phrs.2013.01.007. Epub 2013 Feb 1.

PI3 k/akt inhibition induces apoptosis through p38 activation in neurons.

http://www.ncbi.nlm.nih.gov/pubmed/23376356 

 

http://www.ncbi.nlm.nih.gov/pubmed/23376356 

 

 

Presenilin gene mutations, the APOE4 gene, and bisphosphonate osteoporosis drugs all inhibit the PI3K/AKT pathway and thus can or do cause Alzheimer's disease. 

 

p38 MAPK is one of the forms of MAPK activated by phospholipase C/Protein Kinase C.  p38 MAPK activation leads to the formation of peroxynitrites. 

 

Activation of p38 MAPK induced peroxynitrite generation in LPS plus IFN-gamma-stimulated rat primary astrocytes via activation of iNOS and NADPH oxidase.

Now look at what happens when you block the formation of inducible nitric oxides (inducible nitric oxides combine with superoxide anions to form peroxynitrites). 

 

2005 Nov 7;202(9):1163-9. Epub 2005 Oct 31.

Protection from Alzheimer's-like disease in the mouse by genetic ablation of inducible nitric oxide synthase.

Source

Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10021, USA.

Abstract

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.

 

You basically stop the development of Alzheimer's disease when you block the formation of inducible nitric oxide.  And the beauty of it, is that the same phenolic compounds found in a Mediterranean diet or a diet from India can also be used to scavenge peroxynitrites and stop the progression of Alzheimer's disease.  The most effective of these compounds can partially reverse the disease.  How long it will take me to convince others of this is how long Alzheimer's will remain an incurable disease. 


Myriam
Posted: Friday, April 26, 2013 2:48 PM
Joined: 12/6/2011
Posts: 3326


Here's a BBC News article on a region in India and the low rate of AD based on their diet (though the article is not very specific about the diet.  I wonder whether the spices they use is also a factor. 

 

http://news.bbc.co.uk/2/hi/health/8492918.stm 

 

Though I found this article about the expected increase of AD in India.

 

 

http://www.hindu.com/seta/2011/04/21/stories/2011042155291700.htm
Lane Simonian
Posted: Saturday, April 27, 2013 2:04 AM
Joined: 12/12/2011
Posts: 4813


Thanks very much for the interesting articles, Myriam.  I wish the one article had said something specifically about diet, too.  I think many spices in an Indian diet help protect against Alzheimer's disease, including curcumin, ginger, piperine, and cinnamon. 

 

Curcumin in the form of tumeric and piperine is found in curry. 

 

 

Various studies and research[,] results indicate a lower incidence and prevalence of AD in India. The prevalence of AD among adults aged 70-79 years in India is 4.4 times less than that of adults aged 70-79 years in the United States.[] Researchers investigated the association between the curry consumption and cognitive level in 1010 Asians between 60 and 93 years of age. The study found that those who occasionally ate curry (less than once a month) and often (more than once a month) performed better on a standard test (MMSE) of cognitive function than those who ate curry never or rarely.[]

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2781139/ 

 

http://www.denvernaturopathic.com/curcuminandAlzheimersndnr.htm 

 

Curcumin strongly inhibits phospholipase C gamma which by itself or in conjunction with phospholipase C beta is one of the triggers for Alzheimer's disease. 

 

Animals fed the curcumin diet showed decreased activities of colonic mucosal and tumor phospholipase A2 (50%) and phospholipase C gamma 1 (40%)...

 

http://www.researchgate.net/publication/15386163_Chemoprevention_of_colon_carcinogenesis_by_dietary_curcumin_a_naturally_occurring_plant_phenolic_compound 

 

Phospholipase C initiates a pathway that leads to inducible nitric oxide and superoxide anions which combine to form peroxynitrites.  Curcumin inhibits inducible nitric oxide. 

 

Furthermore, curcumin decreased iNOS tyrosine phosphorylation through inhibiting ERK 1/2 activation and subsequently suppressed iNOS enzyme activity.

 

http://www.ncbi.nlm.nih.gov/pubmed/21094287 

 

By supressing inducible nitric oxide you can inibit many aspects of Alzheimer's 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 β-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 β-amyloid levels, protein tyrosine nitration, astrocytosis, and microgliosis. Thus, iNOS seems to be a major instigator of β-amyloid deposition and disease progression. Inhibition of iNOS may be a therapeutic option in AD.

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2213235/ 

 

Curcumin also scavenges peroxynitrites which means it can also potentially be used to treat Alzheimer's disease. 

 

http://www.sciencedirect.com/science/article/pii/S0161813X10001828 

 

UCLA is currently conducting a clinical trial to determine if a form of curcumin designed to enter the bloodstream better can indeed be used to treat Alzheimer's disease. 

 

 

 

 

 

 


Lane Simonian
Posted: Saturday, April 27, 2013 10:41 AM
Joined: 12/12/2011
Posts: 4813


Curcumin also supresses the production of superoxide anion, hydrogen peroxide and nitrite production.  Other spices (and compounds in spices) were also effective in inhibiting superoxide anion, hydrogren peroxide, and nitrite production. 

 

Preincubation of macrophages with 10 μM capsaicin (from red pepper) or 10 μM curcumin (from turmeric) completely inhibited the superoxide anions, hydrogen peroxide and nitrite radical production in vitro by macrophages. Higher concentrations (500 μM) of eugenol (from clove) and piperine (from pepper) were required to completely inhibit superoxide anion and hydrogen peroxide release by macrophages.

 

http://www.sciencedirect.com/science/article/pii/0167488994901988 

 

http://iospress.metapress.com/content/7r63038012v02t46/ 

 

All of this is important for the following reason.  The nitrite anion produced after the scavenging of peroxynitrites is converted to a nitrite radical when interacting with heme in amyloid plaque and hydrogen peroxide (which is produced early in Alzheimer's disease) and hydrogen peroxide can combine with nitrite to produce peroxynitrites.  This likely explains the role amyloid plaques (or oligomers) play in Alzheimer's disease early on.   

 

http://www.pnas.org/content/100/10/5712.full.pdf 

 

http://informahealthcare.com/doi/abs/10.3109/10715769509065275 

 

 

 

Now here comes the great part: curcumin (and other spices) inhibits phospholipase C gamma (one of the triggers for Alzheimer's disease along with phospholipase C beta), inhibits inducible nitric oxide and superoxide anions limiting the production of peroxynitrites, scavenges peroxynitrites, and then prevents the re-formation of peroxynitrites by inhibiting the formation of hydrogen peroxide and the nitrite radical and breaking down heme.  

 

Spices prevent food from rotting by preventing oxidation; in a sense they prevent the brain from rotting by also acting as antioxidant.  Get these spice components (curcumin, piperine, eugenol in various essential oils, capsaicin, etc.) to the brain in large enough concentrations and you not only prevent or delay the onset of Alzheimer's disease, but you also effectively treat the disease.