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the prevention of Alzheimer's disease
Lane Simonian
Posted: Thursday, February 9, 2012 9:47 AM
Joined: 12/12/2011
Posts: 4863


This article reminded me of how I began to search for ways to prevent and treat Alzheimer's disease eight years ago. http://www.medicalnewstoday.com/releases/241087.php 

I started looking at all the major hypothesis for what caused Alzheimer's disease: diabetes, high blood pressure, high cholesterol levels,calcium dysregulation, etc.  Calcium dysregulation was the one common element in all cases of Alzheimer's disease.  I first read about one of the compounds responsible for calcium release: inositol 1,4,5 triphosphate.  As the authors of the above article suggest if you can limit the production of inositol 1,4,5 triphosphate you can potentially prevent Alzheimer's disease.  Myo-inositol is a compound that can lead to the formation of inositol 1,4,5 triphosphate.  Myo-inositol appears to be the precursor molecule to Alzheimer's disease and is high in people with Down syndrome, high blood pressure, and high glucose levels.

 

http://www.ncbi.nlm.nih.gov/pubmed/16330724 

http://onlinelibrary.wiley.com/doi/10.1046/j.1532-5415.2002.50465.x/abstract 

Hauser and Finelli, The Biosynthesis of Free and Phosphatide Myo-Inositol from Glucose by Mammalian Tissue slices. J. Biol. Chem. 1963.

 

Increases in myo-inositol levels can be partially blocked with lithium, scyllo-inositol, and estrogen, but the first two entail considerable risks and the latter (for reasons to be explained later) increases the risks for Alzheimer's disease when given late.

 

High levels of myo-inositol lead to high levels of phosphatidylinositol 4,5 biphosphate.  Phosphatidyinositol 4,5 biphosphate can be converted into phoshaditylinositol 3,4,5 triphosphate by the phosphatidylinostiol 3 kinase or it can be converted into inositol 1,4,5 triphosphate by phospholipase C gamma and phospholipase C beta.  Factors which inhibit the PI3 kinase increase the risk of Alzheimer's disease: in order of magnitude (from lowest to highest) they are bisphosphonate osteoporosis drugs (such as Fosamax), the APOE4 gene, and presenilin gene mutations.

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751194/ 

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

http://www.nature.com/emboj/journal/v23/n13/full/7600251a.html 

 

As far as I know, there is no effective way to activate this pathway for people with the APOE 4 gene and presenilin gene mutations.

 

The factors which activate phospholipase C gamma include high glucose levels, angiotensin II (a contributor to high blood pressure), and bacterial and viral infections.  The factors which activate phospholipase C beta include estrogen, stress, aluminum fluoride, sodium fluoride, and oxygen and glucose deprivation.  Mercury chloride and methylmercury may also activate phospholipase C.  Two compounds which may inhibit phospholipase C beta activation are neomycin (with many possible bad side effects) and possibly statins (also with many possible bad side effects).  

 

Phospholipase C gamma can be inhibited with phenolic compounds (as contained in various fruits, vegetables, spices, and essential oils) and polyunsaturated fats.  This approach may help prevent Alzheimer's disease. 

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

http://www.ncbi.nlm.nih.gov/pubmed/19661617 

 

Phenolic compounds and polyunsaturated fats in Mediterranean diets, for instance, have the added advantage of inhibiting the activation of Nuclear Factor kappa b and NADPH oxidase (via phospholipase C gamma and beta) which leads to the formation of peroxynitrites--a toxin which directly or indirectly may cause almost all of the damage in Alzheimer's disease.

http://www.ncbi.nlm.nih.gov/pubmed/17586618 

http://www.ncbi.nlm.nih.gov/pubmed/16816118 

http://www.ncbi.nlm.nih.gov/pubmed/19356025 

 

If you inhibit phospholipase C activity, you lower levels of acetylcholinesterases, the formation of amyloid plaques, the formation of peroxynitrites and the subsequent influx of calcium (which kills neurons), the efflux of glutamate (which kills other brain cells), the hyperphosphorylation and nitration of tau proteins (which interferes with neurotransmissions), and the oxidation (disabling) of receptors involved in short-term memory, sleep, mood, social recognition, awareness, and smell.  Fortunately much of this damage can also likely be stopped and partially reversed with phenolic compounds.

 

On a slightly negative note, there are limitations to preventing Alzheimer's disease with phenolic compounds.  Some of the compounds are not readily available for the brain (curcumin, for instance).  Some compounds such as essential oils may stimulate g protein-coupled receptors (thus activating phospholipase C beta) and therefore may be prooxidants when given too often.  Fruit juices high in polyphenols are also often high in sugar, partially negating the effects of the polyphenols.  However, once you identify the pathways that lead to Alzheimer's disease, the potential effectiveness of certain preventive measures become clearer as do perhaps new avenues to prevent the disease.

 

 


Lane Simonian
Posted: Saturday, February 11, 2012 5:52 PM
Joined: 12/12/2011
Posts: 4863


I have been looking for a good schematic to explain Alzheimer's disease. The diagram in this article comes very close.

https://docs.google.com/viewer?a=v&q=cache:CpSrf2CcmgQJ:www.j-alz.com/issues/28/khalifat_supplement.pdf+peroxynitrites+HNE+alzheimer's+disease+2012+mitochondria&hl=en&gl=us&pid=bl&srcid=ADGEESjKIy_uznhuxWpfFjaD4HlkVej4A8dCQNgBZxmbMoIoBh4Moaqe8SPnDtkuRicDkK95WQnQfVsXZW3tNsMcuUAaf5EeNn8WQsoiY22H9cPYi_vdMvSJokuFZlc2yYCzYJ32X9bL&sig=AHIEtbQCdb648IvVzDKEpkg5_MHfvQI38g 

I would just draw the arrows slightly different: the inositol 1,4,5 triphosphate release of calcium to amyloid beta plaques, amyloid beta plaques to peroxynitrites, peroxynitrites to 4HNE, the influx of calcium, and the hyperphosphorylation of tau proteins.  Otherwise, I think the authors have it just about perfect. 


Lane Simonian
Posted: Saturday, February 11, 2012 11:27 PM
Joined: 12/12/2011
Posts: 4863


Here are two more useful diagrams regarding the prevention of Alzheimer's disease. 

http://www.biocarta.com/pathfiles/m_plcpathway.asp 

http://www.biocarta.com/pathfiles/h_pkcpathway.asp 

It is the activation of phospholipase C gamma (y) and phospholipase C beta that trigger the initial high levels of acetycholinesterases (which contribute to memory impairment early in Alzheimer's disease), the processing of the amyloid precursor protein (by Protein Kinase C), the cleaving of this protein to form plaques by calpains (a calcium dependent enzyme), and the formation of peroxynitrites (due to the increase in Nuclear factor kappa b and NADPH oxidase activity)--a toxin likely responsible for short-term memory impairment in Alzheimer's disease.  You can limit the production of phospholipase C gamma and the subsequent production of peroxynitrites with phenolic compounds and polyunsaturated fats (including Omega 3 fatty acids in fish oil, for instance) and limit the damage done by peroxynitrites with phenolic compounds.

http://www.ncbi.nlm.nih.gov/pubmed/12511421 

http://www.sciencedirect.com/science/article/pii/S0005276098000447 

http://www.ncbi.nlm.nih.gov/pubmed/17586618 

https://docs.google.com/viewer?a=v&q=cache:0HGiHS7vZ3cJ:alzheimer.neurology.ucla.edu/pubs/ColePreventionNBA2005.pdf+omega+3+fatty+acids+peroxynitrites&hl=en&gl=us&pid=bl&srcid=ADGEESgTN_Z-5zGLgGyP4JQHwZRPZTy238xTqSKbLirxMr5YnvFDTmMGG5wGEin3JkXpUgaHy6KezHBI7_mHEfngHOBcBZlhkJCJPuh79GaMN_3Ep7G7aFGyDJH2uwmL7eiUbbk7ha8N&sig=AHIEtbQFuf8Qy3ab027XXzH0srK09HxBiQ 

http://www.sciencedirect.com/science/article/pii/S0166432807001313 

 

Phenolic compounds can be used in both the treatment and prevention of Alzheimer's disease.