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New Blood Test Can Predict Alzheimer's
Myriam
Posted: Sunday, March 9, 2014 6:46 PM
Joined: 12/6/2011
Posts: 3326


Researchers have discovered and validated a blood test that can predict with greater than 90 percent accuracy if a healthy person will develop mild cognitive impairment or Alzheimer's disease within three years.  

 

Described in Nature Medicine published online today, the study heralds the potential for developing treatment strategies for Alzheimer's at an earlier stage, when therapy would be more effective at slowing or preventing onset of symptoms. It is the first known published report of blood-based biomarkers for preclinical Alzheimer's. 

 

The test identifies 10 lipids, or fats, in the blood that predict disease onset. It could be ready for use in clinical studies in as few as two years and, researchers say, other diagnostic uses are possible. 

 

"Our novel blood test offers the potential to identify people at risk for progressive cognitive decline and can change how patients, their families and treating physicians plan for and manage the disorder," says the study's corresponding author Howard J. Federoff, MD, PhD, professor of neurology and executive vice president for health sciences at Georgetown University Medical Center. 

 

There is no cure or effective treatment for Alzheimer's. Worldwide, about 35.6 million individuals have the disease and, according to the World Health Organization, the number will double every 20 years to 115.4 million people with Alzheimer's by 2050. 

 

Federoff explains there have been many efforts to develop drugs to slow or reverse the progression of Alzheimer's disease, but all of them have failed. He says one reason may be the drugs were evaluated too late in the disease process. 

 

"The preclinical state of the disease offers a window of opportunity for timely disease-modifying intervention," Federoff says. "Biomarkers such as ours that define this asymptomatic period are critical for successful development and application of these therapeutics." 

 

The study included 525 healthy participants aged 70 and older who gave blood samples upon enrolling and at various points in the study. Over the course of the five-year study, 74 participants met the criteria for either mild Alzheimer's disease (AD) or a condition known as amnestic mild cognitive impairment (aMCI), in which memory loss is prominent. Of these, 46 were diagnosed upon enrollment and 28 developed aMCI or mild AD during the study (the latter group called converters). 

 

In the study's third year, the researchers selected 53 participants who developed aMCI/AD (including 18 converters) and 53 cognitively normal matched controls for the lipid biomarker discovery phase of the study. The lipids were not targeted before the start of the study, but rather, were an outcome of the study. 

 

A panel of 10 lipids was discovered, which researchers say appears to reveal the breakdown of neural cell membranes in participants who develop symptoms of cognitive impairment or AD. The panel was subsequently validated using the remaining 21 aMCI/AD participants (including 10 converters), and 20 controls. Blinded data were analyzed to determine if the subjects could be characterized into the correct diagnostic categories based solely on the 10 lipids identified in the discovery phase. 

 

"The lipid panel was able to distinguish with 90 percent accuracy these two distinct groups: cognitively normal participants who would progress to MCI or AD within two to three years, and those who would remain normal in the near future," Federoff says. 

 

The researchers examined if the presence of the APOE4 gene, a known risk factor for developing AD, would contribute to accurate classification of the groups, but found it was not a significant predictive factor in this study. 

 

"We consider our results a major step toward the commercialization of a preclinical disease biomarker test that could be useful for large-scale screening to identify at-risk individuals," Federoff says. "We're designing a clinical trial where we'll use this panel to identify people at high risk for Alzheimer's to test a therapeutic agent that might delay or prevent the emergence of the disease." 

 

Mark Mapstone, Amrita K Cheema, Massimo S Fiandaca, Xiaogang Zhong, Timothy R Mhyre, Linda H MacArthur, William J Hall, Susan G Fisher, Derick R Peterson, James M Haley, Michael D Nazar, Steven A Rich, Dan J Berlau, Carrie B Peltz, Ming T Tan, Claudia H Kawas, Howard J Federoff. Plasma phospholipids identify antecedent memory impairment in older adults. Nature Medicine, 2014; DOI: 10.1038/nm.3466  


Mimi S.
Posted: Sunday, March 9, 2014 7:34 PM
Joined: 11/29/2011
Posts: 7027


More hope for earlier diagnoses. I wonder how easy the blood test will be to check fort and how much it will cost. The cost right now of a complete diagnostic work up is high, but most people's insurance will pay for it.
Shellasim
Posted: Sunday, March 9, 2014 7:41 PM
Joined: 10/6/2012
Posts: 499


I was just reading this, myself, on the internet and was coming in here to also post. Wow! What do you all think?

~shelley

 http://www.cnn.com/2014/03/09/health/alzheimers-blood-test/index.html?hpt=hp_t2


Lane Simonian
Posted: Sunday, March 9, 2014 10:55 PM
Joined: 12/12/2011
Posts: 5002


I looked at the study of lipid biomarkers in assessing the risk for developing Alzheimer's disease and for me they were mainly just a bunch of codes, but for those who know these lipid components I am sure that they provide important hints as to the pathway to Alzheimer's disease.


In general, the processes that take place which culminate in Alzheimer's disease take place in lipid rafts which in part are composed of cholesterol and saturated fats.  So it is not surprising that lipids provide some of the most obvious biomarkers for the risk for Alzheimer's disease.



Review 

Phospholipids and Alzheimer’s Disease: Alterations, 

Mechanisms and Potential Biomarkers 

Marko Kosicek and Silva Hecimovic *


Abstract: Brain is one of the richest organs in lipid content. Phospholipids 

(glycerophospholipids and sphingolipids) are important building blocks of cell membranes, which provide an optimal environment for protein interactions, trafficking and function.  Because of that, alterations in their cellular levels could lead to different pathogenic processes in the brain, such as in Alzheimer’s disease (AD), the most common type of 

dementia among older populations. There is increasing evidence that phospholipid changes occur during pathogenic processes in AD. It is known that lipids are tightly connected with metabolism of the Amyloid Precursor Protein (APP), which produces Amyloid-beta peptide (Aβ), the main component of senile plaques, which represent the main pathological 

hallmark of AD. However, the mechanism(s) of the lipid-effect on Aβ metabolism and AD pathogenesis is still not completely understood. This review summarizes the current knowledge on phospholipid changes occurring during normal aging and discusses phospholipid changes in the human brain associated with different stages of AD, as well changes in the cerebrospinal fluid and blood/plasma, which are interesting potential 

biomarkers for AD diagnosis and disease monitoring. At the end, we have discussed future perspectives of phospholipid changes as potential biomarkers and as targets for development of novel treatment strategies against AD.






Mz4all
Posted: Friday, March 14, 2014 9:56 PM
Joined: 3/14/2014
Posts: 1


I have been involved with this disease,now since 2006, I have read,researched....listened to doctor's, gone to symposiums, on & on ,concerning this 

Epidemic ,we hear about all the progress , however for millions of Our loved ones it is too late. The stories always stop...then,there are promotions about getting pills, It does not work if one already has Dementia or Alzheimer's 

 Where does one go to get involved with clinical trials , are they free and where are these trials taking place?


Iris L.
Posted: Saturday, March 15, 2014 2:04 AM
Joined: 12/15/2011
Posts: 17587


Clinical trials take place in medical centers all over the country.  Not only are they free, but they may pay YOU and your LO for participation, 

 http://clinicaltrials.gov/  

 

Iris L. 


Iris L.
Posted: Saturday, March 15, 2014 2:26 AM
Joined: 12/15/2011
Posts: 17587


My rheumatologist told me my cognitive impairment is due to  anti-phospholipid syndrome.

Iris L.

Lane Simonian
Posted: Saturday, March 15, 2014 9:39 AM
Joined: 12/12/2011
Posts: 5002


Here is the likely connection between anti-phospholipid syndrome and cognitive impairment.


 2003 Oct;5(5):383-90.

Oxidative stress in systemic lupus erythematosus and antiphospholipid syndrome: a gateway to atherosclerosis.

Abstract

Vascular disease and atherosclerosis are significant clinical features of systemic lupus erythematosus and antiphospholipid syndrome. Oxidation is one of the major factors responsible for atheroma development in this context. Anticardiolipin antibodies seem to play an important role by inducing nitric oxide and superoxide production, resulting in enhanced levels of plasma peroxynitrite, which is a powerful pro-oxidant substance. Furthermore, direct interference of these antibodies with paraoxonase activity, a high-density lipoprotein-related anti-oxidant enzyme, would contribute to the oxidative stress found in these conditions. The accelerated process of atherogenesis found in these diseases can represent a useful model for the study of atherosclerosis in the general population.


Lane Simonian
Posted: Thursday, March 27, 2014 5:46 PM
Joined: 12/12/2011
Posts: 5002


Lipid rafts composed partially of cholesterol and saturated fats appear to be a critical factor in the onset of Alzheimer's disease.  This article is often hard to follow but provides some critical clues as to the inception and progression of the disease. 


 

  Perspectives and prospects   Top 



Amyloid-beta is generated from amyloid precursor protein, and is believed to be an important pathological protein in Alzheimer's disease. Lipid rafts are glycolipid-rich domains of the plasma membrane. Although amyloid precursor protein processing is associated with complex factors, lipid rafts may be an important processor for amyloid precursor protein, as well as amyloid-beta. Generally, the autophagic-lysosomal pathway is aberrant in Alzheimer's disease brain. However, lipid rafts that mediate amyloid precursor protein can disturb autophagy, thus blocking the autophagic-lysosomal pathway and aggravating the disease. Therefore, we speculate that in Alzheimer's disease, lipid rafts play an important role in blocking the autophagic-lysosomal pathway of amyloid precursor protein processing and amyloid-beta degradation, thereby exacerbating the progression of this disease. To our knowledge, no report has addressed this possible association. Furthermore, this review provided evidence, via the Two-system Theory, that the dynamic clearance of a pathological product may result from clearance fail or dysfunction that may subsequently affect neurogenesis and neuronal survival and thus, should be balanced to maintain the normal function of the brain[115]. 


 

http://www.nrronline.org/article.asp?issn=1673-5374;year=2014;volume=9;issue=1;spage=92;epage=100;aulast=Zhou 

 

The peroxynitrite mediated processing of the c-terminal fragment of the amyloid precursor protein takes place in lipid rafts and scavenging peroxynitrites removes a major neurotoxin in Alzheimer's disease. 


 

 2001 Jul;78(1):109-20.

C-terminal fragment of amyloid precursor protein induces astrocytosis.

Abstract

One of the pathophysiological features of Alzheimer's disease is astrocytosis around senile plaques. Reactive astrocytes may produce proinflammatory mediators, nitric oxide, and subsequent reactive oxygen intermediates such as peroxynitrites. In the present study, we investigated the possible role of the C-terminal fragment of amyloid precursor protein (CT-APP), which is another constituent of amyloid senile plaque and an abnormal product of APP metabolism, as an inducer of astrocytosis. We report that 100 nM recombinant C-terminal 105 amino acid fragment (CT105) of APP induced astrocytosis morphologically and immunologically. CT105 exposure resulted in activation of mitogen-activated protein kinase (MAPK) pathways as well as transcription factor NF-kappaB. Pretreatment with PD098059 and/or SB203580 decreased nitric oxide (NO) production and nuclear factor-kappa B (NF-kappaB) activation. But inhibitors of NF-kappaB activation did not affect MAPKs activation whereas they abolished NO production and attenuated astrocytosis. Furthermore, conditioned media derived from CT105-treated astrocytes enhanced neurotoxicity and pretreatment with NO and peroxynitrite scavengers attenuated its toxicity. These suggest that CT-APP may participate in Alzheimer's pathogenesis through MAPKs- and NF-kappaB-dependent astrocytosis and iNOS induction.

 

We are getting very close to the point where we can say what causes Alzheimer's disease and how to treat it. 


Lane Simonian
Posted: Thursday, March 27, 2014 9:22 PM
Joined: 12/12/2011
Posts: 5002


I keep waiting for my epiphany when it comes to Alzheimer's disease, but now I realize that I have probably muddled and stumbled my way close enough to the truth that an epiphany is no longer needed. 


 

These two charts/diagrams show the pathway to Alzheimer's disease (I am having some technical problems so I will post the second chart in the post below).  The precursor to phoshatidylinositol 4,5 biphosphate (PIP2) is myo-inositol and myo-inositol is about 70 percent predictive of the conversion from mild cognitive impairment to Alzheimer's disease.   


 

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


 

High glucose levels, high blood pressure due to high sodium levels, and Down syndrome all increase myo-inositol levels in the brain and all three increase the risk for Alzheimer's disease. 



 


 


 


 


Lane Simonian
Posted: Thursday, March 27, 2014 9:43 PM
Joined: 12/12/2011
Posts: 5002


Now diagram number two.  In non-lipid rafts, phospholipase C activation of protein kinase C leads to a n-truncated form of the soluble amyloid precursor protein which can be easily cleared from the brain.  In lipid rafts, phospholipase C activation of protein kinase C leads to the c-terminal fragment of the soluble amyloid precursor protein which cannot be easily cleared from the brain perhaps because it is in essence stuck in the lipid rafts.  In the blood test, certain lipid markers were 90 percent predictive for the development of Alzheimer's disease.


Statins may look like the answer in terms of lowering cholesterol in lipid rafts but they may not lower cholesterol in the brain.  They may lower protein kinase C activity but they may also lower Co-enzyme Q10 which is an important antioxidant in the brain as well as in the liver.  Lowering Co-enzyme Q10 levels may also lead to global amnesia--one of the potential side effects of statin use.  To disrupt lipid rafts in the brain, you are better off using omega-3 fatty acids such as fish oil (and inhibit phospholipase C gamma activity with polyphenols in spices, essential oils via aromatherapy, and various fruits and vegetables).  So these are the pathways that lead to peroxynitrite formation and to Alzheimer's disease.





Linking lipids to Alzheimer's disease: cholesterol and beyond


Myriam
Posted: Thursday, March 27, 2014 11:06 PM
Joined: 12/6/2011
Posts: 3326


Wow, Lane. This reminds me of the game Pick Up Sticks.
Lane Simonian
Posted: Thursday, March 27, 2014 11:56 PM
Joined: 12/12/2011
Posts: 5002


It kind of looks like that.  The sticks in the non-lipid rafts get picked up and those in the lipid rafts don't.  More important than the sticks themselves or where they end up, is how they are produced.  Stop what is producing them and you stop Alzheimer's disease.
Lane Simonian
Posted: Friday, April 4, 2014 10:31 AM
Joined: 12/12/2011
Posts: 5002


These authors nicely summarize critical aspects of Alzheimer's disease: oxidation is the primary cause of Alzheimer's disease with inflammation as a co-contributor.  The processes which lead to oxidation and inflammation occur primarily in a high lipid/cholesterol environment.  The best way to disrupt this environment early on is with Omega 3-fatty acids.  Used in conjunction with potent antioxidants this is the best way to delay the onset of the disease.  If only more researchers would focus on the best antioxidants for treating Alzheimer's disease, we would not have to wait so long for relatively effective treatments for the disease.


Lipid Integration in Neurodegeneration: An Overview of Alzheimer’s Disease


helpwmom
Posted: Thursday, April 24, 2014 1:32 AM
Joined: 4/12/2014
Posts: 19


Where would a person get this test? And what exactly would you ask for? 

 


Serenoa
Posted: Thursday, April 24, 2014 8:02 AM
Joined: 4/24/2012
Posts: 484


Thank you all for these very informative posts. I do not have the time these day to jump back down the microbiology "rabbit hole," but I think there are some very significant connections in several of the new research articles posted here. Thank you Myriam for posting them, and thank you Lane for adding so much good information. 

 

I think there are commonalities and connections in several recent articles: the Blood Test... post, Chaperone Compounds... post, the Novel Function of Protein... post, and the REST and Stress Resistance... post.

 

What they have in common are that they point to causal factors upstream of the development of plaques/amyloid beta, and they point to oxidative damage as a major cause. Here's how my brain sees it. We have lipid deficiency, mishandled APP, dysfunctional intracellular trafficing, and non-functioning transcription factors. We know that APOE4 is involved with lipid transport. Lipid membranes in the cell (the neuron) are central to cell survival and transport of molecules. The blood test showed marked reduction in lipids known to make up the cell membrane. Something is going wrong with the way the cell is handling APP so that it is not fulfilling its beneficial purpose but ending up as amyloid beta. This involves the "Retromer Protein Complex" and cellular transport. APP regulates micoRNA to control growth and maturation of neurons and it is not able to do that in AD. The RE1-silencing transcription factor (REST) is not functioning to protect AD brains. It is being misdirected, possibly just like APP, and is not getting to the DNA to turn off cell death pathways and activate stress resistance pathways. These are some of the best clues to solving this puzzle I've seen.

 

Lane, I think you are nailing this down very well and I have to go back and try to better understand your conclusions, like the role of lipid rafts. But, there is something here in this recently posted research that we should focus on. The clues and connections here are very strong.


Lane Simonian
Posted: Thursday, April 24, 2014 11:34 AM
Joined: 12/12/2011
Posts: 5002


Great analysis as always, Serenoa.


When the blood biomarker study came out it was in coded form.  Recently they identified the biomarkers in laymen's terms.


http://journals.lww.com/neurotodayonline/pages/imagegallery.aspx?year=2014&issue=04170&article=00004 (see tables)


Many of the biomarkers that are down are either antioxidants (lysine, proline, acylcarnitine, and taurine) or compounds whose synthesis is decreased due to oxidation (serotonin) or altered due to nitration (phenylalanine).


Through inhibition of neuroprotective pathways, through the release of glutamate, through direct interactions with oxidants, and in some cases due to the production of amyloid oligomers, the body's own antioxidant system is exhausted and the disease proceeds unimpeded.


High levels of myo-inositol, the loss of the phosphatidylinositol 3 kinase/Akt pathway, and the activation of phospholipase C gamma and/or beta leads to the activation of protein kinase C.  In the absence of lipid rafts, this pathway leads to the n-terminal fragment of the amyloid precursor protein which is then removed.  The effects of protein kinase C has often studied in mice who may not live long enough to naturally develop the lipid rafts needed for Alzheimer's disease.  But in human beings with high levels of myo-inositol, high phospholipase C activity, inhibition of the phosphatidylinositol 3 kinase/Akt pathway; protein kinase C activity in lipid rafts leads to the activation of p38 MAPK, peroxynitrites, increased beta-secretase activity, and the c-terminal fragment of the amyloid precursor protein.



Protein Kinase C Activation Increases Release of Secreted Amyloid 

Precursor Protein without Decreasing Ab Production in Human 

Primary Neuron Cultures. 



Overexpression and altered metabolism of amyloid precursor 

protein (APP) resulting in increased 4 kDa amyloid b peptide 

(Ab) production are believed to play a major role in Alzheimer’s 

disease (AD). Therefore, reducing Ab production in the brain is 

a possible therapy for AD. Because AD pathology is fairly 

restricted to the CNS of humans, we have established human 

cerebral primary neuron cultures to investigate the metabolism 

of APP. In many cell lines and rodent primary neuron cultures, 

phorbol ester activation of protein kinase C (PKC) increases the 

release of the secreted large N-terminal fragment of amyloid 

precursor protein (sAPP) and decreases Ab release (Buxbaum 

et al,. 1993; Gadzuba et al., 1993; Huang et al, 1993).  In contrast, 

we find that PKC activation in human primary neurons increases 

the rate of sAPP release and the production of APP C-terminal 

fragments and 4 kDa Ab.  Our results indicate species--and cell 

type-specific regulation of APP metabolism.  Therefore, our 

results curtail the use of PKC activators in controlling human 

brain Ab levels.  




 2007 Jun;19(6):1301-8. Epub 2007 Jan 20.

The lipid raft proteins flotillins/reggies interact with Galphaq and are involved in Gq-mediated p38 mitogen-activated protein kinase activation through tyrosine kinase.

Abstract

The heterotrimeric G protein alpha q subunit (Galphaq) mediates a variety of cell functions by activating the effector molecule phospholipase Cbeta. Galphaq activity is regulated by G protein betagamma subunits, G protein-coupled receptors, RGS proteins, and Ric-8. In this study, we identified the lipid raft resident proteins, flotillin-1/reggie-2 and flotillin-2/reggie-1, as Galphaq-binding proteins. The interactions of Galphaq and flotillins were independent of the nucleotide-binding state of Galphaq, and the N-terminal portion of flotillins was critical for the interaction. A short interfering RNA-mediated knockdown of flotillins, particularly flotillin-2, attenuated the UTP-induced activation of p38 mitogen-activated protein kinase (MAPK) but not that of ERK1/2. The activation of p38 MAPK was inhibited by the Src family tyrosine kinase inhibitor PP2 and the cholesterol-depleting agent methyl-beta-cyclodextrin, which is generally used for the disruption of lipid rafts. In contrast, the activation of ERK1/2 was not inhibited by these compounds. These lines of evidence suggested that a Gq-coupled receptor activates specifically p38 MAPK through lipid rafts and Src kinase activation, in which flotillins positively modulate the Gq signaling.



Inhibiting p38 MAPK attenuates cerebral ischemic injury in APP/SWE transgenic mice

The Swedish mutant amyloid precursor protein mutation exacerbates ischemic brain injury, and this could be alleviated by inhibiting p38 mitogen-activated protein kinase activity, according to a study in the Neural Regeneration Research Journal (Vol. 7, No. 14, 2012).

Furthermore, conditioned media derived from CT105-treated astrocytes enhanced neurotoxicity and pretreatment with NO and peroxynitrite scavengers attenuated its toxicity. These suggest that CT-APP may participate in Alzheimer's pathogenesis through MAPKs- and NF-kappaB-dependent astrocytosis and iNOS induction [other way around: p38 MAPK and peroxynitrites lead to the c-terminal fragment of the amyloid precursor protein and they rather than the c-terminal fragment leads to the death of neurons).


Inhibit protein kinase C activity  (polyphenols) in lipid rafts (DHA in fish oil, for instance) and you delay the onset of Alzheimer's disease.  Use effective peroxynitrite scavengers and you treat the disease.



Lane Simonian
Posted: Thursday, April 24, 2014 5:28 PM
Joined: 12/12/2011
Posts: 5002


I am going to try to put this in the simplest terms possible.  The phospholipase C activation of protein kinase C which in a lipid raft environment leads to the activation of p38 MAPK, the formation of peroxynitrites, the nitration of NMDA receptors, the further activation of p38 MAPK, and the further formation of peroxynitrites is the cause of Alzheimer's disease.  Everything else is either connected to this cycle or peripheral to it. This includes but is not limited to the amyloid precursor protein, amyloid oligomers, amyloid plaques, hyperphosphorylated tau, SorL1 gene dysfunction, REST dysfunction, and retromer dysfunction.  Intervene at the early part of the cycle and you delay the onset of Alzheimer's disease. Intervene in the latter stage of the cycle and you effectively treat Alzheimer's disease.  
Serenoa
Posted: Wednesday, April 30, 2014 3:15 PM
Joined: 4/24/2012
Posts: 484


Ah, so then the critical question becomes, why is Phospholipase C (PLC) being activated in Alzheimer's brains and not in normal brains? If PLC is the dysfunction at the begining of the cyle, what age-related factor has allowed this or caused this to happen to PLC?

 

So, based on the above information, we should focus on what activates PLC if we want to find the primary causal factor apart from any of the other factors that come into play downstream in the cycle.

 

Lane, thanks for posting the above articles. I found them very helpful.



Lane Simonian
Posted: Thursday, May 1, 2014 1:06 AM
Joined: 12/12/2011
Posts: 5002


Yes this is it, Serenoa.  There is a whole array of factors that can activate phospholipase C.  They include but are not limited to stress, high glucose levels, angiotensin II (which can cause high blood pressure), excessive alcohol, smoking, certain chronic bacterial and viral infections, certain pesticides and herbicides, bisphenols in plastics, mercury, aluminium fluoride, sodium fluoride, and diesel fumes.  Phenolic compounds in various fruits, vegetables, drinks, and spices inhibit one form of phospholipase C and inhibits the ability of both forms to produce peroxynitrites.  Omega-3 fatty acids promote the neuroprotective phosphatidylinositol-3 kinase/Akt pathway which inhibits the formation of peroxynitrites.  Together along with moderate exercise (which also promotes the phosphatidylinositol-3 kinase/Akt pathway) is likely the best path to either prevent or delay the onset of Alzheimer's disease.  


http://www.pnas.org/content/102/31/10858.full


http://science24.com/paper/11701


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


Lane Simonian
Posted: Thursday, May 1, 2014 9:18 AM
Joined: 12/12/2011
Posts: 5002


The combination of high levels of myo-inositol (which is the precursor of phosphatidylinositol 4,5 biphosphate), inhibition of the phosphatidylinositol 3 kinase (which converts phosphatidylinositol 4,5 biphosphate into phosphatidylinositol 3,4,5 biphosphate) and the activation of phospholipase C (which converts phosphatidylinositol 4,5 biphosphate into inositol 1,4,5 triphosphate) are almost a guarantee for the onset of Alzheimer's disease.


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


PS1 FAD [familial Alzheimer's disease] mutations inhibit the PS1-dependent PI3K/Akt activation, thus promoting GSK-3 activity and tau overphosphorylation at AD-related residues. Our data raise the possibility that PS1 may prevent development of AD pathology by activating the PI3K/Akt signaling pathway. In contrast, FAD mutations may promote AD pathology by inhibiting this pathway.


http://www.ncbi.nlm.nih.gov/pubmed/15192701



 1998 Nov 16;811(1-2):161-5.

Regional levels of brain phospholipase Cgamma in Alzheimer's disease.

Abstract

These results suggest that the increased levels of PLCgamma, by increasing the hydrolysis of PIP2 [phosphatidylinositol 4,5 biphosphate] in the hippocampus and SMTG [superior and middle temporal gyri], may contribute to pathophysiology of AD.

http://www.ncbi.nlm.nih.gov/pubmed/9804940

The pathways that lead to and away from Alzheimer's disease can be positively altered by a diet high in phenols and DHA in fish oil (i.e. a Mediterranean diet) or high in spices (i.e. an Indian diet) and by moderate exercise and such an approach may at least delay the onset of Alzheimer's disease.  This is likely true even for someone with a genetic mutation that leads to early onset Alzheimer's disease.




Serenoa
Posted: Thursday, May 1, 2014 1:15 PM
Joined: 4/24/2012
Posts: 484


http://journals.psychiatryonline.org/article.aspx?articleid=173845

 

High Brain myo-Inositol Levels in the Predementia Phase of Alzheimer’s Disease in Adults With Down’s Syndrome: 

 

http://jcb.rupress.org/content/170/7/1101.short

Lithium induces autophagy by inhibiting inositol monophosphatase

 The autophagy-enhancing properties of lithium were mediated by inhibition of inositol monophosphatase and led to free inositol depletion. This, in turn, decreased myo-inositol-1,4,5-triphosphate (IP3) levels. Our data suggest that the autophagy effect is mediated at the level of (or downstream of) lowered IP3, because it was abrogated by pharmacologic treatments that increased IP3. This novel pharmacologic strategy for autophagy induction is independent of mTOR, and may help treatment of neurodegenerative diseases, like Huntington's disease, where the toxic protein is an autophagy substrate. 

 

 

Ok, so I see there are many connections to myo-inositol. I especially found the Down Syndrome connection very significant, as well as the inhibition of various cell signalling functions. And, what's the deal with Lithium?

 

 


Serenoa
Posted: Thursday, May 1, 2014 5:08 PM
Joined: 4/24/2012
Posts: 484


Also, inositol has been demonstrated to stabilize amyloid beta and make it NON-toxic to neurons. What's the difference between it and MYO-inositol?

 

http://www.jbc.org/content/275/24/18495.short

Inositol Stereoisomers Stabilize an Oligomeric Aggregate of Alzheimer Amyloid β Peptide and Inhibit Aβ-induced Toxicity


Lane Simonian
Posted: Thursday, May 1, 2014 11:07 PM
Joined: 12/12/2011
Posts: 5002


Yes, the connection between myo-inositol, Down syndrome, and Alzheimer's disease is quite interesting.


Role of increased cerebral myo-inositol in the dementia of Down syndrome.

Magnetic Resonance Spectroscopy Unit, Huntington Medical Research Institutes, Pasadena, CA 91105, USA.
Magnetic Resonance in Medicine (Impact Factor: 3.27). 07/1995; 33(6):858-61.
Source: PubMed

ABSTRACT The purpose of this study was to determine cerebral myo-inositol (mI) in adults with Down syndrome (DS), and to trace the chronobiology of DS to Alzheimer disease (AD). AD has characteristic neuropathology of neurofibrillary plaques and tangles; indirect evidence links this to earlier deposition of beta-amyloid. Elevated mI, which distinguishes AD from other common dementias, is also elevated in 23 young patients who have DS without dementia. In one patient who has DS with dementia, mI is elevated and N-acetylaspartate (NAA) decreased. The similarity to AD is striking and may suggest a progressive neurochemical disorder in which elevation of mI precede loss of NAA in both AD and DS.

http://www.researchgate.net/publication/15548283_Role_of_increased_cerebral_myo-inositol_in_the_dementia_of_Down_syndrome



CONCLUSIONS: The approximately 50% higher level of myo-inositol in Down’s syndrome suggests a gene dose effect of the extra chromosome 21, where the human osmoregulatory sodium/myo-inositol cotransporter gene is located. The even higher myo-inositol level in older adults with Down’s syndrome extends to the predementia phase earlier findings of high myo-inositol levels in symptomatic Alzheimer’s disease.



http://ajp.psychiatryonline.org/article.aspx?articleid=173845



The researchers also suspect that high levels of myo-inositol could play a role in predisposing people with Down syndrome to early-onset Alzheimer's disease.  The molecule is known to promote the formation of amyloid plaques - a hallmark of Alzheimer's.



http://news.bbc.co.uk/2/hi/health/4498652.stm



Two other factors that increase myo-inositol in the brain are high levels of glucose and high blood pressure due to high sodium levels.


As a magnesium inhibitor, lithium inhibits phospholipase C beta which produces inositol 1,4,5 triphosphate and it also inhibits the recycling of inositol 1,4,5 triphosphate back into myo-inositol.  It thus inhibits one of the pathways leading to Alzheimer's disease.


In most people with Alzheimer's disease, phospholipase C activity decreases over time due to oxidation and nitration of various receptors. Little inositol 1,4,5 triphosphate remains to recycle back into myo-inositol so myo-inositol levels drop as well.  But where myo-inositol levels remain high (such as caused by the independent activation of phospholipase C by such things as stress, aluminium fluoride, and sodium fluoride) neuropsychiatric problems increase due to the even greater production of peroxynitrites.  Increasing levels of scyllo-inositol rather than levels of myo-inositol may help at this point.


Elan’s Gene Kinney recounted how falling myoinositol levels were discovered when company researchers used NMR to confirm scyllo-inositol had made its way into the brain. The researchers noticed that, as brain scyllo-inositol rose, its myo-isoform fell. Going back to animal models, they found that the myo isoform dropped by as much as 70 percent when the animals imbibed drinking water laced with scyllo-inositol. Why is this important? Previously, researchers had reported elevated brain myoinositol in patients with AD, Down's syndrome, and bipolar disorder, said Kinney (see Miller et al., 1993). More recently, a group in Japan correlated elevated brain myoinositol with behavioral and psychological problems in AD patients. Lithium, which has been used for many years to treat neuropsychiatric disorders, may work in part by reducing myoinositol. In fact, a 30 percent reduction of myoinositol is predictive of lithium efficacy, said Kinney. By reducing myoinositol, could scyllo-inositol treat neuropsychiatric symptoms in AD patients?


http://www.alzforum.org/news/conference-coverage/stockholm-therapeutics-roundup-some-new-some-not-so-much


Much safer and better than lithium and scyllo-inositol is ferulic acid which appears to bind to myo-inositol (and is also a peroxynitrite scavenger).  Here are the results for ferulic acid (in a combination of rice bran oil and Angelica archangelica and in heat processed ginseng; ferulic acid is also found in coconut oil) in the treatment of neuropsychiatric problems in dementia.



 2012 Jul 9. [Epub ahead of print]

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

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.

 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.

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.


Also this study.


http://www.deepdyve.com/lp/elsevier/effects-of-ferulic-acid-and-angelica-archangelica-extract-feruguard-in-1JIk0sQm6J





 


Lane Simonian
Posted: Friday, May 2, 2014 10:06 AM
Joined: 12/12/2011
Posts: 5002


The study indicating that myo-inositol reduced the toxicity of amyloid oligomers did not make sense, so I was happy in a way to see the conclusion from this follow-up study.


We then examined the in vivo effects of the inositol stereoisomers myo-inositol, epi-inositol and scyllo-inositol [when they] were administered to the TgCRND8 mouse model of AD, which demonstrates age-associated cognitive deficits and AD-like pathology.  myo-Inositol was efffective in vitro but ineffective in vivo.


http://onlinelibrary.wiley.com/doi/10.1111/j.1742-4658.2008.06321.x/pdf




Scyllo-inositol on the other hand might help delay the onset of Alzheimer's disease in some people because it inhibits the uptake of myo-inositol in the brain.  A few people, though, died in clinical trials with the drug.



I will put up my favorite chart on the pathways of Alzheimer's disease. Above PIP2 (phosphatidylinositol 4,5 biphosphate) is myo-inositol.  The primary MAPK triggered by protein kinase C is p38 MAPK.  P38 MAPK induces the formation of inducible nitric oxide and superoxide anions which combine to form peroxynitrtes.  Peroxynitrites activate NMDA receptors (an action which can be inhibited with magnesium and/or methoxyphenols) which produces p38 MAPK which leads to the production of more peroxynitrites.



Peroxynitrites activate the beta secretase which leads to the formation of the c-terminal fragment of the amyloid precursor protein.  A second cut in this protein by the gamma secretase caused by the release of intracellular calcium leads to amyloid oligomers and amyloid plaques.  The key is to inhibit the formation of peroxynitrites rather than to inhibit the beta secretase or to remove various forms of amyloid.


[one correction to the chart: it should be PIP3--phosphatidylinositol 3,4,5 triphosphate instead of IP3--inositol 1,4,5 triphosphate on the right side of the chart].





Lane Simonian
Posted: Friday, May 2, 2014 10:24 AM
Joined: 12/12/2011
Posts: 5002


A philosophical question: if one knows the pathway that leads to Alzheimer's disease and the primary cause of Alzheimer's disease how hard is it to treat the disease effectively?  Things still come up that raise doubts about this hypothesis, but they can usually be resolved.  


Or perhaps the question can be asked in a different way, if clinical trials with certain compounds have shown effectiveness in the treatment of Alzheimer's disease is anybody with money anywhere interested in testing them on a larger scale.  If the answer is no, I (we) don't have much hope except to do it on our own.


Serenoa
Posted: Friday, May 9, 2014 10:47 AM
Joined: 4/24/2012
Posts: 484


I hear your frustration Lane. It is crazy how much is known about this disease and yet it eludes the discovery of a cure. 

 

I have been studying the molecule inositol and it's interactions based on the above posts and have now found myself back down the cell biology rabbit hole once again. So, myo-inositol is simply the most common configuration of the inositol molecule which is a natural and necessary organic molecule and not an evil villan as I had imagined. But, the overabundance found in AD brains lead me back to the fact that the gene controlling inositol is found on chromosome 21 (in Down's Syndrome there are three copies) which also has the APP gene and can cause inflammation. 

 

People with Down's Syndrome (trisomy 21) all have AD pathology by around age 40. But, guess what? There is a prevalence of trisomy 21 occurring in AD brains without having Down's Syndrome; meaning that many of the neurons in AD brains actually have three copies of chromosome 21 (called Trisomy 21 Mosaicism).  There has to be a connection. Could AD actually be a form of Down's Syndrome acquired later in life?

 

Familial AD has a mutation in the APP gene which results in more amyloid beta, which in one study is shown to cause missegregation of chromosome 21, which leads to Trisomy 21 Mosaicism and more copies of the APP gene and more amyloid. So, what about Sporadic AD and the occurrence of extra copies of chromosome 21? How is this happening? Here's the evidence:

 

http://www.sciencedirect.com/science/article/pii/S096999619990236X

 

http://www.molbiolcell.org/content/21/4/511.short

 

 



Lane Simonian
Posted: Friday, May 9, 2014 12:07 PM
Joined: 12/12/2011
Posts: 5002


Fascinating.  Peroxynitrites can cause DNA damage and DNA damage can lead to the missegregation of chromosomes.  For some reason chromosome 21 appears to be particularly vulnerable.  This is important because a high level of myo-inositol is not only 70 percent predictive of the conversion from mild cognitive impairment to Alzheimer's disease, but is one of the main factors in Alzheimer's patients who have neuropsychiatric problems.


Frustration is the perfect word, Serenoa. Too much is known about this disease not to have made more progress against it.


Serenoa
Posted: Friday, May 9, 2014 12:58 PM
Joined: 4/24/2012
Posts: 484


Yes! Oxidative damage occurs, and a certain amount is normal and happens to everyone, the body deals with it and repairs the damage. However, when oxidative damage to DNA results in causing a neuron to missegragate durring cell division (i.e. end up with an extra chomosome), that becomes a Down's Syndrome neuron. The body can't repair that. A few of these don't affect the brain, but as they accumulate over a lifetime, their effect is multiplied because they inturn cause more AD pathology. 

 

So, the build up is like a car jack with no release mechanism. The oxidative damage keeps clicking it up notch by notch, chromosome by chromosome, until the car falls off the jack. Sadly, it's like a gift that keeps on giving. A vicious cycle that starts small and becomes progressively more damaging with time. If true, this is very disturbing.



Lane Simonian
Posted: Friday, May 9, 2014 8:06 PM
Joined: 12/12/2011
Posts: 5002


I suppose the question is how often and how widespread is chromosomal damage in Alzheimer's disease.  Without knowing this, it is indeed hard to know what the level of concern should be.
Serenoa
Posted: Saturday, May 10, 2014 7:01 AM
Joined: 4/24/2012
Posts: 484


I agree. We need to know more about the prevalence of this Trisomy 21 Mosaicism in AD, as well as how it happens. I think it fits well with your oxidative damage/peroxynitrite theory Lane, as an amplifying mechanism.

 

 I have been searching "Trisomy 21 Mosaicism" and found more interesting things. It seems to be present in several or many diseases as a "mosaic" disorder, meaning the phenotype (physical form) of the person is normal but Trisomy 21 cells are occurring in certain tissues. Cancer is one example I found where they traced the Leukaemia back to mosaic occurrence of Trisomy 21.

  

I also read a case where the Trisomy 21 reversed itself as new normal cells replaced Trisomy 21 cells in blood and bone marrow. This is also very interesting as it highlights a possible method that antioxidants work to allow new cells to be created free of oxidative damage to replace the Trisomy 21 cells. This may also be the connection to Leukine which works to generate new cells. If neurons can be regenerated without DNA damage, it could possibly reverse AD. However, once the amyloid has built up, or other oxidative factors are present in the brain causing ongoing damage, it may be difficult to regenerate healthy neurons in that toxic environment.

 

Please keep looking into this Lane (or anyone else following this) and let's see what other connections/evidence we can come up with. 

  


Lane Simonian
Posted: Saturday, May 10, 2014 10:32 AM
Joined: 12/12/2011
Posts: 5002


A couple of more small clues at least.



Abstract

It is well established that oxidative stress plays a key role in the degenerative neuronal death and progression of Alzheimer's disease (AD), although it is not clear if it is the primary triggering event in the pathogenesis of this disorder. Mild cognitive impairment (MCI) is a clinical condition between normal aging and AD, characterized by a memory deficit without loss of general cognitive and functional abilities. We performed this study by a comet assay analysis to evaluate the level of primary and oxidative DNA damage in two groups of MCI and AD patients, compared to healthy controls. Data showed a significantly higher level of primary DNA damage in leukocytes of AD and also of MCI patients compared to control individuals (average: 2.09 ± 0.79 and 2.47 ± 1.01, respectively for AD and MCI, versus 1.04 ± 0.31 in controls). Moreover, the amount of oxidised DNA bases (both purines and pyrimidines) was significatively higher in the two groups of patients (AD and MCI) compared to controls. Our results give a further indication that oxidative stress, at least at the DNA level, is an earlier event in the pathogenesis of AD.

Coenzyme Q10 (Ubiquinol-10) Supplementation Improves Oxidative Imbalance in Children With Trisomy 21

To our knowledge, this is the first study to indicate that the pro-oxidant state in plasma of children with trisomy 21, as assessed by ubiquinol-10:total coenzyme Q10 ratio, may be normalized with ubiquinol-10 supplementation. Further studies are needed to determine whether correction of this oxidant imbalance improves clinical outcomes of children with trisomy 21.

That is fascinating that trisomy 21 reversed itself with new cells. 

So here is a possible loop in Alzheimer's disease.  Oxidative stress inhibits the phosphatidylinositol 3-kinase/Akt pathway which disables the body's antioxidant systems in the brain and prevents the regeneration of neurons.  The use of antioxidants and other agents help to restore some function to this pathway.

PI3K-p110-alpha-subtype signalling mediates survival, proliferation and neurogenesis of cortical progenitor cells via activation of mTORC2

 2013 Jun;91(6):771-9. doi: 10.1002/jnr.23205. Epub 2013 Mar 4.

Granulocyte macrophage colony-stimulating factor promotes regeneration of retinal ganglion cells in vitro through a mammalian target of rapamycin-dependent mechanism

 

Lane Simonian
Posted: Saturday, May 10, 2014 1:31 PM
Joined: 12/12/2011
Posts: 5002


Just a few more for now. 


 

 2013 Feb 15;319(4):498-505. doi: 10.1016/j.yexcr.2012.09.017. Epub 2012 Oct 4.

Modeling neurogenesis impairment in Down syndrome with induced pluripotent stem cells from Trisomy 21 amniotic fluid cells.

 
The level of amyloid precursor protein was significantly increased in NPCs [neuronal progenitor cells] derived from T21 AF-iPS [trisomy 21] cells compared with NPCs from normal AF-iPS cells...We observed that T21 iPS-NPCs generated fewer neurons compared with controls. T21 iPS-NPCs exhibit developmental defects during neurogenesis. Our findings suggest that T21 AF-iPS cells serve as a good source to further elucidate the impairment neurogenesis of DS and the onset of Alzheimer's disease. 

 
 2009 Dec;17(6):800-10. doi: 10.1016/j.devcel.2009.09.007.

The E3 ligase TTC3 facilitates ubiquitination and degradation of phosphorylated Akt.


 

Abstract

The serine threonine kinase Akt is a core survival factor that underlies a variety of human diseases. Although regulatory phosphorylation and dephosphorylation have been well documented, the other posttranslational mechanisms that modulate Akt activity remain unclear. We show here that tetratricopeptide repeat domain 3 (TTC3) is an E3 ligase that interacts with Akt. TTC3 contains a canonical RING finger motif, a pair of tetratricopeptide motifs, a putative Akt phosphorylation site, and nuclear localization signals, and is encoded by a gene within the Down syndrome (DS) critical region on chromosome 21. TTC3 is an Akt-specific E3 ligase that binds to phosphorylated Akt and facilitates its ubiquitination and degradation within the nucleus. Moreover, DS cells exhibit elevated TTC3 expression, reduced phosphorylated Akt, and accumulation in the G(2)M phase, which can be reversed by TTC3 siRNA or Myr-Akt. Thus, interaction between TTC3 and Akt may contribute to the clinical symptoms of DS.

 

We have identified a potentially damaging missense change in TTC3, a novel biological candidate for AD that warrants further genetic and functional examination. TTC3, which encodes an akt- kinase-regulated factor, is located in the Down syndrome critical region, and has been implicated in neuronal differentiation and learning and memory impairment.  


 

http://www.ashg.org/2012meeting/abstracts/fulltext/f120123447.htm 


 


 

 2006 May 4;25(19):2697-707.

Activation of Akt signaling is sufficient to maintain pluripotency in mouse and primate embryonic stem cells.

Author information

  • 1Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan.
 

Abstract

Embryonic stem (ES) cells can self-renew indefinitely without losing their differentiation ability to any cell types. Phosphoinositide-3 kinase (PI3K)/Akt signaling plays a pivotal role in various stem cell systems, including the formation of embryonic germ (EG) cells from primordial germ cells and self-renewal of neural stem cells. Here, we show that myristoylated, active form of Akt (myr-Akt) maintained the undifferentiated phenotypes in mouse ES cells without the addition of leukemia inhibitory factor (LIF). The effects of myr-Akt were reversible, because LIF dependence and pluripotent differentiation activity were restored by the deletion of myr-Akt. In addition, myr-Akt-Mer fusion protein, whose enzymatic activity is controlled by 4-hydroxy-tamoxifen, also maintained the pluripotency of not only mouse but also cynomolgus monkey ES cells. These results clearly demonstrate that Akt signaling sufficiently maintains pluripotency in mouse and primate ES cells, and support the notion that PI3K/Akt signaling axis regulates 'stemness' in a broad spectrum of stem cell systems.


 

The use of antioxidants to partially reverse the inhibition of the phosphatidylinositol -3 kinase/Akt pathway would partially restore neurogenesis and that should help partially reverse the disease. 


 


 


Lane Simonian
Posted: Saturday, May 10, 2014 7:05 PM
Joined: 12/12/2011
Posts: 5002


More on the role of the phosphatidyinositol 3 kinase/Akt pathway on memory, learning, and neurogenesis.


The phosphatidylinositol 3-kinase (PI3K)/AKT serine/threonin protein kinase (AKT)/mammalian target of rapamycin kinase (mTOR) signaling pathway in central nervous system (CNS) has been implicated in metabolism regulation and energy homeostasis and has emerged as an important mediator of neuronal physiology, appearing to serve as a direct link between aspects of learning and memory, neuronal survival, neurogenesis and apoptosis.


PI3K signaling has been implicated in aging and lifespan regulation, and the proliferation of adult neuronal progenitor cells, as well as in synaptic plasticity, which gives PI3K relevance to cognitive processes in addition to pathological brain aging and neurodegeneration.


The ability of PI3K to control key functions of the cell provides the incentive for investigations into the effects of the modulation of PI3K signaling pathways in different aspects of neuronal physiology, including its role in neuronal development as well as brain aging and dysfunction.


This is the pathway cut off early by the presenilin 1 gene mutation and late by peroxynitrites.


 

Familial Alzheimer disease (FAD) mutations suppress the ability of PS1 to promote PI3K/AKT signaling, prevent phosphorylation/inactivation of GSK-3 and promote activation of caspase-3. These mutation effects are reversed upon coexpression of constitutively active Akt. Together, our data indicate that the neuroprotective role of PS1 depends on its ability to activate the PI3K/Akt signaling pathway and that PS1 FAD mutations increase GSK-3 activity and promote neuronal apoptosis by inhibiting the function of PS1 in this pathway. These observations suggest that stimulation of PI3K/Akt signaling may be beneficial to FAD patients.


Peroxynitrite induces inactivation of the Akt pathway. Furthermore, overexpression of constitutively active Akt inhibits both peroxynitrite-induced Bax translocation and cell death.


And there you have Alzheimer's disease stripped down to its essence.


Myriam
Posted: Saturday, May 10, 2014 8:05 PM
Joined: 12/6/2011
Posts: 3326


Lane, can you put the following in layman's term: 

 

... our data indicate that the neuroprotective role of PS1 depends on its ability to activate the PI3K/Akt signaling pathway and that PS1 FAD mutations increase GSK-3 activity and promote neuronal apoptosis by inhibiting the function of PS1 in this pathway. These observations suggest that stimulation of PI3K/Akt signaling may be beneficial to FAD patients.