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New Therapeutic Target Discovered for Alzheimer’s Disease
Serenoa
Posted: Monday, July 28, 2014 6:45 AM
Joined: 4/24/2012
Posts: 484


Here is a hypothesis that I think has merit and I'm trying to understand better.

 

 FAD (Familial Alz) is caused by a genetic mutation in the PS1 gene. PS1 affects the processing or production of APP.

 

In sporadic late-onset AD, something other than PS1 is taking place, like oxidative damage, which takes longer but results in the same altered APP processing.

 

 In Down's the extra chromosome leads to altered APP processing.

 

 The common link is altered APP processing which leads to increased beta amyloid production. But that is only the first step in the disease. The second important factor is how the cells deal with the increased beta amyloid. In worst case it adversely affects the functioning of the cell which leads to more altered APP processing, dysregulation of calcium homeostasis, mitochondrial dysfunction, disruption of the cell cycle, phosphorylation of various proteins, etc.

 

Mutation or oxidative damage --> altered APP --> increased --> beta amyloid --> cellular dysfunction --> more altered APP -- cell death

 

Thoughts on this simple outline of the process anyone? 


Serenoa
Posted: Monday, July 28, 2014 6:58 AM
Joined: 4/24/2012
Posts: 484


Maybe we could even divide disease-causing cellular malfunctions into two categories: those that lead to altered APP production, and those that are the result of altered APP production.

 

I think that all of the various theories that have been shown to play a part in AD pathogenesis, like oxidative damage, peroxinitrites, calcium, mitochondria, endosomal, lipid rafts, etc. might fit into this model as causing altered APP production (which leads to beta amyloid) or carrying out the damage resulting from increased beta amyloid production.



Lane Simonian
Posted: Monday, July 28, 2014 10:12 AM
Joined: 12/12/2011
Posts: 4886


Your hypothesis is so good and so well stated that I hate to tamper with it, Serenoa. 


 

I will amplify a bit, though.  Presenilin gene mutations (often due to a substitution out of leucine) inhibit or prevent the activation of the neuroprotective phosphatidylinositol-3 kinase/Akt pathway (a pathway involved in neurogenesis, removal of the soluble amyloid precursor protein, regulation of blood flow in the brain, and the upregulation of various antioxidant systems).  This leads to the increased production of the amyloid precursor protein and to oxidative stress. 


 

Mutations in the amyloid precursor protein but not in the regular amyloid precursor protein results in the activation of g protein-coupled receptors which leads to oxidative stress. 


 

In late onset Alzheimer's disease, the oxidative stress does indeed take longer to set in.  The oxidative stress is due to some combination of high levels of myo-inositol (high glucose levels and high sodium levels. High levels of myo-inositol also are the link between Alzheimer's disease and Down syndrome), the inhibition of the phosphatidylinositol-3 kinase (the APOE4 gene and Fosamax, for instance) over activation of tyrosine receptor kinases (high glucose levels, angiotensin II, certain chronic viral and bacterial infections, traumatic brain injuries) or activation of g proteins either via g protein-coupled receptors or independent activation of g proteins (mercury, aluminum fluoride, sodium fluoride, stress, post traumatic stress disorder, certain pesticides and herbicides).  As a result of oxidative stress, the amyloid precursor protein is cleaved into c-terminal fragment that in turns activates g protein-coupled receptor or at least g proteins leading to more oxidative stress. 


 

These same pathways often lead to the release of intracellular calcium which results first in amyloid oligomers and then amyloid plaques.  The former are a problem because they result in the production of hydrogen peroxide which damages brain tissue and cause inflammation and can contribute to peroxynitrite formation (in part by attracting copper). 


 

http://www.ncbi.nlm.nih.gov/pubmed/16141213 


 

But this second step (the formation of beta amyloid) is not required for neuronal cell death, even though it may contribute to it.  The oxidative stress caused by mutations in the amyloid precursor protein or by the c-terminal fragment of the amyloid precursor protein (or perhaps even the oxidative stress leading to the beta secretase production of the c-terminal fragment) is enough to cause the death of neurons and this can be at least partially prevented by peroxynitrite scavengers. 


 

http://www.ncbi.nlm.nih.gov/pubmed/16141213 


 

http://www.ncbi.nlm.nih.gov/pubmed/11432978 


Serenoa
Posted: Monday, July 28, 2014 11:10 AM
Joined: 4/24/2012
Posts: 484


Please tamper away! It’s very helpful.

 

Ok, so the way that PS1 alters APP is through the inhibition of Phosphatidylinositol-3 kinase/Akt (PI3K/Akt) pathway. This increases oxidative stress and the accumulation APP molecules, while decreasing neurogenesis and blood flow.

 

But does Down Syndrome alter APP through the same mechanism? It seems that the extra APP gene by itself would increase APP molecules (just like inhibition of PI3K/Akt)? But, PI3K/Akt might not be inhibited in this first step.

 

And in Sporadic AD is oxidative damage (or other environmental factors) the factor that inhibits PI3K/Akt and eventually leads to the same result as PS1, only slower?

 
 

 


Lane Simonian
Posted: Monday, July 28, 2014 12:23 PM
Joined: 12/12/2011
Posts: 4886


These are critical questions in the chain of events.  Down Syndrome increases levels of myo-inositol because people with Down Syndrome have an extra copy of the chromosome containing the gene for the sodium/myo-inositol cotransporter.  This result in high levels of phosphatidylinositol 4,5 biphosphate.  Phosphatidylinositol 4,5 biphosphate can be acted upon by the phosphatidylinositol-3 kinase to produce phosphatidylinositol 3,4,5 triphosphate or it can be converted by phospholipase C into inositol 1,4,5 triphosphate which leads to the release of intracellular calcium (and the subsequent production of amyloid oligomers and plaques) and to the activation of protein kinase C which leads to the release of the soluble amyloid precursor protein and which under conditions of oxidative stress leads to the beta secretase cutting of the amyloid precursor protein into a c-terminal fragment. 


Down syndrome and most cases of late onset Alzheimer's disease are likely due to oxidative stress first and then later to the inhibition of the phosphatidylinositol 3-kinase (the opposite order of the effect of presenilin gene mutations).  The end result is the same, but as you note happens sooner with people who have presenilin gene mutations (although even then a diet high in antioxidant polyphenols might delay the onset by several years).


http://www.jneurosci.org/content/17/11/4212.full.pdf


http://www.nature.com/cdd/journal/v13/n9/full/4401831a.html


We are probably as close as we have ever been to understanding how several genetic mutations contribute to the pathways leading to Alzheimer's disease and how several factors that increase oxidative stress operate through many of these same pathways but over a longer period of time. Thanks, Serenoa!


Serenoa
Posted: Monday, July 28, 2014 4:50 PM
Joined: 4/24/2012
Posts: 484


This is interesting. So the increase of myo-inositol in the brain of Down's leads to beta-amyloid production. And you think the increased production of APP in Down's is secondary to that. What about mice who are bread to over produce APP and develop Alz-like pathology?

 

Also, what is happening in Down's that they don't all develop Alz, even though they have the pathology? Whereas all PS1 mutations develop Alz (I think). What's the difference?



Lane Simonian
Posted: Monday, July 28, 2014 6:17 PM
Joined: 12/12/2011
Posts: 4886


In Down syndrome there are high levels of myo-inositol lead to high levels of phosphatidylinositol 4,5 biphosphate due to high levels of myo-inositol. Some of this can be converted into phosphaditylinositol 3,4,5 biphosphate for awhile at least.  And perhaps low levels of homocysteine in people with Down syndrome confer some protection as well.  As long as oxidative stress is kept in check high levels of myo-inositol are not an absolute guarantee of Alzheimer's disease. 


 

http://www.docguide.com/myo-inositol-n-acetylaspartate-are-sensitive-biomarkers-conversion-mci-alzheimers-disease?tsid=6 


 

In the case of people with the presenilin gene mutation, the phosphatidylinositol-3 kinase is apparently cut off altogether.  The only pathway is toward peroxynitrites and the abnormal processing of the amyloid precursor protein.  However, even then, there may be variations due to diet--diets which increase oxidative stress might lead to even earlier onset where antioxidant diets may lead to a little later onset. 


 

So high levels of myo-inositol greatly increase the risk for Alzheimer's disease, but do not guarantee it.  Whereas the presenilin gene mutation inactivation of the phosphatidylinositol-3 kinase guarantees Alzheimer's disease although there may be some interventions that will delay the age of onset. 


 

Under non-oxidative or mild oxidative conditions, non-mutated forms of the amyloid precursor protein or amyloid itself are not problems.  It is only under conditions of oxidative stress (either precipitated by presenilin gene mutations, amyloid precursor protein mutations, other genes, stress, environmental toxins, high levels of glucose, traumatic brain injury, etc.) that the abnormal processing of the amyloid precursor protein occurs and Alzheimer's disease is triggered. 


 

Under conditions of oxidative stress both the c-terminal fragment of the amyloid precursor protein and amyloid oligomers (but not amyloid plaques) makes things worse.  The question of whether it is better just to have the beta secretase cut (to form the c-terminal fragment of the amyloid precursor protein) or to have a beta and gamma secretase cut to form amyloid oligomers is difficult question to answer (you can also just have the gamma secretase cut leading to amyloid oligomers and plaques but this is not a problem as it is a sign of limited oxidative stress: for the beta secretase cut depends upon peroxynitrites and hydrogen peroxide whereas the gamma secretase cut only depends upon the release of intracellular calcium).  Both the c-terminal fragment and amyloid oligomers increase oxidative stress and they may do so in nearly equal amounts.  So if you inhibit the gamma secretase, or remove amyloid oligomers, or the metals around amyloid oligomers you are not doing much, but if you reduce the oxidative stress that leads to the abnormal processing of the amyloid precursor protein or repair some of the subsequent damage done by oxidants such as peroxynitrites and hydrogen peroxide you might be able to accomplish a lot. 


 

In another study, avagacestat treatment [a gamma secretase inhibitor] did not improve learning and memory in APP mice, and actually worsened cognition in normal mice (ARF related news story on Mitani et al., 2012)...The authors attributed the cognitive decline...to accumulation of APP C-terminal fragments, suggesting these peptides could be harmful to people as well. 


 

http://www.alzforum.org/news/research-news/deja-vu-ad-patients-again-look-worse-g-secretase-inhibitor 


 

To try to summarize:  


 

high levels of myo-inositol increase the risk of Alzheimer's disease. 


 

inhibition of the phosphatidylinositol-3 kinase by presenilin gene mutations leads to Alzheimer's disease. 


 

activation of g protein-coupled receptors by mutated amyloid precursor proteins leads to Alzheimer's disease. 


 

The presence of the amyloid precursor protein in the absence of oxidative stresss--not a problem. 


 

Amyloid oligomers and amyloid plaques in the absence of oxidative stress--not a problem. 


 

Oxidative stess leads to the formation of the c-terminal fragment of the amyloid precursor protein. 


 

The c-terminal fragment of the amyloid precursor protein and amyloid oligomers contribute to oxidative stress perhaps in nearly equal measures. 


 

Alzheimer's disease can be prevented or delayed by reducing oxidative stress and it can be treated by reducing oxidative stress and by reversing the damage done by oxidative stress. 


 


 


Lane Simonian
Posted: Tuesday, July 29, 2014 12:03 AM
Joined: 12/12/2011
Posts: 4886


The Down syndrome connection to Alzheimer's disease has me a bit perplexed but from a different angle.  Why do people with an extra chromosome leading to the high production of myo-inositol and to the formation of amyloid precursor proteins almost always have the supposed hallmarks of Alzheimer's disease (plaques and tangles) but only actually have what is essentially Alzheimer's disease less than fifty percent of the time after the age of 40?   


 

Here may be part of the answer, people with Down syndrome have high levels of hydrogen sulfide and hydrogen sulfide is a peroxynitrite scavenger. 


 

 2003 Jan 30;116A(3):310-1.

Endogenous hydrogen sulfide overproduction in Down syndrome.

 
 2004 Aug;90(3):765-8.

The novel neuromodulator hydrogen sulfide: an endogenous peroxynitrite 'scavenger'?

Abstract

Hydrogen sulfide (H2S) is a well-known cytotoxic gas. Recently it has been shown to stimulate N-methyl-D-aspartate (NMDA) receptors to enhance long-term potentiation suggesting a novel neuromodulatory role in vivo. Endogenous levels of H2S in the brain are reported to range between 10 and 160 microm. Considerably lower H2S levels are reported in the brains of Alzheimer's disease (AD) patients, where levels of brain protein nitration (probably mediated by peroxynitrite) are markedly increased. Activation of NMDA receptors leads to intracellular tyrosine nitration by peroxynitrite. Because H2S and peroxynitrite are important mediators in brain function and disease, we investigated the effects of the H2S 'donor', sodium hydrogen sulfide (NaSH) on peroxynitrite-mediated damage to biomolecules and to cultured human SH-SY5Y cells. H2S significantly inhibited peroxynitrite-mediated tyrosine nitration and inactivation of alpha1-antiproteinase to a similar extent to reduced glutathione at each concentration tested (30-250 microm). H2S also inhibited peroxynitrite-induced cytotoxicity, intracellular protein nitration and protein oxidation in human neuroblastoma SH-SY5Y cells. These data suggest that H2S has the potential to act as an inhibitor of peroxynitrite-mediated processes in vivo and that the potential antioxidant action of H2S deserves further study, given that extracellular GSH [glutathione] levels in the brain are very low.


Lane Simonian
Posted: Tuesday, July 29, 2014 9:57 AM
Joined: 12/12/2011
Posts: 4886


Some conclusions about Alzheimer's disease:


Alzheimer's disease is caused by oxidative stress.


Several dozen factors can contribute to oxidative stress in the brain either causing Alzheimer's disease by themselves or in combination with other risk factors.


Certain antioxidants can either prevent or delay the onset of Alzheimer's disease.


Internal or external antioxidants can limit oxidative stress and in such cases a person can have the purported hallmarks of Alzheimer's disease (plaques and tangles) without having the disease.


Good peroxynitrite scavengers can slow down the progression of the disease. Excellent peroxynitrite scavengers can partially reverse the disease.


Serenoa
Posted: Tuesday, July 29, 2014 5:47 PM
Joined: 4/24/2012
Posts: 484


There is no doubt as to the key role that oxidative stress and peroxynitrites play in this disease. There are so many connections there.  I still feel like there is a missing piece to the puzzle. Something else going on that I need to understand. 

 

Thank you Lane for addressing the Down Syndrome question. Why don't they all get AD symptoms along with the pathology? I like your answer. It seems that having overproduction of various things like myo-inositol transporter, APP, hydrogen sulfide, throws things off and causes imbalances, mostly pathogenic, but maybe not all.

 

Another question I have considered is in PS1 (or APP) mutations, being a direct effect on APP processing, why does it take 40 years to manifest AD? Why not right from birth? Even with this genetic defect it still takes 30 to 50 years for the pathology to cause symptoms.

 

My feeling is that it all points to the common factor, the build up of beta-amyloid 42 oligomers (not plaques). I know that the oxidative damage occurs before and without beta-amyloid being involved. But, since altered APP processing is fundamental to AD, and mouse models demonstrate that this alone results in AD pathology. Beta-amyloid oligomers may be playing a bigger role than I thought. Can you have AD without oxidative stress? Can you have AD without altered APP processing and oligomers? Yes, I know you don't have to have plaques, but do you have to have oligomers to have AD?

 

If beta-amyloid is playing a more causative role, how is that happening? What about the cellular receptors (or channels) that can be activated by beta-amyloid oligomers and result in disruption of cellular processes? One such receptor is LilrB2 and PirB. This is making a lot sense to me right now because mice without this receptor are not affected by AD pathology.

 

Human LilrB2 Is a β-Amyloid Receptor and Its Murine Homolog PirB Regulates Synaptic Plasticity in an Alzheimer’s Model

 

http://www.sciencemag.org/content/341/6152/1399.short

 

 



Lane Simonian
Posted: Tuesday, July 29, 2014 7:55 PM
Joined: 12/12/2011
Posts: 4886


Phospholipase C gamma via the release of intracellular calcium activates LILRB2 receptor and cofilin. This is the same pathway that leads to amyloid oligomers. 


 

http://www.bloodjournal.org/content/early/2014/06/03/blood-2014-01-549162?sso-checked=1 


 

http://atvb.ahajournals.org/content/29/3/401.full.pdf 


 

http://www.nature.com/nrc/journal/v7/n6/fig_tab/nrc2148_F1.html 


 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166455/ 


 

The really big question is whether the activation of this pathway (and later deactivation of this pathway) is needed for Alzheimer's disease. 


 

 2007 Feb;35(1):21-44.

Cofilin-mediated neurodegeneration in Alzheimer's disease and other amyloidopathies.

Erratum in

  • Mol Neurobiol. 2007 Oct;36(2):201-4.
 

Abstract

Transport defects may arise in various neurodegenerative diseases from failures in molecular motors, microtubule abnormalities, and the chaperone/proteasomal degradation pathway leading to aggresomal-lysosomal accumulations. These defects represent important steps in the neurodegenerative cascade, although in many cases, a clear consensus has yet to be reached regarding their causal relationship to the disease. A growing body of evidence lends support to a link between neurite transport defects in the very early stages of many neurodegenerative diseases and alterations in the organization and dynamics of the actin cytoskeleton initiated by filament dynamizing proteins in the ADF/cofilin family. This article focuses on cofilin, which in neurons under stress, including stress induced by the amyloid-beta (Abeta) 1-42 peptide, undergoes dephosphorylation (activation) and forms rod-shaped actin bundles (rods). Rods inhibit transport, are sites of amyloid precursor protein accumulation, and contribute to the pathology of Alzheimer's disease. Because rods form rapidly in response to anoxia, they could also contribute to synaptic deficits associated with ischemic brain injury (e.g., stroke). Surprisingly, cofilin undergoes phosphorylation (inactivation) in hippocampal neurons treated with Abeta1-40 at high concentrations, and these neurons undergo dystrophic morphological changes, including accumulation of pretangle phosphorylated-tau. Therefore, extremes in phosphoregulation of cofilin by different forms of Abeta may explain much of the Alzheimer's disease pathology and provide mechanisms for synaptic loss and plaque expansion.

 

Early on, amyloid oligomers increase oxidative stress in Alzheimer's disease (but so too do the c-terminal fragment of the amyloid precursor protein).  One strategy for treating the disease early on is to prevent the formation of oligomers and prevent BACE activation (which leads to the c-terminal fragment).  One of the best ways to do this is to inhibit phospholipase C gamma with polyphenols.  Ferulic acid is a good example. 


 

 2013;37(1):19-28. doi: 10.3233/JAD-130164.

Ferulic acid inhibits the transition of amyloid-β42 monomers to oligomers but accelerates the transition from oligomers to fibrils.

 
Taken together, we have identified a novel phenomenon in which FA inhibits the formation of Aβ42 oligomers while accelerating the transition of Aβ42 oligomers to fibrils, and we have shown that FA protects against Aβ42-induced toxicity in vitro by preventing Aβ42 from forming oligomers. 

 

Ferulic Acid Is a Nutraceutical β-Secretase Modulator That Improves Behavioral Impairment and Alzheimer-like Pathology in Transgenic Mice

  • Takashi Mori mail,

     

     

     
  •  
  • Naoki Koyama equal contributor,

     

     

     
  •  
  • Marie-Victoire Guillot-Sestier equal contributor,

     

     

     
  •  
  • Jun Tan,

     

     
  •  
  • Terrence Town mail 
 

 

Abstract

Amyloid precursor protein (APP) proteolysis is required for production of amyloid-β (Aβ) peptides that comprise β-amyloid plaques in brains of Alzheimer’s disease (AD) patients. Recent AD therapeutic interest has been directed toward a group of anti-amyloidogenic compounds extracted from plants. We orally administered the brain penetrant, small molecule phenolic compound ferulic acid (FA) to the transgenic PSAPP mouse model of cerebral amyloidosis (bearing mutant human APP and presenilin-1 transgenes) and evaluated behavioral impairment and AD-like pathology. Oral FA treatment for 6 months reversed transgene-associated behavioral deficits including defective: hyperactivity, object recognition, and spatial working and reference memory, but did not alter wild-type mouse behavior. Furthermore, brain parenchymal and cerebral vascular β-amyloid deposits as well as abundance of various Aβ species including oligomers were decreased in FA-treated PSAPP mice. These effects occurred with decreased cleavage of the β-carboxyl-terminal APP fragment, reduced β-site APP cleaving enzyme 1 protein stability and activity, attenuated neuroinflammation, and stabilized oxidative stress. As in vitro validation, we treated well-characterized mutant human APP-overexpressing murine neuron-like cells with FA and found significantly decreased Aβ production and reduced amyloidogenic APP proteolysis. Collectively, these results highlight that FA is a β-secretase modulator with therapeutic potential against AD.

 


 


 


 


 


 


Lane Simonian
Posted: Tuesday, July 29, 2014 8:21 PM
Joined: 12/12/2011
Posts: 4886


Even with presenilin gene mutations it takes years for the oxidant pathways to be sufficiently activated and for the body's own antioxidant systems to be exhausted.  And even then the consumption of certain antioxidants may further delay the onset of the disease.


Is it possible to have Alzheimer's disease without oxidative stress?  I don't think so.  Under conditions of oxidative stress can you have Alzheimer's disease without amyloid oligomers?  I don't know.


Lane Simonian
Posted: Tuesday, July 29, 2014 11:38 PM
Joined: 12/12/2011
Posts: 4886


This study ties many things together. 


 

Inherited familial Alzheimer's disease (AD) is characterized by small increases in the ratio of Aβ42 versus Aβ40 peptide which is thought to drive the amyloid plaque formation in the brain of these patients. Little is known however whether ageing, the major risk factor for sporadic AD, affects amyloid beta-peptide (Aβ) generation as well. Here we demonstrate that the secretion of Aβ is enhanced in an in vitro model of neuronal ageing, correlating with an increase in γ-secretase complex formation. Moreover we found that peroxynitrite (ONOO), produced by the reaction of superoxide anion with nitric oxide, promoted the nitrotyrosination of presenilin 1 (PS1), the catalytic subunit of γ-secretase. This was associated with an increased association of the two PS1 fragments, PS1-CTF and PS1-NTF, which constitute the active catalytic centre. Furthermore, we found that peroxynitrite shifted the production of Aβ towards Aβ42and increased the Aβ42/Aβ40 ratio. Our work identifies nitrosative stress as a potential mechanistic link between ageing and AD. 

http://onlinelibrary.wiley.com/doi/10.1002/emmm.201200243/full


 

 

The suggestion is that the peroxynitrite-mediated nitration of presenilin 1 increases the gamma (y) secretase activity which leads to the formation of amyloid oligomers. The amyloid oligomers increase oxidative stress but they are neither the initial source or sources of that stress nor is the subsequent formation of plaques.   In those rare cases where peroxynitrites only produce a c-terminal fragment of the amyloid precursor protein and not amyloid oligomers, the oxidative damage may still be sufficient to cause Alzheimer's disease. 


Lane Simonian
Posted: Wednesday, July 30, 2014 12:20 AM
Joined: 12/12/2011
Posts: 4886


Aha!  Here is the connection between peroxynitrites and the gamma secretase (which requires intracellular caclium release and results in the formation of amyloid oligomers).


We show that HG [high glucose] and peroxynitrite (ONOO-) formed by the interaction of superoxide and nitric oxide promote calcium release through IP3Rs [inositol triphosphate receptors] in atrial cardiomyocytes. 


http://cardiologyacademicpress.com/soap/pdf/delme_431_53034e0b947123.17741017.pdf


Serenoa
Posted: Wednesday, July 30, 2014 6:35 AM
Joined: 4/24/2012
Posts: 484


Excellent! Thank you Lane. Lots to digest here, but one thing that jumps out at me is the shift in production of AB42 over AB40. That's all it takes for amyloidosis since the AB40 does not seem to be toxic to the cell.

 

Also, I was looking at the effects of fructose in relation to diet and health (not Alzheimer's) and noticed some association with PKC in the liver. I haven't looked at fructose in relation to AD yet but your info on PKC and calcium makes me wonder. I bet intake of sugar parallels rise in rates of AD.

 

I guess the piece of the puzzle I'm looking for is a "bad guy" to blame for the increase in AD apart from genetics and natural aging. I know there are lots of environmental and lifestyle factors, but I want something really solid with overwhelming evidence supporting it. And, I think of oxidative stress as a result of a "bad guy" not the bad guy itself. In other words, some amount of oxidative stress in a natural part of aging but too much, or the wrong kind, is unacceptable.



Lane Simonian
Posted: Wednesday, July 30, 2014 12:12 PM
Joined: 12/12/2011
Posts: 4886


Very good, Serenoa.  Awhile back I ran across this article on fructose and methylglyoxal.


Dietary Fructose Feeding Increases Adipose Methylglyoxal Accumulation in Rats in Association with Low Expression and Activity of Glyoxalase-2

http://www.mdpi.com/2072-6643/5/8/3311
Methylglyoxal leads to the activation of phospholipase C beta and to the subsequent release of intracellular calcium, activation of protein kinase C and the formation of peroxynitrites.



 2005 Jan 15;38(2):286-93.

Methylglyoxal-induced nitric oxide and peroxynitrite production in vascular smooth muscle cells.

http://www.ncbi.nlm.nih.gov/pubmed/15607912


Although I don't have the studies to back it up, I am almost certain that a diet high in carbohydrates, sugar, and high fructose corn syrup with limited amounts of polyphenols in fruits, spices, and vegetables has contributed to the rise in Alzheimer's disease, especially in the United States.  

Some amount of oxidative stress is indeed a part of aging.  Extremely high levels of oxidative stress triggered by one or an array of factors eventually is a time bomb for the brain--more rapidly in those with presenilin gene mutations and with amyloid precursor protein mutations.  The key is to delay as long as possible the high levels of oxidative stress needed to produce Alzheimer's disease.

Lane Simonian
Posted: Wednesday, July 30, 2014 6:16 PM
Joined: 12/12/2011
Posts: 4886


This is not exactly the study I was looking for, but it is still useful.  More distinction between different types of fatty acids would be helpful and the threat to the brain presented by carbohydrates for people wtihout Celiac disease is likely due more to the conversion of glucose to myo-inositol and not to the production of zonulin. Otherwise, though, the writer makes some valid points. 


 

Could a Low-Fat Diet be Causing Mental Decline?

 

grain-brain-book
 
Why Low-Carbohydrate Diets are Better for Your Brain Health

Kristin Davis RD

Dr. David Perlmutter is a neurosurgeon and author of the book Grain Brain. While it might sound like Grain Brain supports grain for brain health that idea couldn’t be further from the truth. The book is actually about how BAD grains are. Eating a low-fat, high-carb diet can be detrimental to our brain’s functioning. Perlmutter cites research on the subject of brain health throughout his book, with surprising outcomes. Here are some of the findings.

 

From the Journal of Alzheimer’s Disease, research found that a high-fat diet reduced the risk for developing dementia 44%, while a high-carb diet increased the risk 90%.

 

From the Framingham Heart Study which followed approximately 1800 men and women for up to 18 years, those subjects with the highest cholesterol had the least risk for developing cognitive issues while those with lowest levels had higher risk for cognitive decline. Subsequent studies found that high cholesterol increased longevity.

 

While you may have heard that LDL is the “bad” cholesterol, it’s not really the LDL that causes trouble. We need LDL to deliver cholesterol to the brain. This is good thing! However, damaged LDL, caused by oxidation, cannot do its job effectively. Oxidation is caused by sugar binding to the molecule. It’s called glycation and it’s caused by eating a high-carbohydrate diet. Oxidized LDL can also lead to atherosclerosis.

 

And if you think you already know about gluten sensitivity, I suggest you think again.  Perlmutter explains that gluten sensitivity is not the same as Celiac disease and that eating gluten can affect the brain without ANY gastrointestinal symptoms. The reason is that gluten is pro-inflammatory. Whenever we eat gluten, our bodies make a protein called Zonulin. Zonulin production causes a leaky gut, which in turn can impair the blood-brain barrier. The other term for this? Leaky brain!

 

Haven’t heard the term leaky gut? It’s when our digestive tract can no longer keep foreign objects (from food) out of our blood stream and we end up fighting off particles that don’t belong inside of our bodies.

 

Between inflammation and oxidation, our brains are fighting a losing battle. But it’s a battle that doesn’t have to happen at all if we change what we eat in the first place. Reducing carbohydrates and sugars is one of the easiest ways to affect our future brain function. How empowering is that?

 

For those of us with Celiac disease, zonulin/gluten poses a specific problem, as it triggers an oxidative pathway.   


 

Abstract

The intercellular tight junctions (TJs) of endothelial cells represent the limiting structure for the permeability of the blood-brain barrier (BBB). Although the BBB has been recognized as being the interface between the bloodstream and the brain, little is known about its regulation. Zonulin and its prokaryotic analogue, zonula occludens toxin (Zot) elaborated by Vibrio cholerae, both modulate intercellular TJs by binding to a specific surface receptor with subsequent activation of an intracellular signaling pathway involving phospholipase C and protein kinase C activation and actin polymerization.

 

There are so many factors that increase the risk for oxidative stress that it is difficult to say which factors are determinant in themselves and which require other stressors. 


Serenoa
Posted: Thursday, July 31, 2014 8:11 AM
Joined: 4/24/2012
Posts: 484


OK, I'm just now grasping your earlier post Lane. You said:

 

"In Alzheimer's disease at least, oxidative stress leads to the blockade of the PI(3)K-Akt pathway and also to an increased processing of the amyloid precursor protein and a decreased production of the amyloid precursor protein.  A lose, lose, lose situation."

 

And the article you posted:

Phosphatidylinositol-3-kinase-Akt kinase and p42/p44 mitogen-activated protein kinases mediate neurotrophic and excitoprotective actions of a secreted form of amyloid precursor protein.


 

There is an important clue here if we could figure it out. I have read that AD brains have decreased APP, and one article said it was due to decrease in production of APP not the over metabolism of the APP molecule. Why would APP production decrease? Were they referring to sAPPa maybe? Could a decrease in sAPPa be the result of BASE and y-secretase altering normal APP processing in the lipid membrane? Resulting in the bad APP fragment (c-terminal APP?) and AB42?

 

 And, if APP is decreased in AD brain, what's the deal with Down Syndome AD where there is overproduction of APP???

 

 

 



Lane Simonian
Posted: Thursday, July 31, 2014 11:00 AM
Joined: 12/12/2011
Posts: 4886


I am not sure if my thought process is right here but when you have more of the secreted form of the amyloid precursor protein (before it is sliced up), there will be less parent amyloid precursor protein left.   


 

The secreted form of the amyloid precursor protein is a tricky animal.   Protein kinase C leads to the secretion of the amyloid precursor protein and via Src kinase protein kinase C can either lead to the activation of the neuroprotective phosphatidylinositol 3-kinase/Akt pathway or to the neurodestructive production of peroxynitrites.  Some indications of the latter. 


 

 1998 Apr 15;18(:2907-13.

Protein kinase C activation increases release of secreted amyloid precursor protein without decreasing Abeta production in human primary neuron cultures.

Abstract

 

Overexpression and altered metabolism of amyloid precursor protein (APP) resulting in increased 4 kDa amyloid beta peptide (Abeta) production are believed to play a major role in Alzheimer's disease (AD). Therefore, reducing Abeta 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 Abeta release (; ; ). 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 Abeta. 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 Abeta levels. 


 

 2001 Feb;76(3):846-54.

Activation of microglia by secreted amyloid precursor protein evokes release of glutamate by cystine exchange and attenuates synaptic function.

Barger SW1, Basile AS. 


 


 

And an interesting one for autism where the n-truncated form of the amyloid precursor protein can also be associated with oxidative stress (although apparently not as much as the c-truncated form). 


 


 

 2006 Jun;21(6):444-9.

High levels of Alzheimer beta-amyloid precursor protein (APP) in children with severely autistic behavior and aggression.

Abstract

 

Autism is characterized by restricted, repetitive behaviors and impairment in socialization and communication. Although no neuropathologic substrate underlying autism has been found, the findings of brain overgrowth via neuroimaging studies and increased levels of brain-derived neurotrophic factor (BDNF) in neuropathologic and blood studies favor an anabolic state. We examined acetylcholinesterase, plasma neuronal proteins, secreted beta-amyloid precursor protein (APP), and amyloid-beta 40 and amyloid-beta 42 peptides in children with and without autism. Children with severe autism and aggression expressed secreted beta-amyloid precursor protein at two or more times the levels of children without autism and up to four times more than children with mild autism. There was a trend for children with autism to show higher levels of secreted beta-amyloid precursor protein and nonamyloidogenic secreted beta-amyloid precursor protein and lower levels of amyloid-beta 40 compared with controls. This favors an increased alpha-secretase pathway in autism (anabolic), opposite to what is seen in Alzheimer disease. Additionally, a complex relationship between age, acetylcholinesterase, and plasma neuronal markers was found. 


 

And the comparison with Down syndrome. 


 

 1997 Feb;41(2):271-3.

Plasma levels of amyloid beta proteins Abeta1-40 and Abeta1-42(43) are elevated in Down's syndrome.

Abstract

To investigate the effect of the overexpression of beta-amyloid precursor protein (APP) on the production of two major amyloid beta protein (Abeta) species, Abeta40 and Abeta42(43), we measured amounts of Abeta1-40 and Abeta1-42(43) in the plasma from 44 patients with Down's syndrome (DS) (age, 19-61 years) and 66 age-matched normal controls using enzyme-linked immunosorbent assays. Plasma concentrations of both Abeta1-40 and Abeta1-42(43) were increased about 3-fold and 2-fold, respectively, in DS patients compared with normal controls. Especially, the increases in plasma Abeta1-40 in DS patients were statistically higher than the 1.5-fold increase one might predict based on the gene dose of APP in DS. These findings showed that both Abeta1-40 and Abeta1-42(43) are increased in plasma in DS patients, the former more than the latter, suggesting that overexpression of APP and/or other genes may have different effects on the production of these two Abeta species in DS.

 

Maybe because amyloid precursor protein levels are higher in people with Down syndrome than in Alzheimer's disease, amyloid precursor protein levels remain higher. 

 

 1993 Jun;4(6):757-9.

Plasma amyloid precursor protein is decreased in Alzheimer's disease.

Abstract

Alzheimer's disease is characterized by amyloid deposits whose major protein component is beta A4. beta A4 is a product of the amyloid precursor protein (APP). APP was assayed in partially purified plasma samples from 16 sporadic Alzheimer's disease patients, 12 age-matched controls, 15 Down's syndrome individuals aged 19-36 years and 8 young to middle-aged controls (22-51 years). 14 of the 16 Alzheimer's disease patients had decreased plasma APP when compared with age-matched controls. 14 of the 15 Down's syndrome individuals had similar levels of APP when compared with age-matched and elderly non-demented controls by immunoblotting, whereas one had levels of APP less than controls. Taken together with results from a previous report (Lancet 1992; 340: 453-454), the decreased plasma APP levels mirror the changes observed with cerebrospinal fluid APP levels in Alzheimer's disease


 

  


Serenoa
Posted: Thursday, July 31, 2014 12:06 PM
Joined: 4/24/2012
Posts: 484


Thank you for reposting those. Wow, it really is confusing isn't it. APP is a "tricky animal" indeed!

 

Thanks for the Dr. Pearlmutter info. I think he is right in many regards. I should get his book. I've been researching fructose, but not found any smoking gun yet.


Lane Simonian
Posted: Thursday, July 31, 2014 12:26 PM
Joined: 12/12/2011
Posts: 4886


This maybe the crux of it.  Mild activation of g protein-coupled receptors (such as serotonin receptors) and tyrsosine receptor kinases result in the activation of protein kinase C and the src kinases and the neuroprotective phosphatidylinositol 3 kinase/Akt pathway.  The phoshatidylinositol-3 kinase among other things removes excess secreted amyloid precursor protein alpha.  But if you over-stimulate g protein-coupled receptors (or directly activate g proteins) or tyrsoine kinase receptors it leads to cognitive impairment and potentially to Alzheimer's disease. 

 


 

Mild activation of serotonin receptors: 


 

Proteolytic processing of the amyloid precursor protein (APP) by the β- and γ-secretases releases the amyloid-β peptide (Aβ), which deposits in senile plaques and contributes to the etiology of Alzheimer's disease (AD). The α-secretase cleaves APP in the Aβ peptide sequence to generate soluble APPα (sAPPα). Upregulation of α-secretase activity through the 5-hydroxytryptamine 4 (5-HT4) receptor has been shown to reduce Aβ production, amyloid plaque load and to improve cognitive impairment in transgenic mouse models of AD. Consequently, activation of 5-HT4 receptors following agonist stimulation is considered to be a therapeutic strategy for AD treatment; however, the signaling cascade involved in 5-HT4receptor-stimulated proteolysis of APP remains to be determined. Here we used chemical and siRNA inhibition to identify the proteins which mediate 5-HT4d receptor-stimulated α-secretase activity in the SH-SY5Y human neuronal cell line. We show that G protein and Src dependent activation of phospholipase C are required for α-secretase activity, while, unexpectedly, adenylyl cyclase and cAMP are not involved. Further elucidation of the signaling pathway indicates that inositol triphosphate phosphorylation and casein kinase 2 activation is also a prerequisite for α-secretase activity. Our findings provide a novel route to explore the treatment of AD through 5-HT4 receptor-induced α-secretase activation. 


 

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0087014 


 

Overstimulation of serotonin receptors: 


 

Pathophysiology. Serotonin syndrome’s symptoms and signs appear to result from stimulation of specific central and peripheral serotonin receptors, especially 5HT1a and 5HT2. Others—such as 5HT3 and 5HT4—may also be involved in causing GI symptoms and may affect dopaminergic transmission. 


 

Table 1 

How to recognize serotonin syndrome 

 

System 

Clinical signs and symptoms 

Autonomic 

Diaphoresis, hyperthermia, hypertension, tachycardia, pupillary dilatation, nausea, diarrhea, shivering

Neuromotor 

Hyperreflexia, myoclonus, restlessness, tremor, incoordination, rigidity, clonus, teeth chattering, trismus, seizures

Cognitive-behavioral 

Confusion, agitation, anxiety, hypomania, insomnia, hallucinations, headache


Lane Simonian
Posted: Thursday, July 31, 2014 1:05 PM
Joined: 12/12/2011
Posts: 4886


Our posts crossed, but thanks for the additional comments.  Here is more on the dual nature of serotonin receptors (and by extension all g-protein coupled receptors). 


 

Abstract

The 5-HT1A receptor is a prototypical member of the large and diverse serotonin receptor family. One key role of this receptor is to stimulate cell proliferation and differentiation via the extracellular signal regulated protein kinase (ERK) mitogen activated protein (MAP) kinase. There are few reports on the ability of the 5-HT1A receptor to modulate other MAP kinases such as c-Jun N-terminal kinase (JNK), which is activated by various extracellular stimuli, resulting in cell growth, differentiation, and programmed cell death. We report here for the first time that the 5-HT1A receptor stimulates JNK. JNK stimulation was Pertussis toxin-sensitive and was mediated by Rho family low molecular weight GTPases. The 5-HT1A receptor also increased apoptosis, which was mimicked by the MEK inhibitor PD98059, and blocked by the JNK inhibitor SP600125. These results suggest that the 5-HT1A receptor stimulates both ERK-dependent anti-apoptotic pathways and JNK-dependent pro-apoptotic pathways in CHO cells.

 

Through g protein-coupled receptors and tyrosine kinase receptors the body and brain divy out between pro-cell growth and cell death pathways, but when they go out of whack a person may get cancer or a neurodegenerative disease.  The src kinase is perfectly positioned to contribute to either one. 


 

Regulation of Src Family Kinases in Human Cancers

 
http://www.hindawi.com/journals/jst/2011/865819/
 

Inhibition of Src kinase activity attenuates amyloid associated microgliosis in a murine model of Alzheimer's disease.

 
 
And src kinase produced peroxynitrites result in cell growth (potentially leading to cancer) in parts of the body other than the brain whereas in the brain it leads to cell death. 
 
Peroxynitrite (ONOO) has been vastly implicated in mutagenesis and cancer development. 

 
http://www.sciencedirect.com/science/article/pii/S0008874908001548 

 

Widespread Peroxynitrite-Mediated Damage in Alzheimer’s Disease

 
 
http://www.jneurosci.org/content/17/8/2653.full

 

 

Serenoa
Posted: Thursday, July 31, 2014 2:55 PM
Joined: 4/24/2012
Posts: 484


I thought I had seen JNK pathway connected to fructose before. This is what a quick search turned up. Hmmm...

 

 High Dietary Fructose Induces a Hepatic Stress Response Resulting in Cholesterol and Lipid Dysregulation

 

http://press.endocrine.org/doi/abs/10.1210/en.2003-1167

 

 

 

Fructose and the Metabolic Syndrome: Pathophysiology and Molecular Mechanisms

 Emerging evidence suggests that increased dietary consumption of fructose in Western society may be a potentially important factor in the growing rates of obesity and the metabolic syndrome. This review will discuss fructose-induced perturbations in cell signaling and inflammatory cascades in insulin-sensitive tissues. In particular, the roles of cellular signaling molecules including nuclear factor kappa B (NFkB), tumor necrosis factor alpha (TNF-α), c-Jun amino terminal kinase 1 (JNK-1), protein tyrosine phospha-tase 1B (PTP-1B), phosphatase and tensin homolog deleted on chromosome ten (PTEN), liver X receptor (LXR), farnesoid X receptor (FXR), and sterol regulatory element-binding protein-1c (SREBP-1c) will be addressed. Considering the prevalence and seriousness of the metabolic syndrome, further research on the underlying molecular mechanisms and preventative and curative strategies is warranted

 

http://onlinelibrary.wiley.com/doi/10.1111/j.1753-4887.2007.tb00322.x/abstract

 

 

 

  


Lane Simonian
Posted: Thursday, July 31, 2014 3:36 PM
Joined: 12/12/2011
Posts: 4886


A good find which makes possible a few more connections.


Background

Fructose produces hepatic insulin resistance in humans and animals. We have proposed that the selective metabolism of fructose by the liver can, under conditions of elevated fructose delivery, inflict a metabolic insult that is localized to the hepatocyte. The present study was designed to identify potential cellular effectors of this insult.

Methods

Primary hepatocytes were incubated with 8 mM glucose and 0.12% inulin (G, n = 6) or 8 mM glucose, 0.12% inulin and 28 mU of inulinase (GF, n = 6) in the presence or absence of insulin for 0, 2, or 4 h.

Results

GF produced fructose concentrations of ~0.7 mM over the 4 h experiment. GF induced phosphorylation of MKK7 and JNK, phosphorylation of serine307 on IRS-1, and reduced tyrosine phosphorylation of IRS-1 and -2. GF increased ceramide levels and reactive oxygen species (ROS); however inhibitors of ceramide synthesis or ROS accumulation did not prevent GF-mediated changes in MKK7, JNK or IRS proteins. GF increased cellular methylglyoxal concentrations and a selective increase in methylglyoxal recapitulated the GF-induced changes in MKK7, JNK and IRS proteins.

Conclusions

We hypothesize that GF-mediated changes in stress signaling involve methylglyoxal in primary hepatocytes.

Keywords: 

Sucrose; Insulin resistance; Mitogen-activated protein kinase


http://www.nutritionandmetabolism.com/content/10/1/32




 2005 Jan 15;38(2):286-93.

Methylglyoxal-induced nitric oxide and peroxynitrite production in vascular smooth muscle cells.

In conclusion, MG induces significant generation of NO and O2*- in rat VSMCs, which in turn causes ONOO- [peroxynitrite] formation. An elevated MG level and the consequential ROS/RNS generation would alter cellular signaling pathways, contributing to the development of different insulin resistance states such as diabetes or hypertension.

http://www.ncbi.nlm.nih.gov/pubmed/15607912

Peroxynitrites contribute to diabetes and diabetes leads to greater glucose levels in the brain which leads to peroxynitrite formation in the brain. 

High fructose levels especially from non-fruit sources can contribute to both type 2 diabetes and Alzheimer's disease via the production of peroxynitrites.

Lane Simonian
Posted: Thursday, July 31, 2014 10:39 PM
Joined: 12/12/2011
Posts: 4886


More or less we know that the c-terminal fragment of the amyloid precursor protein is the product of oxidative stress and that it can lead to more oxidative stress, but what about the N-terminal fragment of the amyloid precursor protein.  Here are some hints.


The function of the β-amyloid precursor protein (APP) of Alzheimer's disease is poorly understood. The secreted ectodomain fragment of APP (sAPPα) can be readily cleaved to produce a small N-terminal fragment (N-APP) that contains heparin-binding and metal-binding domains and that has been found to have biological activity. In the present study, we examined whether N-APP can bind to lipids. We found that N-APP binds selectively to phosphoinositides (PIPs) but poorly to most other lipids. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-rich microdomains were identified on the extracellular surface of neurons and glia in primary hippocampal cultures. N-APP bound to neurons and colocalized with PIPs on the cell surface. Furthermore, the binding of N-APP to neurons increased the level of cell-surface PI(4,5)P2 and phosphatidylinositol 3,4,5-trisphosphate. However, PIPs were not the principal cell-surface binding site for N-APP, because N-APP binding to neurons was not inhibited by a short-acyl-chain PIP analogue, and N-APP did not bind to glial cells which also possessed PI(4,5)P2 on the cell surface. The data are explained by a model in which N-APP binds to two distinct components on neurons, one of which is an unidentified receptor and the second of which is a PIP lipid, which binds more weakly to a distinct site within N-APP. Our data provide further support for the idea that N-APP may be an important mediator of APP's biological activity.


http://onlinelibrary.wiley.com/doi/10.1002/jnr.23422/abstract


The mystery receptor appears to be the epidermal growth factor receptor which is activated by heparin.


http://www.ncbi.nlm.nih.gov/pubmed/1712476


The epidermal growth factor receptor can stimulate the phosphatidylinositol-3 kinase but when this kinase is inhibited the epidermal growth factor receptor can also lead to oxidative stress.  


So sometimes, the N-terminal fragment of the amyloid precursor protein is neuroprotective and sometimes it is neurodestructive.




Lane Simonian
Posted: Friday, August 1, 2014 12:08 AM
Joined: 12/12/2011
Posts: 4886


And back to autism.


Conclusions: The results suggest a self-enhancing pathological process in autism that is initiated by intraneuronal deposition of N-truncated Aβ in childhood. The cascade of events includes altered APP metabolism and abnormal intracellular accumulation of N-terminally truncated Aβ which is a source of reactive oxygen species, which in turn increase the formation of lipid peroxidation products.


http://www.actaneurocomms.org/content/pdf/2051-5960-1-61.pdf


The problem with all these amyloid precursor protein products: N-terminally truncated amyloid beta, C-terminally truncated amyloid beta, and amyloid oligomers is that they can increase oxidative stress. 


Lane Simonian
Posted: Friday, August 1, 2014 10:53 AM
Joined: 12/12/2011
Posts: 4886


These studies seem to contradict other studies saying that there are no amyloid plaques in the brains of people with autism.  Age may be the difference between these studies.   


 

Molecular mechanisms: Alzheimer's protein linked to autism

Jessica Wright 

22 June 2012

 

Protein plaques: The brain of a 39-year-old woman who had a duplication of a region on chromosome 15 contains large aggregates (in brown) of a protein related to Alzheimer’s disease.

Amyloid-beta, the small protein that forms plaques in the brains of people with Alzheimer’s disease, is more prevalent in postmortem brains from individuals with autism than in those from controls, according to a study published 2 May in PLoS One1

The protein is also more common in postmortem brains from individuals who had a duplication of the 15q11.2-q13 genomic region, which leads to a syndrome that includes symptoms of autism. This suggests that it could be associated with the severe seizures and sudden unexplained death that characterize the 15q duplication syndrome.

Amyloid-beta has several functions in healthy cells but accumulates in the brains of individuals with Alzheimer’s disease. Studies have also linked this peptide to autism and related disorders.

In the new study, researchers used antibodies against amyloid-beta to detect it in postmortem brains from 11 individuals who had autism, 9 individuals who had a duplication of the 15q11.2-q13 region, and 8 controls.

Overall, neurons from the brains of individuals with the duplication have the highest levels of amyloid-beta, followed by those with other forms of autism, and then controls. For example, individuals with the duplication have about eight times more of the peptide in neurons in the amygdala — a brain region that processes emotion — than do controls, and those with other forms of autism have five times more.

The researchers also found amyloid plaques in the brains of two individuals, aged 51 and 52, who had autism, and one individual aged 39 with the 15q duplication. This suggests that the enhanced levels of amyloid-beta in these individuals are a precursor to Alzheimer’s disease, the researchers say.

http://sfari.org/news-and-opinion/in-brief/2012/molecular-mechanisms-alzheimers-protein-linked-to-autism 

 

The chromosome duplication mentioned in the article leads to more GABA(a) receptor activity.  This is the normal effect without the duplication. 


 

 2008 Jul;106(1):392-404. doi: 10.1111/j.1471-4159.2008.05396.x. Epub 2008 Jul 1.

Etazolate, a neuroprotective drug linking GABA(A) receptor pharmacology to amyloid precursor protein processing.

Abstract

Pharmacological modulation of the GABA(A) receptor has gained increasing attention as a potential treatment for central processes affected in Alzheimer disease (AD), including neuronal survival and cognition. The proteolytic cleavage of the amyloid precursor protein (APP) through the alpha-secretase pathway decreases in AD, concurrent with cognitive impairment. This APP cleavage occurs within the beta-amyloid peptide (Abeta) sequence, precluding formation of amyloidogenic peptides and leading to the release of the soluble N-terminal APP fragment (sAPPalpha) which is neurotrophic and procognitive. In this study, we show that at nanomolar-low micromolar concentrations, etazolate, a selective GABA(A) receptor modulator, stimulates sAPPalpha production in rat cortical neurons and in guinea pig brains. Etazolate (20 nM-2 microM) dose-dependently protected rat cortical neurons against Abeta-induced toxicity. The neuroprotective effects of etazolate were fully blocked by GABA(A) receptor antagonists indicating that this neuroprotection was due to GABA(A) receptor signalling. Baclofen, a GABA(B) receptor [a g protein-coupled receptor] agonist failed to inhibit the Abeta-induced neuronal death. Furthermore, both pharmacological alpha-secretase pathway inhibition and sAPPalpha immunoneutralization approaches prevented etazolate neuroprotection against Abeta, indicating that etazolate exerts its neuroprotective effect via sAPPalpha induction. Our findings therefore indicate a relationship between GABA(A) receptor signalling, the alpha-secretase pathway and neuroprotection, documenting a new therapeutic approach for AD treatment.

 

But the duplication leads to too much protein kinase C being produced leading at first to the N-terminal fragment, then to more c-terminal fragments, then to amyloid oligomers, and then to amyloid plaques (the middle two being mediated by peroxynitrites).  Autistic individuals cannot easily breakdown polyphenols which partially protect their brains against the damage done by peroxynitrites. 


 

Targeting Peroxynitrite as a novel hypothesized treatment for autism spectrum disorders

Maezawa et al. reported that a possible therapeutic target for Rett syndrome is microglia glutamate synthesis or release, confirm that NMDA glutamate receptor antagonist may improve autism spectrum disorders (ASD) (Niederhofer 2007), and suggest that glutaminase inhibitors or gap junction hemichannel blockers may be appropriate therapeutic targets.

Another potential therapeutic target is peroxynitrite. Agonists of NMDA receptors increase concentration of calcium leads to nitric oxide (NO) synthesis. NO reacts with free radical superoxide and produces the powerful oxidant peroxynitrite. Nitric oxide and peroxynitrite may cause glutamate release and neuronal death (Brown and Neher), and peroxynitrite is toxic for mitochondrial activity and DNA (Spencer, Wong et al. 1996). The hyperglutaminergic condition in ASD, the role of glutamate in production of inflammation (which is elevated in ASD; Blaylock and Strunecka, 2009), and peroxynitrite, toxicity of peroxynitrite for DNA, and the prevention of neuronal loss by scavengers of peroxynitrite in co-cultured neurons (Mander and Brown 2005) all point to peroxynitrite as a novel potential treatment target for autism.

Peroxynitrite decomposition catalysts block nitration of glutamate transporters, especially GLT1 and glutamine synthetase (Chen, Muscoli et al.). These two proteins have key roles in transmission of glutamate into the intracellular space. Inhibition of GLT1 and glutamine synthetase by peroxynitrite increases glutamate level and causes neurotoxicity. Therefore, therapeutic approaches intelligently targeting peroxynitrite in brain could be worthwhile to be further studied in preclinical experimental trials for management of ASD. Of course, it is a simplification of the association of peroxynitrite and glutamate with the proposed intervention here. Peroxynitrite has roles in other tissues that should be considered before jumping to this conclusion.

Peroxynitrites may be the appropriate target in Alzheimer's disease, Down syndrome, and autism,  The key is finding the right peroxynitrite scavenger for each condition. 

 

Lane Simonian
Posted: Friday, August 1, 2014 11:20 AM
Joined: 12/12/2011
Posts: 4886


And back to Alzheimer's disease: right pathways partially wrong conclusion. 


 

 2012 Jan;120 Suppl 1:46-54. doi: 10.1111/j.1471-4159.2011.07459.x. Epub 2011 Nov 28.

Activation of α-secretase cleavage.

Abstract

Alpha-secretase-mediated cleavage of the amyloid precursor protein (APP) releases the neuroprotective APP fragment sαAPP and prevents amyloid β peptide (Aβ) generation. Moreover, α-secretase-like cleavage of the Aβ transporter 'receptor for advanced glycation end products' counteracts the import of blood Aβ into the brain. Assuming that Aβ is responsible for the development of Alzheimer's disease (AD), activation of α-secretase should be preventive. α-Secretase-mediated APP cleavage can be activated via several G protein-coupled receptors and receptor tyrosine kinases. Protein kinase C, mitogen-activated protein kinases, phosphatidylinositol 3-kinase, cAMP and calcium are activators of receptor-induced α-secretase cleavage...

 

Here are the four primary paths to Alzheimer's disease: high levels of myo-inositol (Down syndrome, high glucose levels, high sodium levels), inhibition of the phosphatidylinositol 3-kinase (presenilin gene mutations, APOE4 gene, Fosamax), overactivation of tyrosine receptor kinases (glucose, traumatic brain injury, angiotensin II, certain chronic bacterial and viral infections), and overactivation of g protein-coupled receptors or independent activation of g proteins (stress, post-traumatic stress disorder, fructose, aluminum fluoride, sodium fluoride,  mercury, certain pesticides and herbicides).  This is not a complete list but it gives a sense of the wide variety of factors that lead to oxidative stress partially via the production of amyloid oligomers. 


Lane Simonian
Posted: Friday, August 1, 2014 5:04 PM
Joined: 12/12/2011
Posts: 4886


The end is in sight now: both the alpha secretase (the non-amyloidgic pathway) and beta and gamma secretases (the amyloid pathway) are activated by protein kinase C: alpha secretase via the phosphatidylinositol 3-kinase; the beta and gamma secretases via peroxynitrite production. Both pathways lead to the production of an N-terminal (secreted amyloid precursor protein) and a C-terminal fragment, but the phosphatidylinositol-3 kinase sorts them out; whereas inhibition of this kinase contributes to the production of amyloid. 


 

 2010 Aug 12;1348:165-73. doi: 10.1016/j.brainres.2010.05.083. Epub 2010 Jun 2.

Cryptotanshinione upregulates alpha-secretase by activation PI3K pathway in cortical neurons.

 
 
By using several specific protein kinase inhibitors, we showed that phosphatidylinositol 3-kinase (PI3K) mediated the CTS-induced alpha-secretase activation. 

 
 2013;4:2250. doi: 10.1038/ncomms3250.

Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system.

Abstract

Defects in endosomal sorting have been implicated in Alzheimer's disease. Endosomal traffic is largely controlled by phosphatidylinositol-3-phosphate, a phosphoinositide synthesized primarily by lipid kinase Vps34 [a phosphatidylinositol 3-kinase]. Here we show that phosphatidylinositol-3-phosphate is selectively deficient in brain tissue from humans with Alzheimer's disease and Alzheimer's disease mouse models. Silencing Vps34 causes an enlargement of neuronal endosomes, enhances the amyloidogenic processing of amyloid precursor protein in these organelles and reduces amyloid precursor protein sorting to intraluminal vesicles. This trafficking phenotype is recapitulated by silencing components of the ESCRT (Endosomal Sorting Complex Required for Transport) pathway, including the phosphatidylinositol-3-phosphate effector Hrs and Tsg101. Amyloid precursor protein is ubiquitinated, and interfering with this process by targeted mutagenesis alters sorting of amyloid precursor protein to the intraluminal vesicles of endosomes and enhances amyloid-beta peptide generation. In addition to establishing phosphatidylinositol-3-phosphate deficiency as a contributing factor in Alzheimer's disease, these results clarify the mechanisms of amyloid precursor protein trafficking through the endosomal system in normal and pathological states.

 

These novel NO-mediated regulatory mechanisms likely protect BACE1 from being further oxidized by excessive oxidative stress, as from H2O2 and peroxynitrite which are known to upregulate BACE1 and activate the enzyme, resulting in excessive cleavage of APP and Aβ generation; they likely represent the crucial house-keeping mechanism for BACE1 expression/activation under physiological conditions. 


 

http://www.ncbi.nlm.nih.gov/pubmed/21371311 


 

So on the chart below, the left side is the result of phoshatidylinositol-3 kinase activation (neuroprotective) and the right side is activated by peroxynitrites.  And there you have Alzheimer's disease.  Thanks for those of you who have stuck through all these scientific terms. 


 

 


 

 

 
 

Lane Simonian
Posted: Saturday, August 2, 2014 1:55 PM
Joined: 12/12/2011
Posts: 4886


This is very likely the correct explanation of how the APOE4 gene increases the risk for Alzheimer's disease.


 2006 Oct 13;99(:829-36. Epub 2006 Sep 14.

APOE4-VLDL inhibits the HDL-activated phosphatidylinositol 3-kinase/Akt Pathway via the phosphoinositol phosphatase SHIP2.

Here we establish the intracellular mechanism by which APOE4-VLDL [very low density lipids] inhibits the antiapoptotic pathway activated by HDL. We show that APOE4-VLDL diminishes the phosphorylation of Akt by HDL but does not alter phosphorylation of c-Jun N-terminal kinase, p38, or Src family kinases by HDL. Furthermore APOE4-VLDL inhibits Akt phosphorylation by reducing the phosphatidylinositol 3-kinase product phosphatidylinositol-(3,4,5)-triphosphate (PI[3,4,5]P3).

The tyrosine receptor kinases and g protein-coupled receptors activate the neuroprotective phosphtaditylinositol 3-kinase/Akt pathway but when the latter pathway is inhibited by presenilin gene mutations, the APOE4 gene, or the osteoporosis drug Fosamax or when this neuroprotective pathway is inhibited by peroxynitrites formed by the overactivation of tyrosine receptor kinases and g protein-coupled receptors via protein kinase C, src kinases, and p38 MAPK the result is or can be Alzheimer's disease.

We have the pathways that lead to Alzheimer's disease and we have the causal agent for Alzheimer's disease (peroxynitrites--whose formation can be increased by amyloid oligomers or by other fragments of the amyloid precursor protein).  No longer is it necessary to shoot in the dark to find means to prevent or delay the onset of Alzheimer's disease and to effectively treat it. 



Lane Simonian
Posted: Monday, August 4, 2014 5:42 PM
Joined: 12/12/2011
Posts: 4886


Are amyloid oligomers necessary for Alzheimer's disease?  This study suggests that the answer maybe no.


The current study evaluated amyloid-β oligomers (Aβo) in cerebrospinal fluid as a clinical biomarker for Alzheimer’s disease (AD). We developed a highly sensitive Aβo ELISA using the same N-terminal monoclonal antibody (82E1) for capture and detection. CSF samples from patients with AD, mild cognitive impairment (MCI), and healthy controls were examined. The assay was specific for oligomerized Aβ with a lower limit of quantification of 200 fg/ml, and the assay signal showed a tight correlation with synthetic Aβo levels. Three clinical materials of well characterized AD patients (n = 199) and cognitively healthy controls (n = 14 from different clinical centers were included, together with a clinical material of patients with MCI (n = 165). Aβo levels were elevated in the all three AD-control comparisons although with a large overlap and a separation from controls that was far from complete. Patients with MCI who later converted to AD had increased Aβo levels on a group level but several samples had undetectable levels. These results indicate that presence of high or measurable Aβo levels in CSF is clearly associated with AD, but the overlap is too large for the test to have any diagnostic potential on its own.


http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0066381


Three possibilities:


The activation of the gamma (y) secretase (leading to amyloid oligomers and plaques) without activation of the beta secretase (leading to the c-terminal fragment of the amyloid precursor protein): No Alzheimer's disease.


The activation of the beta secretase without the activation of the gamma secretase: Alzheimer's disease.


The activation of both the beta secretase and the gamma secretase: Alzheimer's disease.


Researchers have largely given up on gamma secretase inhibitors.  The focus now is on removal of amyloid oligomers and beta secretase inhibitors.  If you inhibit beta secretase activation by peroxynitrites, you should be able to prevent or at least delay the onset of Alzheimer's disease.


Serenoa
Posted: Tuesday, August 5, 2014 10:40 AM
Joined: 4/24/2012
Posts: 484


Thank you so much all the info Lane. I am overwhelmed. No way I can take all this in and comment intelligently on these things. But, I will try anyway.

 

It really does seem to be coming down to the phophotidalinositol 3 kinase pathway. It seems to be a common link to everything. Wow, this is good stuff. I have to study this more. Phosphates, inositol, phosphorilation, function in membranes, endosome sorting, APP processing, peroxinitrite association, do many connections.



Serenoa
Posted: Tuesday, August 5, 2014 10:48 AM
Joined: 4/24/2012
Posts: 484


So, you are saying basically that it's the C-Terminal fragment of the APP that is causing problems, not the amyloid oligomers (and maybe because they form into plaques which are not as toxic). And the C-Terminal fragment is a product of beta-secretase. Very interesting!

 

What about the N-Terminal fragment of APP? One study said it reacted with metals.



Lane Simonian
Posted: Tuesday, August 5, 2014 2:06 PM
Joined: 12/12/2011
Posts: 4886


I think all of this is correct, Serenoa.  The phosphatidylinositol-3 kinase/Akt pathway is neuroprotective and its inhibition either early by presenilin gene mutations or later by peroxynitrites marks a critical juncture in the development of Alzheimer's disease. 


 

Amyloid oligomers contribute to oxidative stress but their contribution ends once the metals they attract (especially copper) are entombed in amyloid plaques.  Preventing this process with y-secretase inhibitors seems to speed the progression of the disease, because it leaves more c-terminal fragments behind.  The oxidative stress produced by the c-terminal fragment appears to be permanent while that produced by amyloid oligomers is temporary. 


 

http://www.ncbi.nlm.nih.gov/pubmed/11059902 

 

http://www.ncbi.nlm.nih.gov/pubmed/18171695

 

http://www.ncbi.nlm.nih.gov/pubmed/24616909

 

Perhaps by binding copper, the N terminal fragment of the amyloid precursor protein can also become toxic.   


Lane Simonian
Posted: Tuesday, August 5, 2014 5:37 PM
Joined: 12/12/2011
Posts: 4886


Scratch the last guess:


The N-terminal copper-binding domain of the amyloid precursor protein protects against Cu2+ neurotoxicity in vivo

http://www.fasebj.org/content/18/14/1701.short
Maybe the problem is after all related to pyroglutamate (also known as 5-oxoproline).  5-oxoproline can be converted into glutamate which can cause oxidative stress.

 2010 Jun;25(2):145-54. doi: 10.1007/s11011-010-9190-1. Epub 2010 Apr 30.

Acute administration of 5-oxoproline induces oxidative damage to lipids and proteins and impairs antioxidant defenses in cerebral cortex and cerebellum of young rats.

http://www.ncbi.nlm.nih.gov/pubmed/20431931
http://www.mdpi.com/1422-0067/14/10/21021/htm

Glutamate-stimulated peroxynitrite production in a brain-derived endothelial cell line is dependent on N-methyl-d-aspartate (NMDA) receptor activation

And to break the vicious circle:

 2014 Feb;7(2):508-512. Epub 2013 Dec 9.

A peroxynitrite decomposition catalyst prevents mechanical allodynia and NMDA receptor activation in the hind-paw ischemia reperfusion injury rats.