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New Therapeutic Target Discovered for Alzheimer’s Disease
Serenoa
Posted: Monday, June 23, 2014 6:07 PM
Joined: 4/24/2012
Posts: 484


UC SanDiego News Center, 2014

 

http://ucsdnews.ucsd.edu/pressrelease/new_therapeutic_target_discovered_for_alzheimers_disease

 

 A team of scientists from the University of California, San Diego School of Medicine, the Medical University of South Carolina and San Diego-based American Life Science Pharmaceuticals, Inc., report that cathepsin B gene knockout or its reduction by an enzyme inhibitor blocks creation of key neurotoxic pGlu-Aβ peptides linked to Alzheimer’s disease (AD). Moreover, the candidate inhibitor drug has been shown to be safe in humans.

The findings, based on AD mouse models and published online in the Journal of Alzheimer’s Disease, support continued development of cysteine protease inhibitors as a new drug target class for AD. “No other therapeutic program is investigating cysteine protease inhibitors for treating AD,” said collaborator Vivian Hook, PhD, professor in the UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences and in the UC San Diego School of Medicine.

Current AD drugs treat some symptoms of the devastating neurological disorder, but none actually slow its progress, prevent or cure it. No new AD drug has been approved in more than a decade.

The researchers focused on cathepsin B production of N-truncated pGlu-Aβ, a peptide or short chain of amino acids, and the blockade of cathepsin B by E64d, a compound shown to inhibit cysteine proteases, a type of enzyme. AD is characterized by accumulation of a variety of Aβ peptides as oligomers and amyloid plaques in the brain, factors involved in neuronal loss and memory deficits over time. These neurotoxic Aβ peptides are created when enzymes cleave a large protein called amyloid precursor protein (APP) into smaller Aβ peptides of varying toxicity. N-truncated pGlu-Aβ has been shown to be among the most neurotoxic of multiple forms of Aβ peptides.

Much AD research has focused on the APP-cutting enzyme BACE1 β-secretase, but its role in producing pGlu-Aβ was unknown. Cathepsin B is an alternative β-secretase which cleaves the wild-type β-secretase site of APP, which is expressed in the major sporadic and many familial forms of AD. Hook and colleagues looked at what happened after gene knockout of BACE1 or cathepsin B. They found that cathepsin B, but not BACE1, produced the highly toxic pGlu-Aβ.

Perhaps most interestingly, the scientists found that E64d, an enzyme inhibitor of cathepsin B, reduced production of pGlu-Aβ and other AD-associated Aβ peptides. Key was the finding that E64d and cathepsin B gene knock out resulted in improved memory deficits in a mouse model of AD.

“This is an exciting finding,” said Hook. “It addresses a new target – cathepsin B – and an effective, safe small molecule, E64d, to reduce the pGlu-Aβ that initiates development of the disease’s neurotoxicity. No other work in the field has addressed protease inhibition for reducing pGlu-Aβ of AD.”

Hook noted that E64d has already been shown to be safe in clinical trials of patients with muscular dystrophy and would, therefore, likely prove safe for treating AD as well. She hopes to launch Phase 1 human clinical trials in the near future with a modified version of the drug candidate.

 

 


Serenoa
Posted: Monday, June 23, 2014 6:20 PM
Joined: 4/24/2012
Posts: 484


Disturbed Ca2+ Homeostasis Increases Glutaminyl Cyclase Expression; Connecting Two Early Pathogenic Events in Alzheimer’s Disease In Vitro

 

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0044674

 

A major neuropathological hallmark of Alzheimer’s disease (AD) is the deposition of aggregated β amyloid (Aβ) peptide in the senile plaques. Aβ is a peptide of 38–43 amino acids and its accumulation and aggregation plays a key role early in the disease. A large fraction of β amyloid is N-terminally truncated rendering a glutamine that can subsequently be cyclized into pyroglutamate (pE). This makes the peptide more resistant to proteases, more prone to aggregation and increases its neurotoxicity. The enzyme glutaminyl cyclase (QC) catalyzes this conversion of glutamine to pE. In brains of AD patients, the expression of QC is increased in the earliest stages of pathology, which may be an important event in the pathogenesis. In this study we aimed to investigate the regulatory mechanism underlying the upregulation of QC expression in AD. Using differentiated SK-N-SH as a neuronal cell model, we found that neither the presence of Aβ peptides nor the unfolded protein response, two early events in AD, leads to increased QC levels. In contrast, we demonstrated increased QC mRNA levels and enzyme activity in response to another pathogenic factor in AD, perturbed intracellular Ca2+ homeostasis. The QC promoter contains a putative binding site for the Ca2+ dependent transcription factors c-fos and c-jun. C-fos and c-jun are induced by the same Ca2+-related stimuli as QC and their upregulation precedes QC expression. We show that in the human brain QC is predominantly expressed by neurons. Interestingly, the Ca2+- dependent regulation of both c-fos and QC is not observed in non-neuronal cells. Our results indicate that perturbed Ca2+ homeostasis results in upregulation of QC selectively in neuronal cells via Ca2+- dependent transcription factors. This suggests that disruption of Ca2+ homeostasis may contribute to the formation of the neurotoxic pE Aβ peptides in Alzheimer’s disease.

 

Ok, I'm intrigued. This seems like a solid lead to me.


Serenoa
Posted: Tuesday, June 24, 2014 9:02 AM
Joined: 4/24/2012
Posts: 484


Based on these two articles and what I have learned in previous posts, here is my understanding of this aspect of AD pathology. First the APP (amyloid precursor protien) is cleaved by the enzyme BASE1 beta secretase or Cathepsin B. Both enzymes lead to the formation of Abeta. However, Cathepsin B leads to the formation of an N-truncated form of Abeta which is very toxic. The N-truncated Abeta can be acted upon by

cysteine protease to form a very toxic version of Abeta called pGlu-Abeta.

 

OK, in linear form it would be: APP > Cathepsin B > N-truncated Abeta > cysteine protease > toxic pGlu-Abeta.

 

So the intervention in the first article is to inhibit the Cathepsin B enzyme thus preventing the formation of the toxic form of Abeta.

 

The second article targets cysteine protease by linking it to a know pathogenic factor in AD, dysregulated Ca+ homeostasis (neurons not being able to regulate the amount of calcium coming into the cell). So if you can fix Ca+ homeostasis then you can prevent toxic pGlu-Abeta.

 

In previous posts we have linked the dysregulation of Ca+ homeostasis to many other factors including the inhibition of the Pl3K/Akt pathway by oxidative damage. I feel like there is some evidence here that could lead to an intervention.



Lane Simonian
Posted: Thursday, June 26, 2014 12:29 AM
Joined: 12/12/2011
Posts: 4863


When I first started researching Alzheimer's disease ten years ago, the calcium hypothesis was the first one that seemed to make sense.  So I started to try to trace the origins of intracellular calcium release and later what caused the influx of calcium into cells.   


 

Like BACE, Cathepsin B is the product of phospholipase C beta (via g proteins) and phospholipase C gamma (via tyrosine kinase receptors). 


 

http://www.ncbi.nlm.nih.gov/pubmed/1341708 


 

Less important, though, then the role of phospholipase C in the release of intracellular calcium (which leads to various forms of amyloid oligomers) is the role of phospholipase C in the production of peroxynitrites. 


 


 

I just found this interesting speculation as to the potential role of BACE and Cathepsin B in cutting the amyloid precursor protein. 


 

One reason why cathepsin B has been overshadowed by BACE could be that, as Hook and colleagues demonstrated several years ago, the enzyme prefers to cleave wild-type APP, and displays much lower activity toward the altered site created by the Swedish mutation. The mutant sequence is preferred by BACE, and pops up in many of the FAD animal models which have been used to study the role of BACE in vivo. For studying β-cleavage inhibitors, Hook and coworkers favor the guinea pig model, which has a wild-type APP sequence that matches the β-secretase cleavage site in humans.

 

Hook used that animal to look at the role of cathepsin B in APP processing in the CNS. In her talk, she showed that infusion of selective cathepsin B inhibitor CA-074Me into the brains of guinea pigs reduced Aβ40 and Aβ42 levels by approximately one-half. In a second talk, Hook showed that another cathepsin B inhibitor, loxistatin, had the same effect after direct intracerebroventricular infusion. She saw decreased production of Aβ and the C-terminal β-secretase fragment of APP in the brain and in isolated synaptosomes. These results suggest that cathepsin B does participate in Aβ production in vivo as a β-secretase, and that inhibitors may have some potential as Aβ-lowering agents. This work is now in press in Biological Chemistry, Hook said.

 

A listener was quick to ask how Hook could reconcile her results with the recent paper from Li Gan showing that AD mice with the cathepsin B gene knocked out have worse plaque pathology than mice with the enzyme (see ARF related news story). In that study, the researchers found no evidence that cathepsin B acted as a secretase, but in fact found that it was able to degrade Aβ fibrils.

 

Hook pointed out that the AD mouse model used in that paper (the hAPP J20 line) incorporated the Swedish mutation, which could explain why the researchers saw no evidence for APP processing by cathepsin B. In animals with wild-type human APP, there could be a different outcome. Clearly, there is a lot more work to be done, but the data so far suggest that where Aβ production is concerned, BACE may be just one part of the story.—Pat McCaffrey.

 

http://www.alzforum.org/news/conference-coverage/sfn-old-and-new-bace-and-cathepsin-b-share-v-secretase-stage 


 

 


Lane Simonian
Posted: Thursday, June 26, 2014 12:56 AM
Joined: 12/12/2011
Posts: 4863


p38 MAPK is involved both in the production of peroxynitrites and cathepsin B.


This strongly suggests that p38 MAPK and NF-kappaB are essential to the IL-6-induced activation of cathepsin B or uPA and that these two IL-6-activated pathways can act independently.


http://www.ncbi.nlm.nih.gov/pubmed/17849265


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


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


So apparently p38 Mapk upregulates both cathepsin B and BACE1 (via peroxynitrites).  I am not sure if one produces a more toxic amyloid oligomer than the other.


Lane Simonian
Posted: Thursday, June 26, 2014 10:14 AM
Joined: 12/12/2011
Posts: 4863


This one is for autism, but has implications for Alzheimer's disease. 


 

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. The latter enhance Aβ deposition and sustain the cascade of changes contributing to metabolic and functional impairments of neurons in autism of an unknown etiology and caused by chromosome 15q11.2-q13 duplication.

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3893450/ 

 


Lane Simonian
Posted: Thursday, June 26, 2014 10:33 AM
Joined: 12/12/2011
Posts: 4863


I knew this was going to be a tough nut to crack.  In many studies, Cathepsin B has been linked to the production and clearance of n-truncated amyloid, but this clearance only occurs with the activation of Akt which does not happen in Alzheimer's disease.  So you are left with a n-truncated and c-truncated amyloid which can further be cut by the release of intracellular calcium.  So, so far I have read about three forms of amyloid: one a c-terminal fragment caused by the peroxynitrite and hydrogen peroxide mediated activation of the BACE1 enzyme, an N-truncated amyloid (apparently without calcium release), and an N-truncated amyloid with calcium release (pyroglutamate amyloid).  


 2013 Aug;126(2):189-205. doi: 10.1007/s00401-013-1129-2. Epub 2013 May 18.

N-truncated amyloid β (Aβ) 4-42 forms stable aggregates and induces acute and long-lasting behavioral deficits.

Abstract

N-truncated Aβ4-42 is highly abundant in Alzheimer disease (AD) brain and was the first Aβ peptide discovered in AD plaques. However, a possible role in AD aetiology has largely been neglected. In the present report, we demonstrate that Aβ4-42 rapidly forms aggregates possessing a high aggregation propensity in terms of monomer consumption and oligomer formation. Short-term treatment of primary cortical neurons indicated that Aβ4-42 is as toxic as pyroglutamate Aβ3-42 and Aβ1-42. In line with these findings, treatment of wildtype mice using intraventricular Aβ injection induced significant working memory deficits with Aβ4-42, pyroglutamate Aβ3-42 and Aβ1-42. Transgenic mice expressing Aβ4-42 (Tg4-42 transgenic line) developed a massive CA1 pyramidal neuron loss in the hippocampus. The hippocampus-specific expression of Aβ4-42 correlates well with age-dependent spatial reference memory deficits assessed by the Morris water maze test. Our findings indicate that N-truncated Aβ4-42 triggers acute and long-lasting behavioral deficits comparable to AD typical memory dysfunction.


Lane Simonian
Posted: Thursday, June 26, 2014 11:06 AM
Joined: 12/12/2011
Posts: 4863


So which form of beta secretase do you inhibit and which form of amyloid do you target?  Researchers are likely much better off working upstream of both beta secretases and amyloid oligomers through the inhibition of p38 MAPK and peroxynitrites.  Plus once, the toxic oligomers form plaques the toxicity is gone, but the damage done by peroxynitrites remains.
Lane Simonian
Posted: Thursday, June 26, 2014 3:11 PM
Joined: 12/12/2011
Posts: 4863


A list of plants that inhibit p38 Mapk signalling. 


 

Table 2: Plant extracts that inhibit the p38 signaling in macrophages.


Plant Action target of p38 Reference


 

Archidendron  clypearia Suppression of PGE2 production; amelioration of EtOH/HCl-induced gastritis [28


 

Scutellaria  baicalensis Inhibition of iNOS, COX-2, PGE2, IL-1, IL-2, IL-6, IL-12, and TNF-expression [118

  

Phaseolus  angularis Suppression of the release of PGE2 and NO; amelioration of EtOH/HCl-induced gastritis [119


 

Artemisia  vestita Inhibition of TNF- release; beneficial for the treatment of endotoxin shock or sepsis [141

  

Boswellia  serrata Inhibition of TNF-, IL-1, and IL-6 [142


 

Hibiscus  sabdariffa Suppression of nitrite, PGE2 release, and hepatic inflammation [143


 

Clinopodium  vulgare Suppression of NO production; MMP-9 activation [144]

  

Eriobotryae  folium Suppression of LPS-induced NO and PGE2 production [145]

  

Elaeocarpus  petiolatus Inhibition of the production of PGE2, TNF-, and IL-1 [146]

  

Polygonum  cuspidatum Inhibition of IL-6, TNF-, NO, and PGE2 [147

  

Ginkgo  biloba Inhibition of LPS-induced iNOS and COX-2 expression [148]

  

Lycium  chinense Inhibition of LPS-induced NO, PGE2, TNF-, and IL-6 production [149

  

Hopea  odorata Inhibition of NO, PGE2, and TNF- release; amelioration of gastritis and ear edema



 

And compounds that inhibit p38 Mapk signalling. 


 

Table 3: Naturally occurring compounds that inhibit p38 signaling in macrophages.


Compound Action target of p38 Reference


Sugiol Inhibition of IL-1, TNF-, and ROS production [151

 

Quercetin Inhibition of NO and TNF- [114

 

Ajoenes Inhibition of NO, PGE2, TNF-, IL-1, and IL-6 production [116

 

Ginsan Enhanced phagocytic activity; downregulation of TNF-, IL-1, IL-6, IFN-, and IL-18 [152

 

4-Methoxyhonokiol Inhibition of iNOS and COX-2 expression; inhibition of dye leakage and paw swelling [153

 

Schisandrin Suppression of NO production and PGE2 release [154

 

Rengyolone Inhibition of iNOS and COX-2 expression [155

 

Pseudocoptisine Inhibition of proinflammatory mediators such as iNOS, COX-2, TNF-, and IL-6 [156

 

Mycoepoxydiene Inhibition of LPS-induced proinflammatory mediators including TNF-, IL-1, IL-6, and NO [157

 

Britanin Suppression of NO, PGE2, TNF-, IL-1, and IL-6 [158

 

Hyperin Inhibition of NO production through suppression of iNOS expression [159

 

Carnosol Inhibition of LPS-stimulated NO production; antioxidative activity [160]

 

 

http://www.hindawi.com/journals/mi/2014/352371/

 

Some of these plants and compounds have shown promise in the treatment of Alzheimer's disease. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


Serenoa
Posted: Thursday, June 26, 2014 4:37 PM
Joined: 4/24/2012
Posts: 484


Excellent information, and lots of it. Thank you very much Lane.

 

One thing you mentioned that jumps out at me is the relationship between Autism and Alzheimer's (AD). The commonality is the Amyloid Precursor Protein (APP). This molecule seems to be involved in many dysfunctions in one way or another: Down Syndrome, AD, and now Autism. This is an important clue. 

 

A lot of what you posted Lane, p38, MAPK, etc. is going right over my head since I have forgotten much of what I learned a while ago about cellular pathways. I will keep re-reading. I'm focusing on APP for now and found several articles that seem to say that in Autism APP is processed differently than in AD. 

 

"We have observed that sAPPα levels are increased and BDNF levels decreased in the plasma of patients with severe autism as compared to controls. Further, we show that Aβ1-40, Aβ1-42, and sAPPβ levels are significantly decreased in the plasma of patients with severe autism."

 

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0020405#pone-0020405-g005

 

So maybe we need to look at what is affecting the processing of APP again. What factors would cause it to go wrong in one way with Autism and another way in AD and Down Syndrome? I know you have posted on this before Lane but perhaps you could recap for us and add any new insights. 



Lane Simonian
Posted: Thursday, June 26, 2014 6:58 PM
Joined: 12/12/2011
Posts: 4863


Very good work, Serenoa.  There seems to be a different mix of amyloid oligomers in autism than there is in Alzheimer's disease, although maybe further study is needed to determine if this is correct.  I read once that autistic individuals have trouble breaking down phenols which may lead to increased behavioral problems, but except in the case of severe autism may provide some protection against cognitive impairment (as phenols scavenge peroxynitrites). 


 

http://www.tacanow.org/family-resources/phenols-salicylates-additives/ 


 

http://www.jneurosci.org/content/30/15/5346/reply 


 

Protein kinase C leads to the release of the soluble amyloid precursor proteins which apparently can be cleaved into either a c-terminal or n-truncated form, both of which can be toxic (likely through the enhanced production of hydrogen peroxide).  p38 Mapk seems to stimulate either cut.   

 


Serenoa
Posted: Friday, June 27, 2014 7:11 AM
Joined: 4/24/2012
Posts: 484


Found something very interesting while reviewing basic APP information on Wikipedia.

 

"APP knockout mice are viable and have relatively minor phenotypic effects including impaired long-term potentiation and memory loss without general neuron loss.[26] On the other hand, transgenic mice with upregulated APP expression have also been reported to show impaired long-term potentiation.[27]

The logical inference is that because Aβ accumulates excessively in Alzheimer's disease its precursor, APP, would be elevated as well. However, neuronal cell bodies contain less APP as a function of their proximity to amyloid plaques.[28] The data indicate that this deficit in APP results from a decline in production rather than an increase in catalysis. Loss of a neuron's APP may affect physiological deficits that contribute to dementia."

 

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

 

Can you make any sense of this Lane? If APP plays a role in neuroregeneration and functioning maybe we should be looking at the things that are affecting APP and not its downstream products the various types of amyloid beta. As we have been saying on here, the plaques are more or less a symptom and not a primary cause of AD (unless they are affecting APP production). Leukine has been shown to promote regeneration, what if it is acting on APP to affect changes, like I saw in my mother.

 


Lane Simonian
Posted: Friday, June 27, 2014 10:12 AM
Joined: 12/12/2011
Posts: 4863


The secreted form of the amyloid precursor protein is neuroprotective and is regulated by protein kinase C.  Protein kinase C activity decreases in Alzheimer's disease due to oxidation and nitration.  It is possible that the decrease in the secreted amyloid precursor protein contributes to memory impairment in Alzheimer's disease.


Secreted amyloid precursor protein-alpha (sAPPalpha) is a neuroprotective and neurotrophic protein derived from the parent APP molecule. 


http://www.ncbi.nlm.nih.gov/pubmed/19463893



Overexpression and altered metabolism of amyloid precursor protein (APP) resulting in increased 4 kDa amyloid β peptide (Aβ) production are believed to play a major role in Alzheimer’s disease (AD). Therefore, reducing Aβ 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 Aβ release (Buxbaum et al., 1993Gadzuba et al., 1993Hung 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 Aβ. 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 Aβ levels.


http://www.jneurosci.org/content/18/8/2907.long


http://www.ncbi.nlm.nih.gov/pubmed/9576922 (the mechanism might not be right on this one for the decline in protein kinase C alpha)


I think the positive role of leukine is through the activation of the phosphatidylinositol 3-kinase/Akt pathway (have not been able to find anything yet on whether it can increase the secreted amyloid precursor protein in Alzheimer's disesae).


On an interesting side note, the chromosome 15q duplication in autism appears to increase the activation of serotonin receptors (a g protein-coupled receptor).  This would lead to an increase in phospholipase C and intracellular calcium release.  


http://www.ncbi.nlm.nih.gov/pubmed/22431635


http://dmm.biologists.org/content/3/1-2/3.full




The n-truncated amyloid oligomer appears to occur first and this maybe why people with autism have this form and not other forms of amyloid oligomers in their brain.  I would not say that Alzheimer's disease is a more advanced form of autism but that might not be far off.


Lane Simonian
Posted: Saturday, June 28, 2014 1:58 AM
Joined: 12/12/2011
Posts: 4863


One of the main differences between autism and Alzheimer's disease is that peroxynitrite levels are probably higher and cause more damage in Alzheimer's disease than in autism (as people with autism likely have higher levels of polyphenols that scavenge peroxynitrites since they cannot breakdown polyphenols).  


 

This description of the causes and consequences of peroxynitrite production in autism, though, largely applies to Alzheimer's disease as well. 


 


 

Autism as a NO/ONOO- Cycle disease 

Martin L. Pall 

 

Washington State University, USA 


 

The NO/ONOO- cycle is a primarily local biochemical vicious cycle, such that depending where it is localized in the body, may be able to generate a variety of chronic inflammatory diseases. The elements of the cycle are: Elevated levels of oxidative  stress, peroxynitrite (ONOO-), nitric oxide (NO), superoxide, intracellular Ca2+, inflammatory cytokines and other inflammatory markers, NF-kappaB, excitotoxicity glutamatergic activity and NMDA activity and some of the TRP group of receptors, as well as mitochondrial dysfunction and lowered tetrahydrobiopterin (BH4) activity. With two exceptions, each of these have been found to occur in autism patients and most have been shown to play a causal role in the disease. One exception, the TRP group of receptors, there are few data on their possible role in autism. There may be a second possible partial exception: although excitotoxicity and elevated glutamatergic activity are well documented, there is some evidence that the NMDA activity may be low, rather than high - this will be discussed in the presentation. In general, then, there is an excellent agreement between the predictions of the NO/ONOO- cycle and the biochemical properties of autism patients. There is similarly a good agreement between the cycle and the properties of stressors reported to cause autism, when exposures occur in the perinatal period; some of the unique properties of autism may be due to the impact of this biochemistry/physiology on the developing brain, as has been the conventional wisdom about autism. The properties of such initiating stressors, including infections, toxic metals and organic toxicant exposures and how they may act to initiate the cycle will be discussed.   


 

http://omicsonline.org/2161-0460/2161-0460-S1.004-039.pdf 


Serenoa
Posted: Sunday, June 29, 2014 7:49 AM
Joined: 4/24/2012
Posts: 484


I'm starting to understand the basics of APP a little better but there are so many aspects to it that are way beyond me. I've tried to absorb everything in your posts Lane and I think some of it has stuck in my brain. But again I find that I need to back up and look at the big picture and the easily understood facts. The answers may lie in the various forms of APP as to how it affects the brain. Here is what I have learned about the basics.

 

APP is a trans-membrane protein. The interactions and functions of the cell (neuron) membrane is very important to this disease.

 

 APP is produced throughout the body but a certain form is very abundant in the brain. This may address why AD only affects the brain.

 

APP seems to be upregulated after traumatic brain injury. Much evidence suggests that it is neuroprotective but some evidence points to it possibly causing neuronal death.

 

Upregulation of APP after brain injury is linked to immune system response and their is massive evidence that the immune system plays a beneficial role in neuroprotection.

 

 

APP may contribute to brain overgrowth in Autism.

 

APP overproduction may lead to AD in Down Syndrome.

 

And lastly, APP levels have been found to be decreased in AD brains.

 

 



Lane Simonian
Posted: Sunday, June 29, 2014 10:17 AM
Joined: 12/12/2011
Posts: 4863


Very clearly and importantly said.  I looked for the reason why the amyloid precursor protein may be neuroprotective and found this interesting article. 


 

 2002 Jun;175(2):407-14.

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.

Abstract

The alpha-secretase-derived form of the amyloid precursor protein (sAPPalpha), which is released from neurons in an activity-dependent manner, has been shown to promote long-term survival of hippocampal and cortical neurons in culture and can protect those neurons against excitotoxic and ischemic injury in culture and in vivo. The signal transduction pathway(s) activated by sAPPalpha has not been established. We now report that sAPPalpha activates the phosphatidylinositol-3-kinase (PI(3)K)-Akt kinase signaling pathway in cultured hippocampal neurons. sAPPalpha also stimulates phosphorylation of p42 (ERK1) and p44 (ERK2) mitogen-activated protein (MAP) kinases by a PI(3)K-independent pathway. Treatment of neurons with sAPPalpha protects them against death induced by trophic factor deprivation and exposure to glutamate, and these survival-promoting effects of sAPPalpha are abolished or attenuated when either PI(3)K or p42/p44 MAP kinases are selectively blocked. Exposure of neurons to sAPPalpha resulted in a decrease in the level of IkappaBbeta and an increase in NF-kappaB DNA binding activity, both of which were blocked by wortmannin, suggesting that the transcription factor NF-kappaB may be a downstream target of the PI(3)K-Akt pathway that may play a role in the cell survival-promoting action of sAPPalpha. These findings suggest that the PI(3)K-Akt pathway and p42/p44 MAP kinases mediate responses of neurons to sAPPalpha in physiological and pathological settings, with implications for synaptic plasticity and the pathogenesis of Alzheimer's disease.

 

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. 


Lane Simonian
Posted: Sunday, June 29, 2014 10:32 AM
Joined: 12/12/2011
Posts: 4863


When you put these two together, you likely have the answer to Alzheimer's disease. 


 


 

 2006 Sep;13(9):1506-14. Epub 2006 Jan 20.

Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells.

Abstract

The mechanisms of peroxynitrite-induced apoptosis are not fully understood. We report here that peroxynitrite-induced apoptosis of PC12 cells requires the simultaneous activation of p38 and JNK MAP kinase, which in turn activates the intrinsic apoptotic pathway, as evidenced by Bax translocation to the mitochondria, cytochrome c release to the cytoplasm and activation of caspases, leading to cell death. Peroxynitrite induces inactivation of the Akt pathway. Furthermore, overexpression of constitutively active Akt inhibits both peroxynitrite-induced Bax translocation and cell death.

 

http://www.ncbi.nlm.nih.gov/pubmed/16410804 

 

Furthermore, conditioned media derived from CT105-treated [c-terminal fragment of the amyloid precursor protein] 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. 


 

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


 


 


Serenoa
Posted: Sunday, June 29, 2014 9:01 PM
Joined: 4/24/2012
Posts: 484


Excellent. Thanks Lane. Looks like I have some more reading to do. Lots of clues here.

Serenoa
Posted: Monday, June 30, 2014 8:35 AM
Joined: 4/24/2012
Posts: 484


I ran across another reference to cell adhesion this morning and decided look at it's relationship to APP. Turns out that there are many connections, and this is another step toward understanding how APP is involved in AD. Cell adhesion is vital to all multi-cellular organisms and any disruption of it leads to problems. Cell adhesion seems to be one of the functions of APP.

Abnormal cleavage of APP impairs its functions in cell adhesion and migration

"Our results suggest that impaired cell adhesion and migration induced by abnormal cleavage of APP could contribute to the pathological effects in FAD brain."

 

http://www.researchgate.net/publication/247152651_Abnormal_cleavage_of_APP_impairs_its_functions_in_cell_adhesion_and_migration

 

 

Beta amyloid precursor protein mediates neuronal cell-cell and cell-surface adhesion.

"These data suggest that the APP, which is expressed primarily on differentiated neuronal cells, may play a role in the mediation of both cell-cell and cell-substrate adhesion."

 

http://www.ncbi.nlm.nih.gov/pubmed/1645774

 

 

Anything here that connects to PI3k/Atk pathway or peroxinitrites or other things?

 

 


Serenoa
Posted: Monday, June 30, 2014 8:56 AM
Joined: 4/24/2012
Posts: 484


Lane, more evidence here, and this is filled with factors you commonly refer to, like p38 MAPK, so I know you will be able to interpret it for us.

 

 

Adhesion of monocytes to type I collagen stimulates an APP-dependent proinflammatory signaling response and release of Aβ1-40

 

Results

Pull-down assays demonstrated that THP-1 adhesion to collagen stimulated a tyrosine kinase-associated signaling response which included subsequent phosphorylation of p38 MAP kinase and increased association of APP with α2β1 integrin, specifically. In addition, cell adhesion was dependent upon APP expression since APP siRNA knockdown attenuated THP-1 adhesion to collagen compared to mock transfected controls. One consequence of the tyrosine kinase-dependent signaling response was increased secretion of interleukin-1β (IL-1β) and Aβ1-40 but not the Aβ1-42 fragment of APP. Increased secretion of IL-1β was dependent upon p38 MAP kinase activity while Aβ1-40 secretion required Src family kinase activity since the specific p38 inhibitor, SB202190, and the Src family kinase inhibitor, PP2, attenuated IL-1β and Aβ1-40 secretion, respectively.

Conclusions

These data demonstrate that APP is involved in classic integrin-dependent tyrosine kinase-associated adhesion and activation of peripheral monocytic cells. Moreover, divergent APP-dependent signaling is required for increased secretion of both IL-1β and Aβ1-40 as a component of the adhesion-dependent change in phenotype. This suggests that APP may have a broad role in not only mediating cell-matrix adhesion but also in the function of peripheral immune cells.

 

http://link.springer.com/article/10.1186%2F1742-2094-7-22


Serenoa
Posted: Tuesday, July 1, 2014 7:08 AM
Joined: 4/24/2012
Posts: 484


This article provides an overload of information. It is connecting APP to oxidative damage to mitochondirial dysfunction. And, it shows how these relate to both Down Syndrome and AD. Very interesting.

 

Altered Metabolism of the Amyloid β Precursor Protein Is Associated with Mitochondrial Dysfunction in Down's Syndrome

 

Discussion

These experiments indicate that there is a marked alteration in AβPP processing and Aβ trafficking in cortical DS astrocytes and neurons that can be replicated in normal human astrocytes by inhibition of mitochondrial energy metabolism. Moreover, mitochondrial function is impaired in DS astrocytes, as indicated by reduced mitochondrial redox activity and membrane potential.

However, despite impaired mitochondrial function, DS astrocytes are completely viable in culture. We suggest, therefore, that impaired energy metabolism in DS cells gives rise to increased β-secretase cleavage of AβPP and altered Aβ trafficking resulting in intracellular accumulation of aggregated Aβ42. Similar patterns of AβPP processing were detected in the DS brain. These results raise the possibility that impaired mitochondrial energy metabolism in the DS brain may contribute to the pathogenesis of AD.

 

 

http://www.sciencedirect.com/science/article/pii/S0896627302006049


Serenoa
Posted: Tuesday, July 1, 2014 6:26 PM
Joined: 4/24/2012
Posts: 484


I had discounted the mitochondrial connection as being a critical causal factor, but I am reconsidering that in light of it's connections to APP processing and oxidative damage. Here is more evidence.

 

Changes in mitochondrial function are pivotal in neurodegenerative and psychiatric disorders: How important is BDNF?

 

Abstract

The brain is at the very limit of its energy supply and has evolved specific means of adapting function to energy supply, of which mitochondria form a crucial link. Neurotrophic and inflammatory processes may not only have opposite effects on neuroplasticity, but also involve opposite effects on mitochondrial oxidative phosphorylation and glycolytic processes, respectively, modulated by stress and glucocorticoids, which also have marked effects on mood. Neurodegenerative processes show marked disorders in oxidative metabolism in key brain areas, sometimes decades before symptoms appear (Parkinson's and Alzheimer's diseases). We argue that brain-derived neurotrophic factor couples activity to changes in respiratory efficiency and these effects may be opposed by inflammatory cytokines, a key factor in neurodegenerative processes.

 

 

http://onlinelibrary.wiley.com/doi/10.1111/bph.12531/full

 

  


Lane Simonian
Posted: Friday, July 4, 2014 10:40 AM
Joined: 12/12/2011
Posts: 4863


Cell adhesion does appear to be affected by the phosphatidylinositol-3 kinase/Akt pathway and in some cases peroxynitrites inhibit this pathway and cell adhesion (such as in Alzheimer's disease). 


 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1219394/pdf/9531503.pdf 


 

The Src kinase can lead to the activation of phosphatidylinositol-3 kinase/Akt pathway but it can also increase the production of p38 Mapk and peroxynitrites. And peroxynitrites may inhibit the ability of the Src kinase to activate the phosphatidylinositol 3-kinase/Akt pathway. 


 

http://www.ncbi.nlm.nih.gov/pubmed/12842830 


 

With more certainty it can be said that peroxynitrites contribute to mitochondrial dysfunction.   


 

http://www.nature.com/cdd/journal/vaop/ncurrent/abs/cdd201472a.html 


 

I have been away from a computer for a few days (blissfully in a way), but will try to catch up as quickly as I can since so much good information has been posted in the last few days. 


 


 


Serenoa
Posted: Tuesday, July 15, 2014 2:13 PM
Joined: 4/24/2012
Posts: 484


Here's a thought about APP.  And, this is just me hypothesizing. 

 

Imagine that APP is good. But, that it can be corrupted when it follows the wrong path. What if there were two paths that APP can follow. Both of these paths are normal and good. But one path is narrow and one is wide. The narrow path leads to a very healthy brain. The wide path also leads to a healthy brain, but only if it is not filled up with lots of traffic. There is no traffic guard to limit the amount of APP taking the wide path, while the narrow path will only allow a certain amount of APP. So if the wide path fills up with too much APP, bad things result, like amyloid-beta production.

 

In Down Syndrome there is too much APP produced, therefore, the excess has to take the wide path. This results in Alz.

 

In Alz mice which are bread to over produce APP, again the excess is forced to take the wide path.

 

However, in sporadic Alz, it is not so much the overproduction of APP, but instead it is something inhibiting the narrow (healthy) path and forcing all the APP to take the wide path. There is no line waiting to walk the wide path like there is for the narrow path, so APP leaves sooner causing a reduction of APP in the brain. And there you have the causes of Alz.

 

Sorry, if this is weird. It's how I think sometimes.



Lane Simonian
Posted: Tuesday, July 15, 2014 9:50 PM
Joined: 12/12/2011
Posts: 4863


I like the way you think, Serenoa.  There are some interesting connections between the amyloid precursor protein and oxidative stress.  Amyloid precursor protein mutations increase oxidative stress and oxidative stress increases the processing of the amyloid precursor protein into a c-terminal fragment (which may in turn increase oxidative stress).


http://www.ncbi.nlm.nih.gov/pubmed/16478525


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


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






Serenoa
Posted: Tuesday, July 15, 2014 10:37 PM
Joined: 4/24/2012
Posts: 484


Yes, that is good evidence that oxidative/peroxynitrite damage (or a mutation in the APP gene) is causing abnormal processing of the APP molecule. Excellent. And, it seems logical that for every APP that is abnormally processed, there is one less beneficially-processed APP molecule. Perhaps a double whammy.

 

 Very happy to see you are back Lane. Hope you had a nice vacation or if not a vacation, at least a break from the message boards.


Serenoa
Posted: Wednesday, July 16, 2014 8:14 AM
Joined: 4/24/2012
Posts: 484


So, I'm I right in saying that there are three classifications of things that lead to c-terminal or amyloid-beta in regard to APP processing? They would be 1) an over production of APP (as in Down Syndrome and APP mice), 2) oxidative stress (as in late-onset Alz), 3) gene mutation as in PS1 (early-onset Alz).

 

Simple overproduction of APP seems to lead to Alz.

 

Oxidative stress' effect on APP also seems to lead to Alz.

 

Is this a accurate generalization? If not, where am I going wrong with this logic? Thanks.



Lane Simonian
Posted: Wednesday, July 16, 2014 11:04 PM
Joined: 12/12/2011
Posts: 4863


This is essential it, Serenoa!  Very well analyzed.  Certain forms of amlyoid precursor proteins (such as found in various mutations) seem to increase oxidative stress in and of themselves, whereas other forms of amyloid precursor proteins occur concurrently with oxidative stress and that stress leads to a c terminal fragment that for awhile further increases oxidative stress.


I am still on my vacation visiting national parks in the West that my father either worked at or took us to as children.  


So many good posts in recent days that I have not been able to respond to or research further, but the cooperative work of so many people on this board to find answers to Alzheimer's disease always impresses and uplifts me.



Myriam
Posted: Thursday, July 17, 2014 1:13 AM
Joined: 12/6/2011
Posts: 3326


Lane, safe travels! Sounds like a wonderful trip.
Serenoa
Posted: Thursday, July 17, 2014 9:39 AM
Joined: 4/24/2012
Posts: 484


Lane, do not let the message boards or thoughts of Alz treatments distract you from the glories of our National Parks. This research can get obsessive at times (at least for me) and sometimes you need to let it go for a while. Also, I find that going back through old posts and topics can answer a lot of my questions, and I always have a lot of questions.

Lane Simonian
Posted: Wednesday, July 23, 2014 12:00 PM
Joined: 12/12/2011
Posts: 4863


Src kinases may play a critical intermediary role in the development of Alzheimer's disease.  Src kinases like phospholipase C gamma are activated by tyrosine receptor kinases (platelet derived growth factor receptors, epidermal growth factor receptors, insulin receptors, insulin growth factor receptors, etc.).  Platelet derived growth factor receptors which can be activated by high levels of glucose and angiotensin II (a risk factor for high blood pressure) appear to be the most important of these receptors in most cases of Alzheimer's disease.


 2003 Mar 14;278(11):9290-7.

Platelet-derived growth factor induces the beta-gamma-secretase-mediated cleavage of Alzheimer's amyloid precursor protein through a Src-Rac-dependent pathway.

http://www.ncbi.nlm.nih.gov/pubmed/12645527
Rac1 is a small g protein that can activate phospholipase C gamma.  Other g proteins activate phospholipase C beta and src kinases.  

The src kinase can lead to the formation of peroxynitrites or it can activate the neuroprotective phosphatidylinositol 3-kinase/Akt pathway. Presenilin gene 1 mutations and high levels of peroxynitrites prevent the latter.

The mechanisms of peroxynitrite-induced apoptosis are not fully understood. We report here that peroxynitrite-induced apoptosis of PC12 cells requires the simultaneous activation of p38 and JNK MAP kinase, which in turn activates the intrinsic apoptotic pathway, as evidenced by Bax translocation to the mitochondria, cytochrome c release to the cytoplasm and activation of caspases, leading to cell death. Peroxynitrite induces inactivation of the Akt pathway. Furthermore, overexpression of constitutively active Akt inhibits both peroxynitrite-induced Bax translocation and cell death.


Mutant Presenilin-1 Induces Apoptosis and Downregulates Akt/PKB

  1. Raymond P. Roos1,3

+Show Affiliations

  1. The Journal of Neuroscience,19(13): 5360-5369;

Abstract

Most early onset cases of familial Alzheimer’s disease (AD) are caused by mutations in presenilin-1 (PS1) and presenilin-2 (PS2). These mutations lead to increased β-amyloid formation and may induce apoptosis in some model systems. Using primary cultured hippocampal neurons (HNs) and rat pheochromocytoma (PC12) cells transiently transfected with replication-defective recombinant adenoviral vectors expressing wild-type or mutant PS1, we demonstrate that mutant PS1s induce apoptosis, downregulate the survival factor Akt/PKB, and affect several Akt/PKB downstream targets, including glycogen synthase kinase-3β and β-catenin. Expression of a constitutively active Akt/PKB rescues HNs from mutant PS1-induced neuronal cell death, suggesting a potential therapeutic target for AD. Downregulation of Akt/PKB may be a mechanism by which mutant PS1 induces apoptosis and may play a role in the pathogenesis of familial AD.

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

Polyphenols in spices, fruits, vegetables, essential oils (via aromatherapy), etc. can inhibit tyrosine kinases and thus can potentially delay the onset of Alzheimer's disease.

http://www.ncbi.nlm.nih.gov/pubmed/21356239 (polyphenols for cancer prevention, but with implications for Alzheimer's disease).

http://www.ncbi.nlm.nih.gov/pubmed/22673542

Thanks very much Myriam and Serenoa.  I enjoyed my trip very much--such beautiful country.

Myriam
Posted: Wednesday, July 23, 2014 2:11 PM
Joined: 12/6/2011
Posts: 3326


Welcome back!!
Serenoa
Posted: Thursday, July 24, 2014 8:09 AM
Joined: 4/24/2012
Posts: 484


Yes, welcome back! I think you have nailed it again Lane. Tyrosine kinases and phosphorylation of cellular proteins is the key.

 

I have been researching and reviewing, learning and brainstorming a lot in the last few weeks. The failures of the multitudes of experts to discover the true cause of this disease, and my own failure to put together the clues that will lead to a treatment has been haunting me. However, with the help of this forum and the availability of good scientific data, I think there is hope, and I am not giving up. My ideas lately, I think, are bringing me closer to understanding the possible real causes of AD, many of which Lane has been explaining for a long time.


Lane Simonian
Posted: Thursday, July 24, 2014 11:47 AM
Joined: 12/12/2011
Posts: 4863


I always appreciate your insights and input, Serenoa.  I think that you are on the right track.   


 

Here's a bit more on the Src kinase.  When it activates phosphatidylinositol-3 kinase/Akt pathway it helps sort out the amyloid precursor protein. 


 

When the phosphatidylinositol 3-kinase/Akt pathway is inhibited (by presenilin gene mutations and peroxynitrites, for instance) the src kinase increases the activation of p38 Mapk which results in the formation of more peroxynitrites and to the c-terminal fragment of the amyloid precursor protein. 


 

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 isoform]. 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 


 

http://www.ncbi.nlm.nih.gov/pubmed/23907271 


 

Involvement of Protein Kinase C and Src Family Tyrosine Kinase in Gαq/11-induced Activation of c-Jun N-terminal Kinase and p38 Mitogen-activated Protein Kinase*


 
http://www.jbc.org/content/273/36/22892.long

 

 
A significant amount of evidence suggests that the p38-mitogen-activated protein kinase (MAPK) signalling cascade plays a crucial role in synaptic plasticity and in neurodegenerative diseases. In this review we will discuss the cellular localisation and activation of p38 MAPK and the recent advances on the molecular and cellular mechanisms of its substrates: MAPKAPK 2 (MK2) and tau protein. In particular we will focus our attention on the understanding of the p38 MAPK-MK2 and p38 MAPK-tau activation axis in controlling neuroinflammation, actin remodelling and tau hyperphosphorylation, processes that are thought to be involved in normal ageing as well as in neurodegenerative diseases. We will also give some insight into how elucidating the precise role of p38 MAPK-MK2 and p38 MAPK-tau signalling cascades may help to identify novel therapeutic targets to slow down the symptoms observed in neurodegenerative diseases such as Alzheimer's and Parkinson's disease. 

 
http://www.hindawi.com/journals/jst/2012/649079/ 

 
http://www.neuronlab.org/pdf/1228038847.pdf 

Lane Simonian
Posted: Friday, July 25, 2014 11:20 AM
Joined: 12/12/2011
Posts: 4863


O.k. now the seeming contradictory studies regarding protein kinase C and Alzheimer's disease make sense.  Protein kinase C causes the secretion of the amyloid precursor protein and the sorting out of this protein via the two step activation of Src kinases and the phosphatidylinositol-3 kinase. However, when the phosphatidyinositol-3 kinase is inhibited by presenilin gene 1 mutations or by factors that lead to oxidative stress, the src kinases just leads to the production of more peroxynitrites and the c-terminal fragment of the amyloid precursor protein.  This probably means that src kinase activators such as diabetes drug metformin may help reduce the risk of Alzheimer's disease in those without the presenilin gene 1 mutation early on but not later on.  Also drugs that cross the blood brain barrier and inhibit the phosphatidylinositol 3-kinase should not be prescribed to those at risk for Alzheimer's disease.


Relatedly, mutated amyloid precursor proteins and the c-terminal fragment of the amyloid precursor protein stimulate g proteins that activate protein kinase C that lead to the formation of more peroxynitrites. This is a negative feedback mechanism of Alzheimer's disease that contributes to at least the initial progression of the disease (the peroxynitrite nitration of NMDA receptors is likely the main negative feedback mechanism as the disease passes the early stages).


Overexpression and altered metabolism of amyloid precursor protein (APP) resulting in increased 4 kDa amyloid β peptide (Aβ) production are believed to play a major role in Alzheimer’s disease (AD). Therefore, reducing Aβ 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 Aβ release (Buxbaum et al., 1993Gadzuba et al., 1993Hung 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 Aβ. 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 Aβ levels.


http://www.jneurosci.org/content/18/8/2907.long



 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.

Amyloid precursor protein carboxy-terminal fragments modulate G-proteins and adenylate cyclase activity in Alzheimer's disease brain.

G protein-mediated neuronal DNA fragmentation induced by familial Alzheimer's disease-associated mutants of APP.

http://www.ncbi.nlm.nih.gov/pubmed/8650548