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New Therapeutic Target Discovered for Alzheimer’s Disease
Serenoa
Posted: Tuesday, August 5, 2014 8:24 PM
Joined: 4/24/2012
Posts: 484


Just reviewing. The y-sectetase inhibitors seemed to fail for two reasons: they also inhibit NOTCH receptor (which is bad), and they lead to more C-terminal APP (which is bad). But they did reduce beta amyloid which didn't seem to matter, probably because any benefit from less amyloid was out weighed by the other two negative factors.
Lane Simonian
Posted: Tuesday, August 5, 2014 9:20 PM
Joined: 12/12/2011
Posts: 4886


That's exactly the same conclusion that I have come to, too.
Serenoa
Posted: Wednesday, August 6, 2014 6:58 AM
Joined: 4/24/2012
Posts: 484


You have probably already posted this but here is one of the first studies to confirm the BACE Inhibitor hypothesis. Exactly as you say...

 

BACE inhibitor reduces APP-β-C-terminal fragment accumulation in axonal swellings of okadaic acid-induced neurodegeneration

http://www.sciencedirect.com/science/article/pii/S0969996105003396

Serenoa
Posted: Wednesday, August 6, 2014 7:01 AM
Joined: 4/24/2012
Posts: 484


Also, Merc and Atra Zenica are both working on a BACE Inhibitor. So, there does seem to be something to this.

 

What's the deal with Albumin? I read somewhere that is may also act as a BACE inhibitor. One clinical trial has completed but no results have been posted.



Lane Simonian
Posted: Wednesday, August 6, 2014 9:53 AM
Joined: 12/12/2011
Posts: 4886


Good article and I had not seen it before.  BACE inhibition is likely the way to go early, before most of the amyloid precursor protein has been converted into something else (c-terminal fragments, amyloid oligomers, amyloid plaques).  One of the early candidates was withdrawn because it caused liver damage.  I read once from a blogger that Merck's Bace inhibitor was a curcumin analog.  That would make a lot of sense as curcumin is a peroxynitrite inhibitor and scavenger and peroxynitrites and hydrogen peroxide contribute to the activation of BACE.  I was not able to confirm the bloggers information, though, so I am not sure if he really had inside information. 


Ferulic acid which is a methoxyphenol like curcumin has a similar effect on BACE.


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.


http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0055774


Albumin interacts with peroxynitrites and that is why it may be a BACE inhibitor as well.


It turns out that when glutathione or other thiol agents (albumin, cysteine) interact with peroxynitrite they produce an agent called a nitrosothiol which has anti-inflammatory and pro-vasodilatory effects. 


http://phoenixrising.me/research-2/the-heart-of-the-matter/a-guide-to-cardiovascular-issues-in-cfs-ivc-peroxynitrite-and-the-heart. 


Serenoa
Posted: Wednesday, August 6, 2014 11:58 AM
Joined: 4/24/2012
Posts: 484


OK, now check this out. Activation of NMDA receptors stimulates x-secretase and reduces amyloid! Say what!???

 

Synaptic NMDA Receptor Activation Stimulates α-Secretase Amyloid Precursor Protein Processing and Inhibits Amyloid-β Production

Altered amyloid precursor protein (APP) processing leading to increased production and oligomerization of Aβ may contribute to Alzheimer's disease (AD). Understanding how APP processing is regulated under physiological conditions may provide new insights into AD pathogenesis. Recent reports demonstrate that excitatory neural activity regulates APP metabolism and Aβ levels, although understanding of the molecular mechanisms involved is incomplete. We have investigated whether NMDA receptor activity regulates APP metabolism in primary cultured cortical neurons. We report that a pool of APP is localized to the postsynaptic compartment in cortical neurons and observed partial overlap of APP with both NR1 and PSD-95. NMDA receptor stimulation increased nonamyloidogenic α-secretase-mediated APP processing, as measured by a 2.5-fold increase in cellular α-C-terminal fragment (C83) levels after glutamate or NMDA treatment. This increase was blocked by the NMDA receptor antagonists d-AP5 and MK801 but not by the AMPA receptor antagonist CNQX or the L-type calcium channel blocker nifedipine, was prevented by chelation of extracellular calcium, and was blocked by the α-secretase inhibitor TAPI-1. Cotreatment of cortical neurons with bicuculline and 4-AP, which stimulates glutamate release and activates synaptic NMDA receptors, evoked an MK801-sensitive increase in C83 levels. Furthermore, NMDA receptor stimulation caused a twofold increase in the amount of soluble APP detected in the neuronal culture medium. Finally, NMDA receptor activity inhibited both Aβ1-40 release and Gal4-dependent luciferase activity induced by β-γ-secretase-mediated cleavage of an APP-Gal4 fusion protein. Altogether, these data suggest that calcium influx through synaptic NMDA receptors promotes nonamyloidogenic α-secretase-mediated APP processing.

 

 

http://www.jneurosci.org/content/29/14/4442.short

Lane Simonian
Posted: Wednesday, August 6, 2014 12:18 PM
Joined: 12/12/2011
Posts: 4886


So many twist and turns.  Even after ten years I find myself having troubles remaining patient with the seemingly slew of contradictory findings.  Here is one possible explanation for how NMDA receptor activation early on can lead to the non-amyloidgic alpha secretase.


ABSTRACT It is well known that NMDA receptors (NMDARs) can both induce neurotoxicity and promote neuronal survival under different circumstances. Recent studies show that such paradoxical responses are related to the receptor location: the former to the extrasynaptic and the latter to the synaptic. The phosphoinositide 3-kinase (PI3K)/Akt kinase cascade is a key pathway responsible for the synaptic NMDAR-dependent neuroprotection. However, it is still unknown how synaptic NMDARs are coupled with the PI3K/Akt pathway. Here, we explored the role of an adaptor protein-adaptor protein containing pH domain, PTB domain, and leucine zipper motif (APPL1)-in this signal coupling using rat cortical neurons. We found that APPL1 existed in postsynaptic densities and associated with the NMDAR complex through binding to PSD95 at its C-terminal PDZ-binding motif. NMDARs, APPL1, and the PI3K/Akt cascade formed a complex in rat cortical neurons. Synaptic NMDAR activity increased the association of this complex, induced activation of the PI3K/Akt pathway, and consequently protected neurons against starvation-induced apoptosis. Perturbing APPL1 interaction with PSD95 by a peptide comprising the APPL1 C-terminal PDZ-binding motif dissociated the PI3K/Akt pathway from NMDARs. Either the peptide or lentiviral knockdown of APPL1 blocked synaptic NMDAR-dependent recruitment and activation of PI3K/Akt pathway, and consequently blocked synaptic NMDAR-dependent neuroprotection. These results suggest that APPL1 contributes to connecting synaptic NMDARs with the intracellular PI3K/Akt cascade and the downstream prosurvival signaling pathway in rat cortical neurons.


 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.

As the disease progresses the phosphatidylinositol 3-kinase is deactivated.  Then NMDA receptor activation has no redeeming qualities.

Serenoa
Posted: Wednesday, August 6, 2014 7:28 PM
Joined: 4/24/2012
Posts: 484


What is they have it backwards? What if it's the x-secretase activity that promotes NMDA receptor? Either way, apparently NMDA activity is good in certain places or in association with certain pathways.

 

Endogenous secreted amyloid precursor protein-α regulates hippocampal NMDA receptor function, long-term potentiation and spatial memory

Secreted amyloid precursor protein-α (sAPPα) levels are reduced during the pathogenesis of Alzheimer's disease, but the significance of this for neural function is not well understood. Here, we show that intrahippocampal infusion of antibodies targeted to endogenous sAPPα reduced long-term potentiation (LTP) in the dentate gyrus of adult rats by approximately 50%. Conversely, infusion of recombinant sAPPα dose-dependently increased LTP and facilitated in vitro tetanically evoked NMDA receptor-mediated currents. Pharmacological inhibition of α-secretase and other a-disintegrin-and-metalloproteases by TAPI-1 reduced both LTP and tetanus-evoked NMDA receptor-mediated currents in dentate granule cells. Both effects were prevented by co-application of exogenous recombinant sAPPα. Similarly, spatial memory was inhibited by intrahippocampal TAPI-1, an effect that was prevented by co-application of recombinant sAPPα. Together these findings indicate that endogenous sAPPα is a key contributor to synaptic plasticity and spatial memory. Its reduced production in Alzheimer's disease may thus contribute to the clinical memory deficits.

 

http://www.sciencedirect.com/science/article/pii/S0969996108000880

 

  

Also, you posted about lipid rafts previously and I didn't grasp it very well but this simple difference in APP processing in and out of lipid rafts makes sense to me.

 

From Wiki:

The amyloidogenic processing of APP has been linked to its presence in lipid rafts. When APP molecules occupy a lipid raft region of membrane, they are more accessible to and differentially cleaved by beta secretase, whereas APP molecules outside a raft are differentially cleaved by the non-amyloidogenic alpha secretase.[22] Gamma secretase activity has also been associated with lipid rafts.[23] The role of cholesterol in lipid raft maintenance has been cited as a likely explanation for observations that high cholesterol and apolipoprotein E genotype are major risk factors for Alzheimer's disease.[24]


Lane Simonian
Posted: Wednesday, August 6, 2014 8:03 PM
Joined: 12/12/2011
Posts: 4886


I liked the clear discussion of the potential role of lipid rafts in Alzheimer's disease.  Here is a related aspect:


We found that α-secretase activity is significantly elevated in the presence of FAs [fatty acids] with short chain length and in the presence of polyunsaturated FAs.


Funny because I just read today that the short chain fatty acids in milk, cheese, and other dairy products may reduce the risk of diabetes.


Sometimes, I cannot figure out the order of things.  Perhaps, the key point, though, is that NMDA receptor activation during non-oxidative states may be good, but under oxidative stress is bad.


J Neurosci. 2005 Oct 12;25(41):9367-77.

NMDA receptor activation inhibits alpha-secretase and promotes neuronal amyloid-beta production.

Abstract

Acute brain injuries have been identified as a risk factor for developing Alzheimer's disease (AD). Because glutamate plays a pivotal role in these pathologies, we studied the influence of glutamate receptor activation on amyloid-beta (Abeta) production in primary cultures of cortical neurons. We found that sublethal NMDA receptor activation increased the production and secretion of Abeta. This effect was preceded by an increased expression of neuronal Kunitz protease inhibitory domain (KPI) containing amyloid-beta precursor protein (KPI-APP) followed by a shift from alpha-secretase to beta-secretase-mediated APP processing. This shift is a result of the inhibition of the alpha-secretase candidate tumor necrosis factor-alpha converting enzyme (TACE) when associated with neuronal KPI-APPs. This KPI-APP/TACE interaction was also present in AD brains. Thus, our findings reveal a cellular mechanism linking NMDA receptor activation to neuronal Abeta secretion. These results suggest that even mild deregulation of the glutamatergic neurotransmission may increase Abeta production and represent a causal risk factor for developing AD.






Lane Simonian
Posted: Wednesday, August 6, 2014 8:31 PM
Joined: 12/12/2011
Posts: 4886


Cannot link to the book, but it has a great description of the role of the overactivation of NMDA receptors in cell death.  


Cell Death: The Role of PARP - Page 26 - Google Books Result

And src also plays a role in regulating NMDA receptors.

 2001 Jun;11(3):336-42.

NMDA receptor regulation by Src kinase signalling in excitatory synaptic transmission and plasticity.

Abstract

Regulation of postsynaptic glutamate receptors is one of the main mechanisms for altering synaptic efficacy in the central nervous system. Recent studies have given insight into the upregulation of the NMDA receptor by Src family tyrosine kinases, which bind to scaffolding proteins in the NMDA receptor complex. Src acts as a common step in signalling cascades that link G-protein-coupled receptors with protein kinase C via the intermediary cell-adhesion kinase beta. This signalling to NMDA receptors is required for long-term potentiation in the CA1 region of the hippocampus.

Depending on the level of oxidative stress, these pathways and receptors can lead to either the alpha secretase (non-amyloidgic) or beta and gamma secretase (amyloidgic).  


Studies on how oxidative stress enhances Abeta production have revealed that oxidative stress decreases the activity of alpha-secretase while promoting the expression and activation of beta- and gamma-secretase, enzymes critical for the generation of Abeta from APP [4650].

http://www.hindawi.com/journals/omcl/2013/316523/

Lane Simonian
Posted: Wednesday, August 6, 2014 9:08 PM
Joined: 12/12/2011
Posts: 4886


A bit more evidence that the alpha secretase is activated by the phosphatidylinositol 3-kinase.


 2006 Mar;20(3):512-4. Epub 2006 Jan 9.

The neuropeptide PACAP promotes the alpha-secretase pathway for processing the Alzheimer amyloid precursor protein.

Abstract

The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has neurotrophic as well as anti-apoptotic properties and is involved in learning and memory processes. Its specific G protein-coupled receptor PAC1 is expressed in several central nervous system (CNS) regions, including the hippocampal formation. Here we examined the effect of PAC1 receptor activation on alpha-secretase cleavage of the amyloid precursor protein (APP) and the production of secreted APP (APPsalpha). Stimulation of endogenously expressed PAC1 receptors with PACAP in human neuroblastoma cells increased APPsalpha secretion, which was completely inhibited by the PAC1 receptor specific antagonist PACAP-(6-3. In HEK cells stably overexpressing functional PAC1 receptors, PACAP-27 and PACAP-38 strongly stimulated alpha-secretase cleavage of APP. The PACAP-induced APPsalpha production was dose dependent and saturable. This increase of alpha-secretase activity was completely abolished by hydroxamate-based metalloproteinase inhibitors, including a preferential ADAM 10 inhibitor. By using several specific protein kinase inhibitors, we show that the MAP-kinase pathway [including extracellular-regulated kinase (ERK) 1 and ERK2] and phosphatidylinositol 3-kinase mediate the PACAP-induced alpha-secretase activation. Our findings provide evidence for a role of the neuropeptide PACAP in stimulation of the nonamyloidogenic pathway, which might be related to its neuroprotective properties.

And that the beta secretase is regulated by hydrogen peroxide and peroxynitrites.


This study demonstrates for the first time that BACE1 is highly modified by NO via multiple mechanisms: low and high levels of NO suppress BACE1 via transcriptional and post translational regulation, in contrast with the upregulation of BACE1 by H2O2-mediated oxidation. 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.




Serenoa
Posted: Thursday, August 7, 2014 11:51 AM
Joined: 4/24/2012
Posts: 484


Really interesting. I'm understanding more and more. Have to process all this. Thanks Lane.
Lane Simonian
Posted: Friday, August 8, 2014 6:45 PM
Joined: 12/12/2011
Posts: 4886


Here is what goes wrong in Alzheimer's disease.  Normally NMDA receptor activation would lead to the activation of phosphatidylinositol 3-kinase (as well as Wnt) and then to the extracellular regulatory kinase. This is the non-amyloid, non-peroxynitrite pathway.  


http://www.ncbi.nlm.nih.gov/pubmed/22423111


http://www.ncbi.nlm.nih.gov/pubmed/16401644



But because of multiple factors that cause oxidative stress p38 MAPK is upregulated which leads to peroxynitrite formation, which overactivates the NMDA receptor which leads to more p38 MAPK activation which leads to more peroxynitrites.  This is the vicious cycle that has to be broken by peroxynitrite scavengers such as eugenol and ferulic acid for Alzheimer's disease to be effectively treated.  Thank you, Serenoa for asking the questions and doing the research that is leading to a better understanding of Alzheimer's disease. 


 

 


 


 


Lane Simonian
Posted: Friday, August 8, 2014 9:05 PM
Joined: 12/12/2011
Posts: 4886


The effects of eugenol in various essential oils and ferulic acid on NMDA receptors and on dementia.


 1997 Apr 4;225(2):93-6.

Eugenol protects neuronal cells from excitotoxic and oxidative injury in primary cortical cultures.

Abstract

We examined the neuroprotective efficacy of eugenol against N-methyl-D-aspartate (NMDA)-, oxygen-glucose deprivation-, and xanthine/xanthine oxidase-induced neurotoxicity in primary murine cortical cultures. Eugenol (100-300 microM) attenuated NMDA (300 microM)-induced acute neurotoxicity by 20-60%. At the same concentration range, eugenol also inhibited NMDA (300 microM)-induced elevation in neuronal 45Ca2+ uptake by 10-30%. In the oxygen-glucose deprivation (50 min) neurotoxicity, eugenol (100-300 microM) prevented acute neuronal swelling and reduced neuronal death by 45-60% in a concentration-dependent fashion. Oxidative neuronal injury induced by xanthine/xanthine oxidase was also significantly reduced (75-90%) by eugenol (100- 300 microM) addition. These results suggest that eugenol may play a protective role against ischemic injury by modulating both NMDA receptor and superoxide radical.

The results suggest that ferulic acid is a novel competitive N-methyl-D-aspartate (NMDA) receptor antagonist and neuroprotector.


http://www.ncbi.nlm.nih.gov/pubmed/9147382


Eugenol in rosemary essential oil via aromatherapy (with lemon oil essential oil as an added stimulant and lavender and orange at night for relaxation).

Results:  All patients showed significant improvement in personal orientation related to cognitive function on both the GBSS-J and TDAS after therapy. In particular, patients with AD showed significant improvement in total TDAS scores. Result of routine laboratory tests showed no significant changes, suggesting that there were no side-effects associated with the use of aromatherapy. Results from Zarit's score showed no significant changes, suggesting that caregivers had no effect on the improved patient scores seen in the other tests.

Conclusions:  In conclusion, we found aromatherapy an efficacious non-pharmacological therapy for dementia. Aromatherapy may have some potential for improving cognitive function, especially in AD patients.

http://onlinelibrary.wiley.com/doi/10.1111/j.1479-8301.2009.00299.x/full


Ferulic acid in Angelica archangelica and rice bran oil (feru-guard).

Results: Treatment with Feru-guard led to decreased scores on the Neuropsychiatric Inventory in 19 of 20 patients and significantly decreased the score overall. The treatment also led to significantly reduced subscale scores on the Neuropsychiatric Inventory ("delusions", "hallucinations", "agitation/aggression", "anxiety", "apathy/indifference", "irritability/lability" and "aberrant behavior"). There were no adverse effects or significant changes in physical findings or laboratory data.

CONCLUSION:

Feru-guard may be effective and valuable for treating the behavioral and psychological symptoms of dementia in frontotemporal lobar degeneration and dementia with Lewy bodies.

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

Ferulic acid supported by other peroxynitrite scavengers in panax ginseng.


Improvement of Cognitive Deficit in Alzheimer’s Disease Patients by Long Term Treatment with Korean Red Ginseng

Jae-Hyeok Heo, Soon-Tae Lee, [...], and Manho Kim

Additional article information

Abstract

A 24-week randomized open-label study with Korean red ginseng (KRG) showed cognitive benefits in patients with Alzheimer’s disease. To further determine long-term effect of KRG, the subjects were recruited to be followed up to 2 yr. Cognitive function was evaluated every 12 wk using the Alzheimer’s Disease Assessment Scale (ADAS) and the Korean version of the Mini Mental Status Examination (K-MMSE) with the maintaining dose of 4.5 g or 9.0 g KRG per d. At 24 wk, there had been a significant improvement in KRG-treated groups. In the long-term evaluation of the efficacy of KRG after 24 wk, the improved MMSE score remained without significant decline at the 48th and 96th wk. ADAS-cog showed similar findings. Maximum improvement was found around week 24. In conclusion, the effect of KRG on cognitive functions was sustained for 2 yr follow-up, indicating feasible efficacies of long-term follow-up for Alzheimer’s disease.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659550/

 2012 Jul 9. [Epub ahead of print]

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

Abstract

OBJECTIVES:

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

METHODS:

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

RESULTS:

The treatment groups showed significant improvement on the MMSE and ADAS. Patients with higher dose group (4.5 g/day) showed improvements in ADAS cognitive, ADAS non-cognitive, and MMSE score as early as at 12 weeks, which sustained for 24-week follow-up.

DISCUSSION:

These results demonstrate the potential efficacy of a heat-processed form of ginseng on cognitive function and behavioral symptoms in patients with moderately severe AD.

Mechanism + means=Effective treatments for Alzheimer's disease




Lane Simonian
Posted: Saturday, August 9, 2014 11:49 AM
Joined: 12/12/2011
Posts: 4886


The main difference between the toxicity of amyloid oligomers and the c-terminal fragment of the amyloid precursor protein appears to be the ability of amyloid oligomers to generate hydrogen peroxide (by attracting copper and zinc which stimulate an enzyme that converts superoxide anions into hydrogen peroxide).  


Here, we monitored levels of hydrogen peroxide accumulation during different stages of aggregation of Abeta-(1-40) and ABri and found that in both cases it was generated as a short "burst" early on in the aggregation process. Ultrastructural studies with both peptides revealed that structures resembling "soluble oligomers" or "protofibrils" were present during this early phase of hydrogen peroxide formation. Mature amyloid fibrils derived from Abeta-(1-40) did not generate hydrogen peroxide. We conclude that hydrogen peroxide formation during the early stages of protein aggregation may be a common mechanism of cell death in these (and possibly other) neurodegenerative diseases.


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


Summary.

Carboxyl-terminal fragments (CTs) of the amyloid precursor protein have been shown to be highly neurotoxic and are though to contribute to the neuropathology of Alzheimer’s disease. We compared the effects of expressing CT99 in the human neuroblastoma MC65 with the effects of hydrogen peroxide on the parental SK-N-MC cells. CT99 and hydrogen peroxide generated a different pattern of free radicals and their toxic effects were differentially protected by a battery of antioxidants. Hydrogen peroxide caused a cell cycle arrest at phase S and apoptosis mediated through caspase-3 activation in a pattern similar to that described for amyloid-β neurotoxicity. However, CT99 apoptosis appeared to be mediated through an unidentified mitochondrial pathway. Both oxidative injury types induced heme oxygenase-1 expression as a neuroprotective response. Overall we found a coincidence in the nonespecific stress oxidative effects of CT99 and hydrogen peroxide, but clear differences on their respective potencies and pathways of neurotoxicity.

http://link.springer.com/article/10.1007%2Fs00702-006-0492-8

Once copper and zinc are entombed in amyloid plaques, hdyrogen peroxide stops being produced.  And yet, Alzheimer's disease continues to advance.  This indicates that while amyloid oligomers may contribute to Alzheimer's disease through their production of hydrogen peroxide, neither amyloid oligomers nor hydrogen peroxide are required for the advancement of Alzheimer's disease.  Removing amyloid oligomers probably only slightly slows down the progression of the disease.  The real problem begins with the production of the c-terminal fragment.


 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.

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




Lane Simonian
Posted: Saturday, August 9, 2014 8:27 PM
Joined: 12/12/2011
Posts: 4886


Do amyloid oligomers increase peroxynitrite levels either via the increased production of hydrogen peroxide or by attracting copper ions?  I have found a half a dozen different answers to this question today, but the answer may be yes to a certain degree.  The good news is that many peroxynitrite scavengers are also hydrogen peroxide scavengers and metal ion chelators.  
Lane Simonian
Posted: Sunday, August 10, 2014 12:27 PM
Joined: 12/12/2011
Posts: 4886


I have been looking for this conclusion for quite awhile:


Further CTs [carboxyl-terminal fragments] have resulted more neurotoxic to neuronal cultures (Suh et al., 2000) and greater activators of glial cells than Ab [amyloid beta] (Rah et al., 2001). 


http://link.springer.com/article/10.1007%2Fs00702-006-0492-8#page-1


The big question now is whether a beta secretase inhibitor alone is enough to stop the progression of Alzheimer's disease early on or whether peroxynitrite scavengers are needed instead.




Lane Simonian
Posted: Monday, August 11, 2014 10:05 AM
Joined: 12/12/2011
Posts: 4886


An example of how a peroxynitrite scavenger and a hydrogen peroxide scavenger can prevent the death of neurons.


Piceatannol attenuates hydrogen-peroxide- and peroxynitrite-induced apoptosis of PC12 cells by blocking down-regulation of Bcl-XL and activation of JNK.


Kim H.J.Lee K.W.Kim M.S.Lee H.J.

There is mounting evidence implicating the accumulation of intracellular reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease. Recently, considerable attention has been focused on identifying naturally occurring antioxidants that are able to reduce excess ROS and RNS, thereby protecting against oxidative stress and neuron death. The present study investigated the possible protective effects of piceatannol (trans-3,4,3',5'-tetrahydroxystilbene), which is present in grapes and other foods, on hydrogen-peroxide- and peroxynitrite-induced oxidative cell death. PC12 rat pheochromocytoma (PC12) cells treated with hydrogen peroxide or SIN-1 (a peroxynitrite-generating compound) exhibited apoptotic death, as determined by nucleus condensation and cleavage of poly(ADP-ribose)polymerase (PARP). Piceatannol treatment attenuated hydrogen-peroxide- and peroxynitrite-induced cytotoxicity, apoptotic features, PARP cleavage and intracellular ROS and RNS accumulation. Treatment of PC12 cells with hydrogen peroxide or SIN-1 led to down-regulation of Bcl-X(L) and activation of caspase-3 and -8, which were also inhibited by piceatannol treatment. Hydrogen peroxide or SIN-1 treatment induced phosphorylation of the c-Jun-N-terminal kinase (JNK), which was inhibited by piceatannol treatment. Moreover, SP600125 (a JNK inhibitor) significantly inhibited hydrogen-peroxide- and peroxynitrite-induced PC12 cell death, revealing inactivation of the JNK pathway as a possible molecular mechanism for the protective effects of piceatannol against hydrogen-peroxide- and peroxynitrite-induced apoptosis of PC12 cells. Collectively, these findings suggest that the protective effect of piceatannol against hydrogen-peroxide- and peroxynitrite-induced apoptosis of PC12 cells is associated with blocking the activation of JNK and the down-regulation of Bcl-XL.

The use of various aromatic plants is the key to treating Alzheimer's disease.


Serenoa
Posted: Monday, August 11, 2014 4:37 PM
Joined: 4/24/2012
Posts: 484


I still have not had time to get my thoughts together on all this information. However, it is very exciting to be narrowing down the potential causes of AD so specifically and in such a well-supported way.

 

One concept that is dawning on me is that peroxinitrites and other oxidative stressors don't just appear out of nowhere. They are created by the body in response to various factors, right? They are a mechanism by which the body is damaging itself, but they are not the cause, they are the means. Like a gun doesn't shoot you, a person does. The gun is just the means by which the damage is done, and the gun can be used for good or evil. Just like oxidative conditions can be beneficial in ridding the body of infections but can also damage tissue. That's my thought for the day.  


Lane Simonian
Posted: Monday, August 11, 2014 5:03 PM
Joined: 12/12/2011
Posts: 4886


Good insights, as always.  Oxidative stress is the cause of cell death in Alzheimer's disease, but a long list of factors can eventually produce the oxidative stress present in Alzheimer's disease.  They include but are not limited to a diet high in sugar, fructose, and salt, various genetic mutations, smoking, excessive alcohol consumption, various chronic bacterial and viral infections, exposure to various pesticides and herbicides, mercury, aluminium fluoride, sodium fluoride, stress (including post traumatic stress disorder), various air pollutants, and traumatic brain injuries.  Perhaps, bisphenols in plastics and nitrites and nitrates in meat are other causal factors.  The point is that there is rarely one single source for oxidative stress. So when people say, I know x person who ate a healthy diet, exercised, did not smoke or drink and still got Alzheimer's disease, we do not know what genetic, environmental, or medicines or medical procedures may have contributed to the disease.  All we know is that is does not occur by accident. Some thing or things are triggering oxidative damage.


And peroxynitrites are not necessarily bad.  Under the right circumstances, they can kill bacteria and cancer cells.  But at high levels, they also kill healthy cells.  And when they deplete antioxidant systems in the brain, their damage is unimpeded except when very powerful outside antioxidants are introduced.


Serenoa
Posted: Tuesday, August 12, 2014 6:32 AM
Joined: 4/24/2012
Posts: 484


Lane you said,

"The big question now is whether a beta secretase inhibitor alone is enough to stop the progression of Alzheimer's disease early on or whether peroxynitrite scavengers are needed instead."

 

I like this beta secretase/ctAPP hypothesis. I think it has merit since it fits so well with the evidence. But my thought is that a beta secretase inhibitor alone is not enough because it still leaves in place the thing that first upregulated the beta secretase pathway. That factor, peroxinitrites for example, would still be around to cause other damage. And, that factor is upstream of the ctAPP-induced damages, even though the vicious cycle would be interrupted. And, that factor may still be inhibiting the alpha secretase pathway! Therefore, you must stop or prevent that initial factor that leads to oxidative molecules, or scavenge those molecules after they are produced.

 

 So, there may actually be three courses of action: 1. inhibit beta secretase 2. prevent oxidation 3. activate alpha secretase. Some of these may overlap.

 

 Leukine has been shown to activate the Pl3k/Akt pathway which upregulates alpha secretase. This may be the mechanism by which it demonstrated some benefit to my mother. But alone, it is not a cure because it doesn't inhibit beta secretase or prevent the oxidation that is activating beta secretase and doing other damage.

 

 What say you Lane? And thank you very much for tying all this together for us.

 

 



Lane Simonian
Posted: Tuesday, August 12, 2014 9:31 AM
Joined: 12/12/2011
Posts: 4886


Some combinations of intuition and reason tell me that you are right, Serenoa. You probably have to work upstream from the beta secretase to prevent or at least delay the onset of Alzheimer's disease.  Take all the modifiable factors such as reducing consumption of carbohydrates, sugar, fructose, salt, smoking, alcohol consumption and add the helpful factors such as exercise, aromatherapy, and a diet heavy in fruits and vegetables, spices, and Omega 3-fatty acids,  and perhaps you can at least delay the onset of Alzheimer's disease even when the unmodifiable factors put you at high risk.