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A supercomputer found new ways to elucidate the creation of the toxic oligomers associated with AD
Myriam
Posted: Tuesday, February 18, 2014 10:46 PM
Joined: 12/6/2011
Posts: 3326


Researchers studying peptides using the Gordon supercomputer at the San Diego Supercomputer Center (SDSC) at the University of California, San Diego (UCSD) have found new ways to elucidate the creation of the toxic oligomers associated with Alzheimer's disease.  

 

Igor Tsigelny, a research scientist with SDSC, the UCSD Moores Cancer Center, and the Department of Neurosciences, focused on the small peptide called amyloid-beta, which pairs up with itself to form dimers and oligomers. 

The scientists surveyed all the possible ways to look at the dynamics of conformational changes of these peptides and the possibility that they might organize into the oligomers theorized to be responsible for the degenerative brain disease. In the February 14 issue of the Journal of Alzheimer's Disease, the researchers suggest their results may generate new targets for drug development. 

 

"Our research has identified amino acids for point mutations that either enhanced or suppressed the formation and toxicity of oligomer rings," said Tsigelny, the study's lead author. "Aggregation of misfolded neuronal proteins and peptides may play a primary role in neurodegenerative disorders, including Alzheimer's disease." 

 

Tsigelny also noted that recent improvements in computational processing speed have allowed him and other researchers to use a variety of tools, including computer simulations, to take new approaches to examining amyloid-beta, which has proven too unstable for traditional approaches such as x-ray crystallography. 

 

The researchers investigated the single and dimer forms of the peptide with a combination of computational methods including molecular dynamics, molecular docking, molecular interactions with the membrane, as well as mutagenesis, biochemical, and electron microscopy studies. They then looked at how those dimers interacted with additional peptides and which larger structures resulted. The researchers found that depending on their configurations, some dimers did not lead to any further oligomerization and some form toxic oligomers implicated in the development of Alzheimer's disease. 

 

"Remarkably, we showed a greater diversity in amyloid-beta dimers than previously described," said Eliezer Masliah, professor of pathology and medicine at UC San Diego, and a member of the research team. "Understanding the structure of amyloid-beta dimers might be important for the design of small molecules that block formation of toxic oligomers." 

 

Based on their results, the researchers were able to identify key amino acids that altered the formation and toxicity of oligomer rings. "Our data is only theoretical, but there is a good chance the oligomers we have been modeling exist for real," noted Masliah. "Some important recent publications have come out that support our work." 

 

The in silico experiments allowed the single amyloid-beta monomers to associate randomly, according to Masliah. However, he noted that within the brains of Alzheimer's patients, the formation of oligomers and fibrils depends on any number of biochemical influences such as peptide concentration, oxidation, neurotoxins, and acidity. 

 

According to the researchers, their work implicates a more dynamic role for the amyloid-beta dimers than previously thought. It also suggests that the way dimers form and then grow into larger structures is a rapidly changing process. 

"This, as well as previous results, suggests that targeting selected amyloid-beta dimers may be important in an effort to ameliorate the episodic memory described in mild cognitive impairment and the early stages of Alzheimer's disease," said Masliah. 

 

Masliah and Tsigelny's collaborators included UC San Diego's Yuriy Sharikov, Valentina Kouznetsova, Jerry Greenberg, Wolfgang Wrasidlo, Tania Gonzalez, Paula Desplats, Sarah E. Michael, Margarita Trejo-Morales, and Cassia Overk.  

 

Igor F. Tsigelny, Yuriy Sharikov, Valentina L. Kouznetsova, Jerry P. Greenberg, Wolfgang Wrasidlo, Tania Gonzalez, Paula Desplats, Sarah E. Michael, Margarita Trejo-Morales, Cassia R. Overk, Eliezer Masliah. Structural Diversity of Alzheimer's Disease Amyloid-β Dimers and Their Role in Oligomerization and Fibril Formation. Journal of Alzheimer's Disease, 2014 DOI: 10.3233/JAD-131589 

 

  


Lane Simonian
Posted: Wednesday, February 19, 2014 3:23 PM
Joined: 12/12/2011
Posts: 4986


This disease which used to spin my head in loops is now becoming almost crystal clear.


The main pathway to peroxynitrites early on in Alzheimer's disease is phospholipase C--protein kinase C and src kinase--p38 MAPK.  The pathway to amyloid oligomers and plaques is phospholipase C--intracellular calcium release--protein kinase C and src kinase.


Protein kinase C leads to the secretion of the amyloid precursor protein and src leads to the c-terminal fragment of the amyloid precursor protein. The release of intracellular calcium leads to amyloid oligomers and then plaques.


All that has to be present for Alzheimer's disease is peroxynitrites and this can happen in the presence of just the c terminal fragment of the amyloid precursor protein (you don't need either oligomers or plaques).


Amyloid plaques have long been thought to be the cause of neuron loss in Alzheimer’s disease.  Now researchers report that excess of mutated amyloid precursor protein (APP) inside the neurons is sufficient to induce neuron death.  The report challenges the notion that amyloid deposits outside of the cells are necessary for neuron death in Alzheimer’s disease.


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.



A Mediterranean diet both inhibits the formation of peroxynitrites and scavenges them.


The oligomers do contribute to the formation of peroxynitrites and that is what makes them more toxic than the plaques.  Peroxynitrite scavengers convert peroxynitrites into water and a nitrite anion.  Oligomers attract copper and zinc which increases the conversion of superoxide anions into hydrogen peroxide (some of the superoxide anions also combine with inducible nitric oxide to form peroxynitrites).  Hydrogen peroxide when it combines with the nitrite anion forms water and peroxynitrites.   Many antioxidants become depleted in this futile cycle.  In the presence of copper ions, nitric oxide and oxygen (O2) can also combine to produce peroxynitrites.  If you remove the oligomers or chelate the metals, you reduce but do not stop the production of peroxynitrites.  That is why these approaches are showing only slight efficacy in the treatment of Alzheimer's disease.


As the disease, progresses copper and zinc are entombed in the amyloid plaque and hydrogen peroxide stops being produced.  However, two problems remain: few if any antioxidants remain to scavenge peroxynitrites and secondly peroxynitrite mediated nitration of NMDA receptors leads to the production of more peroxynitrites.  Namenda is designed to combat this, but it is not a very good inhibitor of Namenda receptors.


So it comes back to the old axiom, stop the production of peroxynitrites and you prevent Alzheimer's disease; effectively scavenge peroxynitrites and you effectively treat the disease.


Lane Simonian
Posted: Thursday, February 20, 2014 9:49 AM
Joined: 12/12/2011
Posts: 4986


I am not sure if I have ever shown these diagrams together, but they are likely the key to understanding Alzheimer's disease. 


 

Linking lipids to Alzheimer's disease: cholesterol and beyond 

Amyloidogenic processing of APP largely occurs in lipid rafts. Cholesterol and low-density lipoprotein (LDL) receptor-related protein (LRP), an apolipoprotein E (APOE) receptor, promote the localization of β-site APP cleavage enzyme 1 (BACE1) to lipid raft...The relative abundance or absence of the lipids listed (shown in the blue boxes) directly influences the activity of BACE1 or γ-secretase... PLC-mediated hydrolysis of PtdIns(4,5)P2 promotes amyloidogenesis... 


 

From a separate article: APOE4 preferentially binds to the low density lipoprotein in a complex with cholesterol that bind to the LDL receptor, allowing internalization of cholesterol into the glia. 


 

My commentary:  The left side of the chart below is the one that leads to Alzheimer's disease.  The activity of phospholipase C increases in lipid rafts composed partly of low density lipoproteins ("bad" cholesterol) and saturated fats.  The APOE4 gene increases the extent of these lipid rafts.  Omega 3 fatty acids increase the amount of unsaturated fats in the brain and thus decrease the risk for Alzheimer's disease.  Phenolic compounds such as in various fruits, vegetables, and spices decrease phospholipase C gamma (phospholipase Cy) activation.  Thus combine, omega 3 fatty acids with a diet high in phenolic compounds (along with moderate exercise) and that is the best way to reduce one's risk for Alzheimer's disease. 



Lane Simonian
Posted: Thursday, February 20, 2014 12:54 PM
Joined: 12/12/2011
Posts: 4986


More on the vicious cycle of Alzheimer's disease. 


 

 2012 Feb;17(2):197-207. doi: 10.1007/s00775-011-0842-3. Epub 2011 Sep 14.

Amyloid beta-heme peroxidase promoted protein nitrotyrosination: relevance to widespread protein nitration in Alzheimer's disease.

Abstract

Amyloid beta (Aβ) peptide accumulation has been demonstrated to play a central role in Alzheimer's disease (AD). Substantial evidence indicates that protein nitrotyrosination contributes to Aβ-dependent neurotoxicity; however, the molecular mechanism is unknown. Recent research has shown that Aβ complexes with heme to form Aβ-heme, and increases the pseudo-peroxidase activity of heme. We found that Aβ-heme uses H(2)O(2) and NO(2)(-) to cause nitration of enolase and synaptic proteins more effectively than heme. Thus, the increased peroxidase activity of Aβ-heme may be the molecular link between excess Aβ and the widespread protein nitration in AD. Interestingly, the site of enolase nitration that was catalyzed by Aβ-heme is different from that induced by heme. Moreover, the secondary structural perturbations of Aβ-heme-treated and heme-treated enolase are also different. These observations suggest that Aβ-heme targets specific amino acid sequences in enolase. Furthermore, our data show that Aβ-heme peroxidase activity is independent of the aggregation state of Aβ, suggesting an important role of soluble Aβ in addition to Aβ aggregates and oligomers in AD pathogenesis.

 

The action performed by this peroxidase is the following: 


 

ONOO- (peroxynitrite) + 2e- + 2H+=H20 + NO2- 


 

When the above study was brought to my attention by a member of this board, it made no sense to me because this is the enzyme that contributes to the scavenging of peroxynitrites. 


 

But here again is the problem, soluble amyloid oligomers attract copper and zinc and the enzyme (superoxide dismutase) that converts superoxide anions into hydrogen peroxide depends on copper and zinc.  The hydrogen peroxide then combines with the nitrite anion (which is a product of peroxynitrite scavenging) to reform peroxynitrites. 


 

H2O2 + NO2-= ONOO- + H20 


 

Copper ions can also produce peroxynitrite directly via electron donation. 


 

NO + O2 + e-= ONOO- 


 

Copper and zinc become entombed in amyloid plaques, but peroxynitrites nitrate the NMDA receptor, leading to the further production of peroxynitrites.  


Peroxynitrite formation begins before the formation of amyloid oligomers (or simultaneously with them) and continues after they have been converted into plaques.  Thus removing oligomers or copper and zinc will only slightly slow down the progression of the disease for awhile.   


 

The framework is there for the prevention and treatment of Alzheimer's disease.  What is missing is the exact doses of the compounds that accomplish one or the other or both. 

 

 


Myriam
Posted: Friday, February 21, 2014 9:37 PM
Joined: 12/6/2011
Posts: 3326


Verrrry interesting!
Lane Simonian
Posted: Saturday, February 22, 2014 10:17 AM
Joined: 12/12/2011
Posts: 4986


Here is likely the explanation for why amyloid oligomers are more toxic than amyloid plaques. 


 

 2010 Aug 9;163(1-3):1-6. doi: 10.1016/j.regpep.2010.05.001. Epub 2010 May 15.

Dual functions of beta-amyloid oligomer and fibril in Cu(II)-induced H2O2 production.

Abstract

Amyloid-beta (Abeta) aggregation and Cu(II)-related oxidative stress are involved in the dysfunction and death of neurons in Alzheimer's disease (AD). However, the relationship between Abeta and Cu(II) is not clear. Furthermore, the pro- or anti-oxidant properties of Abeta are also under great debate. Here the H2O2 [hydrogen peroxide] generating ability of Abeta42 in its monomeric, oligomeric and fibrillar forms was studied in the presence of Cu(II). The results show that Abeta42 in both oligomeric and fibrillar forms can promote H2O2 generation at lower concentrations of Cu(II) and Abeta42 oligomer can promote H2O2 generation to a higher extent. Nevertheless, the promoting effect of Abeta42 oligomer and fibril may convert to an inhibitory effect when the concentration of Cu(II) is increased. This indicates the dual functions of Abeta42 oligomer and fibril in Cu(II)-induced H2O2 production. Hereby we present a new perspective on the roles of Abeta42 in Cu(II)-mediated oxidative stress and add new evidence to the viewpoint that Abeta42 oligomer may be primarily responsible for the pathogenesis of AD.

 

 

There are four pathways to peroxynitrite formation in Alzheimer's disease: the first two primarily involve amyloid oligomers.  The third one which is the trigger for Alzheimer's does not involve oligomers or plaques.  The fourth one amyloid oligomers can make worse. 


 

Rationalization of the origin of peroxynitrite-related damages in the brain of Alzheimer’s disease (AD) patients linking to functional hyperemia, inexplicable on the basis of the accepted hydrogen peroxide catalytic route, is here provided by molecular modeling. The present theoretical work indeed strongly supports the facile occurrence of an Aß-catalyzed generation of peroxynitrite in the brain, alternative to the already accepted H2O2-route, whenever ascorbate, dioxygen and nitric oxide are present near Cu-Aß complexes without the necessity of generating short-lived superoxide ions. The proposed route requires nitric oxide and dioxygen to be simultaneously present at sufficiently high concentrations near Cu-Aß complexes, requirement which is frequently fulfilled in brain during functional hyperemia. Conversely, hydrogen peroxide would be produced during resting phases. 


 

Peroxynitrite (sometimes called peroxonitrite) is an anion with the formula ONOO−. It is an unstablestructural isomer of nitrate, NO3−. Although its conjugate acid is highly reactive, peroxynitrite is stable in basic solutions.[1][2] It is prepared by the reaction of hydrogen peroxide with nitrite:

H2O2 + NO2− → ONOO− + H2O

Peroxynitrite is an oxidant and nitrating agent. Because of its oxidizing properties, peroxynitrite can damage a wide array of molecules in cells, including DNA and proteins. Formation of peroxynitrite in vivo has been ascribed to the reaction of the free radical superoxide with the free radical nitric oxide:[3][4] 

 

Our results suggest that activated p38 MAPK may serve as a potential signaling molecule in ONOO(-) generation through dual regulatory mechanisms, involving iNOS induction [inducible nitric oxide] and NADPH oxidase activation [superoxide anion]...And from another article 

Activation of microglial NADPH oxidase is synergistic with glial iNOS expression in inducing neuronal death: a dual-key mechanism of inflammatory neurodegeneration

 

Background

Inflammation-activated glia are seen in many CNS pathologies and may kill neurons through the release of cytotoxic mediators, such as nitric oxide from inducible NO synthase (iNOS), and possibly superoxide from NADPH oxidase (NOX). We set out to determine the relative role of these species in inducing neuronal death, and to test the dual-key hypothesis that the production of both species simultaneously is required for significant neuronal death.

 

Taken together, our results suggest that a switch of NMDA receptor-favorite intracellular signal pathways from ERK1/2 to p38 MAPK and the elevated basal level of [Ca2+]i with age might be critical for the developmental changes in NMDA neurotoxicity in hippocampal neuron. 


 

I think that is it: we have all the pathways that lead to peroxynitrites and the subsequent death of neurons in Alzheimer's disease.  Amyloid oligomers are neither the primary cause nor innocent bystanders, they are contributors to the disease.  You can have the death of neurons without them.  So removing them or chelating out copper will only slow down the progression of the disease. 


 

Thanks, Myriam! 


Lane Simonian
Posted: Saturday, February 22, 2014 1:35 PM
Joined: 12/12/2011
Posts: 4986


Eugenol (in various essential oils) and its derivatives can play a very important role in limiting the damage done by hydrogen peroxide/amyloid oligomer/copper ion complexes, by the activation of p38 MAPK, and by the activation of the NMDA receptors (and the subsequent release of glutamate and calcium influx) in Alzheimer's disease.



 1989;21(7):745-9.

Inhibitory effect of eugenol on Cu2+-catalyzed lipid peroxidation in human erythrocyte membranes.

Abstract

1. The effects of eugenol on lipid peroxidation catalyzed by hydrogen peroxide (H2O2) or benzoyl peroxide (BPO) in the presence of copper ions were studied in human erythrocyte membranes. 2. The production of hydroxyl radicals was suggested in the peroxidation system catalyzed by H2O2/Cu2+. 3. H2O2/Cu2+-dependent peroxidation was inhibited by eugenol in a concentration-dependent manner; peroxidation was inhibited 62% by 200 microM eugenol. 4. In the presence of eugenol, the peroxidation catalyzed by BPO/Cu2+ was inhibited in a concentration-dependent manner, and more than 100 microM eugenol completely inhibited peroxidation. 5. The inhibitory effect of eugenol was non-competitive against Cu2+ in H2O2/Cu2+- and BPO/Cu2+-dependent peroxidation. 6. It is suggested that eugenol inhibits formation of hydroxyl radicals.



Abstract

Eugenol and isoeugenol, two components of clover oil, have been reported to possess several biomedical properties, such as anti-inflammatory, antimicrobial and antioxidant effects. This study aims to examine the anti-inflammatory effects of eugenol, isoeugenol and four of their derivatives on expression of inducible nitric oxide synthase (iNOS) activated by lipopolysaccharide (LPS) in mouse macrophages (RAW 264.7), and to investigate molecular mechanisms underlying these effects. We found that two derivatives, eugenolol and glyceryl-isoeugenol, had potent inhibitory effects on LPS-induced upregulation of nitrite levels, iNOS protein and iNOS mRNA...Finally, we demonstrated that glyceryl-isoeugenol suppressed the phosphorylation of ERK1/2, JNK and p38 MAPK, whereas eugenolol suppressed the phosphorylation of ERK1/2 and p38 MAPK. Taken together, these results suggest that that eugenolol and glyceryl-isoeugenol suppress LPS-induced iNOS expression by down-regulating NF-kB and AP-1 through inhibition of MAPKs and Akt/IkB-alpha signaling pathways. Thus, this study implies that eugenolol and glyceryl-isoeugenol may provide therapeutic benefits for inflammatory diseases.

 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.

Eugenol inhibits Aβ-induced excessive influx of calcium ion into neurons that causes neuronal death.


Eugenol and its derivatives help to protect neurons against hydrogen peroxide-mediated tissue damage and peroxynitrite-mediated neuronal cell death in Alzheimer's diseases.  It also reverses part of the oxidative damage done by peroxynitrites and contributes to the regeneration of neurons in the hippocampus. Not far now.


Lane Simonian
Posted: Sunday, February 23, 2014 10:31 AM
Joined: 12/12/2011
Posts: 4986


Tying some loose ends together.  P38 MAPK not only produces peroxynitrites, it also increases the production of the c terminal fragment of the amyloid precursor protein via the enzyme BACE1 


 

Abstract

Cerebral amyloid angiopathy, associated to most cases of Alzheimer’s disease (AD), is characterized by the deposition of amyloid ß-peptide (Aß) in brain vessels, although the origin of the vascular amyloid deposits is still controversial: neuronal versus vascular. In the present work,we demonstrate that primary cultures of human cerebral vascular smooth muscle cells (HC-VSMCs) have all the secretases involved in amyloid ß-protein precursor (APP) cleavage and produce Aß1–40 and Aß1–42. Oxidative stress, a key factor in the etiology and pathophysiology of AD, up-regulates ß-site APP cleaving enzyme 1 (BACE1) expression, as well as Aß1–40 and Aß1–42 secretion in HC-VSMCs. This process is mediated by c-Jun N-terminal Kinase and p38 MAPK signaling and appears restricted to BACE1 regulation as no changes in the other secretases were observed. In conclusion, oxidative stress-mediated up-regulation of the amyloidogenic pathway in human cerebral vascular smooth muscle cells may contribute to the overall cerebrovascular amyloid angiopathy observed in AD patients. 


 


 

Collectively, these data demonstrate that mOS [mild oxidative stress] does not modify BACE1 expression but alters BACE1 subcellular compartmentalization to favour the amyloidogenic processing of APP, and thus offer new insight in the early molecular events of AD pathogenesis. 


 

And the critical observation tying it all together. 


 

Furthermore, conditioned media derived from CT105 [c-terminal fragment]-treated astrocytes enhanced neurotoxicity and pretreatment with NO and peroxynitrite scavengers attenuated its toxicity 

 


Lane Simonian
Posted: Sunday, February 23, 2014 12:39 PM
Joined: 12/12/2011
Posts: 4986


One more piece of the puzzle.  Peroxynitrites oxidize BH4 which results in the production of superoxide anions rather than the beneficial form of nitric oxide.  Superoxide anions can combine with inducible nitric oxide to form peroxynitrites or they can be converted into hydrogen peroxide by superoxide dismutase (which depends on zinc and copper attracted to amyloid oligomers).  Hydrogen peroxide combines with nitrite anions (a product of peroxynitrite scavenging) to reform peroxynitrites.  P38 MAPK leads to the formation of peroxynitrites (and the c-terminal fragment of the amyloid precursor protein) and the release of intracellular calcium leads to the formation of amyloid oligomers and both lead to the further production of peroxynitrites.


Amyloid oligomers augment the cycle but they do not cause it.  One can have Alzheimer's disease with just the c-terminal fragment of the amyloid precursor protein (produced by BACE1).  Whether with just this fragment, with amyloid oligomers, or amyloid plaques, the key to treating Alzheimer's disease is with peroxynitrite scavengers.


Conclusion: 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.


Lane Simonian
Posted: Sunday, February 23, 2014 8:55 PM
Joined: 12/12/2011
Posts: 4986


This does not sound exciting, but important nevertheless: I just found a site with about 200 citations for BACE1 and Alzheimer's disease. These three may have been the most important. 


 


 

High beta-secretase activity elicits neurodegeneration in transgenic mice despite reductions in amyloid-beta levels: implications for the treatment of Alzheimer disease.

 

These results demonstrate that high levels of BACE1 activity are sufficient to elicit neurodegeneration and neurological decline in vivo. This pathogenic pathway involves the accumulation of APP C-terminal fragments but does not depend on increased production of human Abeta. Thus, inhibiting BACE1 may block not only Abeta-dependent but also Abeta-independent pathogenic mechanisms. 


 


 

 2007 Jul;28(7):1009-14.

The increased activity of BACE1 correlates with oxidative stress in Alzheimer's disease

Hence, the increase of BACE1 activity occurring in sporadic AD is likely the effect, rather the cause, of ABeta accumulation and oxidative stress. 

 
 2002 Aug;10(3):279-88.

Oxidative stress increases expression and activity of BACE in NT2 neurons.

 
 
Our results support the hypothesis that oxidative stress and A beta production are strictly interrelated events and suggest that inhibition of BACE may have a therapeutic effect synergic with antioxidant compounds. 

 
Hydrogen peroxide and peroxynitrites activate BACE1.  Inhibiting BACE1, removing transition metals, or amyloid oligomers only slows down the subsequent production of peroxynitrites.  To prevent the disease you need strong antioxidants which is exactly what you need to treat the disease. Take ferulic acid especially in combination with other peroxynitrite scavengers as an example. 

 
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. 

 
 2009 Feb;12(1):124-30. doi: 10.1089/jmf.2007.0646.

Evaluation of the peroxynitrite scavenging activity of heat-processed ginseng.

Abstract

To ascertain the principal active peroxynitrite (ONOO(-)) scavenging components of heat-processed Panax ginseng C.A. Meyer (sun ginseng [SG]), the ONOO(-) scavenging activities of fractions and components of SG were compared. The results demonstrated that the ONOO(-) scavenging ability of SG was due to its ether fraction containing phenolic compounds. High-performance liquid chromatography analysis and ONOO(-) scavenging activity tests of the phenolic acids contained in SG identified vanillic acid, ferulic acid, p-coumaric acid, syringic acid, and maltol as the main active ONOO(-) scavenging components of SG. The ONOO(-) scavenging activities of phenolic acids and maltol were dependent on the degrees of their proton donating ability.

 
 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.

 

Not quite end of story, but close enough that there is no excuse not to make substantial progress against this disease in the next couple of years. It is not the end to the disease, but the promise (already seen in some cases) of a better life with the disease. 

 

 


Lane Simonian
Posted: Monday, February 24, 2014 10:47 AM
Joined: 12/12/2011
Posts: 4986


From 15 years ago:


Long-term treatment of subjects at risk for AD, using more efficacious antioxidant therapeutic agents could potentially slow neuronal degeneration and delay or prevent the onset of the disease.


William R. Markesberry, The Role of Oxidative Stress in Alzheimer's Disease


Thus, the role of a Mediterranean diet high in antioxidants in delaying the onset of Alzheimer's disease and extending the length and quality of life for those with Alzheimer's disease.  Thus, the role of antioxidant methoxyphenols such as eugenol, curcumin, ferulic acid, syringic acid, and vanillic acid in improving behavior and/or cognition in Alzheimer's patients from the earliest to latest stages in case studies and human clinical trials.  


Alzheimer's disease is an oxidant driven disease triggered by either genetics, diet (high sugar, high carbohydrates, salt, saturated fats, "bad" cholesterol), environmental toxins (pesticides, herbicides, aluminium fluoride, mercury, diesel fumes, particulate matter, for instance), drugs (such as bisphosphonate osteoporosis drugs), lifestyle (lack of exercise, excessive alcohol consumption outside of red wine, smoking, etc.), and accidents (traumatic brain injury and repeated concussions, for instance).  The damage done to the brain by these insults is largely reversible via antioxidants.