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Lane Simonian
Posted: Friday, February 10, 2017 10:54 PM
Joined: 12/12/2011
Posts: 4986



Over the years, I have attempted to present the evidence for the causes and treatment of Alzheimer's disease to try to make progress against the disease.  I will try to do it here as simply and as clearly as I can.

Early in Alzheimer's disease various forms of amyloid, environmental toxins, psychological stress, chronic smoking, an unhealthy diet, etc. trigger Alzheimer's disease via the following pathway: g protein-coupled receptors or receptor tyrosine kinases, protein kinase C, NMDA receptor overactivation, peroxynitrite (ONOO-), and caspase 3 (see following chart):

http://www.frontiersin.org/files/Articles/131867/fncel-09-00091-HTML/image_m/fncel-09-00091-g003.jpg

Various forms of amyloid only cause damage if protein kinase C is activated or put it another way amyloid only causes damage if it leads to the formation of peroxynitrite and the activation of caspase 3.  Prevent oxidative stress and amyloid does no damage.

Malinow’s team found that when mice are missing the PKC alpha gene, neurons functioned normally, even when amyloid beta was present. Then, when they restored PKC alpha, amyloid beta once again impaired neuronal function. In other words, amyloid beta doesn’t inhibit brain function unless PKC alpha is active.

...peroxynitrite formation in cerebral blood vessels is needed for the cerebrovascular effects of Abeta...These effects of Abeta were abolished by ROS scavengers (tempol, MnTBAP), NADPH oxidase inhibition, NOS inhibition (L-NNA) and by the peroxynitrite decomposition catalyst FeTPPS or PARP inhibition. Thus, Abeta leads to endothelial DNA damage and PARP activation via oxidative–nitrosative stress.

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

A natural scavenger of peroxynitrites, rosmarinic acid, protects against impairment of memory induced by Abeta(25-35).

 

If you remove amyloid early on, you are removing only one source of oxidative stress. At best, you may slightly delay the onset of the disease and briefly slow down its early progression.

Receptors upstream of protein kinase C are damaged as Alzheimer's disease.  At this point removing different forms of amyloid does not work at all.

Decreased levels of protein kinase C in Alzheimer brain.

At this point, the critical pathway is NMDA receptor activation, peroxynitrite formation, damage to glutamate transport systems, and NMDA receptor activation.  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917574/

 

http://www.jbc.org/content/271/11/5976.full

Mechanism of Oxidative Stress and Synapse Dysfunction in the Pathogenesis of Alzheimer’s Disease: Understanding the Therapeutics Strategies

We suggest that oxidative stress mediated through NMDAR and their interaction with other molecules might be a driving force for tau hyperphosphorylation and synapse dysfunction. Thus, understanding the oxidative stress mechanism and degenerating synapses is crucial for the development of therapeutic strategies designed to prevent AD pathogenesis.

In conclusion, through this review, we have tried to give our perspective on the wide variety of interaction between NMDAR-mediated oxidative stresses with the etiology of Alzheimer’s disease. NMDAR-mediated oxidative stress mechanisms are likely to play an important role in the synapse dysfunction in the pathogenesis of AD. Moreover, mitochondrial-mediated oxidative stress and apoptosis are also suggested to be contributing factors in AD pathogenesis. Furthermore, oxidative stress-mediated kinase and tau phosphorylation provides a connection of synapse dysfunction in AD. As we are not getting complete remedies from antioxidant therapy or known NMDAR antagonist drug used for AD pathology, should we go for combinational therapy? Or are there so many intermediate molecules between NMDAR to neurodegeneration? Should we go for target intermediate molecules? Therefore, understanding the role of oxidative stress-associated molecule and kinases in synapse dysfunction during AD pathogenesis may also lead to the development of mechanism-based therapeutics and better constructive strategies.

So several options exist, one is to inhibit NMDA receptor activation.  The approved drug Namenda unfortunately does not work very well.  As a possible alternative at low doses is gabapentin.

These findings suggest that the inhibitory effect of GBP (gabapentin) on NMDA receptors may play an important role in the antinociceptive property of GBP; however, it does not appear that GABA(A) and glycine receptors or GIRK channels contribute to the pharmacological properties of GBP.

Table 1 demonstrates a significant difference in MMSE scores before and after gabapentin treatment. These were all completed by an independent psychologist. All of the subjects demonstrated an improvement.

Table 2 demonstrates a positive difference between pre- and posttreatment scores for affective lability, behavioral dyscontrol, cognitive impairment, depression, and psychotic symptoms. These findings, though not placebo controlled, suggest that gabapentin at least temporarily improved cognitive, emotional, and behavioral functioning in patients with dementia.

Another option, inhibit enzymes between NMDA receptor activation and peroxynitrite formation.  Exhibit A: Anavex 2-73 which inhibits neuronal nitric oxide synthase (nNOS).

George Perry, PhD, dean and professor at the University of Texas at San Antonio and editor-in-chief of the Journal of Alzheimer's Disease, said in a news release that the sample size of 32 patients was small.

Still, “I have never seen mild-to-moderate Alzheimer’s patients maintain near baseline cognitive and activities of daily living function and positive correlation with all other measures over a 41-week trial period in any prior study with an approved or experimental drug,” he said. [By the way, Professor George Perry is one of the leading proponents of the peroxynitrite hypothesis of Alzheimer's disease].

Option three use peroxynitrite scavengers to treat Alzheimer's disease.

The neuroprotection by THC and CBD was because of attenuation of peroxynitrite. 

This study is the first to demonstrate CBD's ability to prevent the development of a social recognition deficit in AD transgenic mice. Our findings provide the first evidence that CBD may have potential as a preventative treatment for AD with a particular relevance for symptoms of social withdrawal and facial recognition.

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

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

 

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

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.


 

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

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.

 
 


  And eugenol which is found in various essential oils

 

 

 

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.

  

 

Effect of aromatherapy on patients with Alzheimer's disease.

 

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.

 

Serenoa
Posted: Saturday, February 11, 2017 5:10 AM
Joined: 4/24/2012
Posts: 484


Ran across this interesting reference to an antioxidant I had not head of before. Any thoughts?

Neuroprotective effects of tempol, a catalytic scavenger of peroxynitrite-derived free radicals, in a mouse traumatic brain injury model.

https://www.ncbi.nlm.nih.gov/pubmed/18319733?dopt=Abstract

 

Tempol: 8 Science-Proven Health Benefits and Where to Buy It

https://selfhacked.com/2016/08/15/tempol/


Lane Simonian
Posted: Saturday, February 11, 2017 6:39 AM
Joined: 12/12/2011
Posts: 4986


As always great research, Serenoa.  Most references to tempol are as a scavenger of superoxide anions.  I had almost forgotten its role as a peroxynitrite scavenger which is more important.  

TEMPOL protects human neuroblastoma SH-SY5Y cells against Beta-amyloid-induced cell toxicity.

 Amyloid-beta peptide (Abeta) has been implicated in the pathogenesis of Alzheimer's disease (AD). It can cause cell death in Alzheimer's disease by evoking a cascade of oxidative damage to neurons. Antioxidant compounds may help to elucidate and develop a treatment for Alzheimer's disease...TEMPOL inhibited Abeta(1-42)-induced superoxide anion generation and hydroxyl radical generation to a striking degree. Based on these results, it is concluded that TEMPOL effectively protects SH-SY5Y cells against Beta-amyloid-induced damage by suppressing the generation of reactive oxygen species especially, superoxide anion.

Possible protective role of tempol on amyloidosis and oxidative stress in experimentally induced-Alzheimer's like in mice

Alzheimers disease is the most common cause of dementia where the loss of intellectual and social abilities is severe enough to interfere with daily functioning. This may be a warning sign to our economy as unfortunately, the disease is growing up especially in the developing countries . Deposition of amyloid in brain is one of the pathological hallmarks of AD that is often associated with oxidative stress response. In this study, we investigated the possible mechanisms of tempol (superoxide scavenger), in a lipopolysaccharide model of Alzheimer\'s disease...Lipopolysaccharide increased oxidative stress burden and finally caused amyloid deposition in brain. These effects were reversed by using tempol. Tempol decreased parameters of Alzheimer's disease and oxidative markers serving as a good protective against Alzheimer's disease.

  

I just found this very interesting article:

It has been shown that APP mice exhibit signs of oxidative/nitrosative stress in brain vessels before these signs appear in neurones, glial cells or Abeta plaques, indicating that the vasculature is an early target of the Abeta peptide...Moreover, in aged APP mice treated in vivo for 4–6 weeks with antioxidants such as Tempol (a SOD mimetic) or N-acetylcysteine (NAC, a precursor of glutathione required for the catalytic activity of glutathione peroxidase, another enzyme that degrades H2O2 in addition to catalase, cerebrovascular responses were normalized to levels of wild-type littermates. Taken together, these observations point to oxidative stress as the main underlying deleterious mechanism through which Abeta alters the reactivity of the cerebral vasculature. In fact, not only does superoxide anions limit the bioavailability of NO, but the reaction between superoxide anion and NO proceeds much faster than the dismutation of superoxide anion by SOD, thus favouring the synthesis of the most potent oxidant, peroxynitrite, and together these events perturb pathways required for vasomotor function.

On the negative side:

Moreover, we recently found that in vivo treatment with either Tempol or NAC (for 4–6 weeks) did not result in any improvement in cerebrovascular function, as shown here for the basal NO synthesis evaluated by measuring the passive decrease in diameter induced by the non-selective NOS inhibitor NG-nitro-L-arginine (L-NNA), nor in any detectable change in vessel wall stiffnessThe results suggest that factors other than oxidative stress are involved in the functional deficits that accompany this model of cerebrovascular fibrosis, at least at this late stage of the pathology. 

The results for n-acetylcysteine I can understand as the transport system for this compound is damaged in Alzheimer's disease.  Two conclusions could be reached for tempol--it cannot fully reverse the damage done by nitro-oxidative stress late in Alzheimer's disease or as the authors' suggests not all the damage is the direct result of nitro-oxidatve stress in the late stages of the disease. Actually both explanations may be correct.

A good recent article:

"Tempol as an antioxidant; an updated review on current knowledge"

 

 


Lane Simonian
Posted: Saturday, February 11, 2017 10:56 AM
Joined: 12/12/2011
Posts: 4986


Completing the loop:

Protein kinase C-mediated enhancement of NMDA currents by metabotropic glutamate receptors in Xenopus oocytes.

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

Peroxynitrite Inhibits Glutamate Transporter Subtypes 

 

Dysfunction of NMDA receptors in Alzheimer’s disease

 N-methyl-d-aspartate receptors (NMDARs) play a pivotal role in the synaptic transmission and synaptic plasticity thought to underlie learning and memory. NMDARs activation has been recently implicated in Alzheimer’s disease (AD) related to synaptic dysfunction. Synaptic NMDARs are neuroprotective, whereas overactivation of NMDARs located outside of the synapse cause loss of mitochondrial membrane potential and cell death. NMDARs dysfunction in the glutamatergic tripartite synapse, comprising presynaptic and postsynaptic neurons and glial cells, is directly involved in AD. This review discusses that both beta-amyloid (Abeta) and tau perturb synaptic functioning of the tripartite synapse, including alterations in glutamate release, astrocytic uptake, and receptor signaling. Particular emphasis is given to the role of NMDARs as a possible convergence point for Abeta and tau toxicity and possible reversible stages of the AD through preventive and/or disease-modifying therapeutic strategies...

Regulation of extracellular concentrations of glutamate is also essential to neurons. Over-stimulation can let the synaptic regulation aberrant, leading to alterations in learning and memory, and more serious, neurodegeneration. Glutamate transport systems have the potential to terminate the excitatory signaling, transport glutamate to extrasynaptic receptors, and protect the neurons from excitotoxic injury. The majority of glutamate transport in the CNS, particularly as related to excitatory transmission, is mediated by the sodium-dependent EAATs. When glutamate release surpasses the capacity of astrocyte clearance mechanisms, or expression of EAATs decreased, excitotoxicity can occur. Dysfunction or reduced expression of GLT-1/EAAT-2 has been documented in both chronic and acute neurodegenerative disorders.

Protein kinase C activation is the trigger for Alzheimer's disease (via g protein-coupled receptors and receptor tyrosine kinases).  The inhibition of glutamate transport due to nitration is responsible for the progression of Alzheimer's disease.  And here is the general solution.

Mechanism of Oxidative Stress and Synapse Dysfunction in the Pathogenesis of Alzheimer’s Disease: Understanding the Therapeutics Strategies

We suggest that oxidative stress mediated through NMDAR and their interaction with other molecules might be a driving force for tau hyperphosphorylation and synapse dysfunction. Thus, understanding the oxidative stress mechanism and degenerating synapses is crucial for the development of therapeutic strategies designed to prevent AD pathogenesis.

In conclusion, through this review, we have tried to give our perspective on the wide variety of interaction between NMDAR-mediated oxidative stresses with the etiology of Alzheimer’s disease. NMDAR-mediated oxidative stress mechanisms are likely to play an important role in the synapse dysfunction in the pathogenesis of AD. Moreover, mitochondrial-mediated oxidative stress and apoptosis are also suggested to be contributing factors in AD pathogenesis. Furthermore, oxidative stress-mediated kinase and tau phosphorylation provides a connection of synapse dysfunction in AD. As we are not getting complete remedies from antioxidant therapy or known NMDAR antagonist drug used for AD pathology, should we go for combinational therapy? Or are there so many intermediate molecules between NMDAR to neurodegeneration? Should we go for target intermediate molecules? Therefore, understanding the role of oxidative stress-associated molecule and kinases in synapse dysfunction during AD pathogenesis may also lead to the development of mechanism-based therapeutics and better constructive strategies.


It is all there except for determining the best NMDA receptor antagonists, the best inhibitors of intermediate enzymes, and the best peroxynitrite scavengers.  

 


Lane Simonian
Posted: Saturday, February 11, 2017 8:41 PM
Joined: 12/12/2011
Posts: 4986


I am starting to get the mechanism: due to nitro-oxidative stress glutamate transporters are unable to deliver glutamate to astrocytes for uptake.

RESULTS: Hydrogen peroxide and peroxynitrite inhibited glutamate uptake in a concentration-dependent manner.

Regulation of synaptic transmission and glutamate levels in the synaptic cleft is performed by glutamate transporters. Glutamate transport is a sodium- and potassium-coupled process that is capable of concentrating intracellular glutamate up to 10 000-fold compared with the extracellular space. These transporters are located throughout the human central nervous system as well as other tissues. Recent physiologic studies provide evidence that glutamate transporters keep synaptic concentrations of glutamate low enough to prevent receptor desensitization and/or excitotoxicity. New insights into the biology of these transporters suggest that their dysfunction may contribute to neurologic disease.

Brain tissue has a remarkable ability to accumulate glutamate. This ability is due to glutamate transporter proteins present in the plasma membranes of both glial cells and neurons. The transporter proteins represent the only (significant) mechanism for removal of glutamate from the extracellular fluid and their importance for the long-term maintenance of low and non-toxic concentrations of glutamate is now well documented. In addition to this simple, but essential glutamate removal role, the glutamate transporters appear to have more sophisticated functions in the modulation of neurotransmission. They may modify the time course of synaptic events, the extent and pattern of activation and desensitization of receptors outside the synaptic cleft and at neighboring synapses (intersynaptic cross-talk). Further, the glutamate transporters provide glutamate for synthesis of e.g. GABA, glutathione and protein, and for energy production. They also play roles in peripheral organs and tissues (e.g. bone, heart, intestine, kidneys, pancreas and placenta). Glutamate uptake appears to be modulated on virtually all possible levels, i.e. DNA transcription, mRNA splicing and degradation, protein synthesis and targeting, and actual amino acid transport activity and associated ion channel activities. A variety of soluble compounds (e.g. glutamate, cytokines and growth factors) influence glutamate transporter expression and activities. Neither the normal functioning of glutamatergic synapses nor the pathogenesis of major neurological diseases (e.g. cerebral ischemia, hypoglycemia, amyotrophic lateral sclerosis, Alzheimer's disease, traumatic brain injury, epilepsy and schizophrenia) as well as non-neurological diseases (e.g. osteoporosis) can be properly understood unless more is learned about these transporter proteins. Like glutamate itself, glutamate transporters are somehow involved in almost all aspects of normal and abnormal brain activity.

 

Deficient glutamate tranport is associated with neurodegeneration in Alzheimer's disease

The mechanisms of synapse damage in Alzheimer's disease (AD) are not fully understood. Deficient functioning of glutamate transporters might be involved in synaptic pathology and neurodegeneration by failing to clear excess glutamate at the synaptic cleft...These results suggest that decreased glutamate transporter activity in AD is associated with increased excitotoxicity and neurodegeneration, supporting the possibility that abnormal functioning of this system might be involved in the pathogenesis of synaptic damage in AD.

Since reactive oxygen species are mediators of Abeta toxic effects and uptake inhibition [of glutamate] by Abeta was prevented by antioxidants, it is conceivable that, among other effects, Abeta produces glutamate transporter oxidation and dysfunction.


The result is a vicious circle in Alzheimer's disease, glutamate release leads to the production of peroxynitrite via NMDA receptors, peroxynitrite inhibits the transport of and uptake of glutamate which leads to the further activation of NMDA receptors which leads to the further production of peroxynitrte. Break the cycle with efficient NMDA receptor antagonists and effective peroxynitrite scavengers and one can treat Alzheimer's disease.


Lane Simonian
Posted: Saturday, February 11, 2017 9:22 PM
Joined: 12/12/2011
Posts: 4986


Here is the likely answer as to why tempol is not more effective in the treatment of Alzheimer's disease, particularly as it progresses.

When probed against individual ROS [reactive oxygen species} and RNS [reactive nitrogen species], edaravone was superior to tempol in scavenging hydrogen peroxide and peroxynitrite (or products of its decomposition), and blocking formation of lipid peroxides...Weak scavenging of hydrogen peroxide and peroxynitrite may explain the inability of tempol to protect SH [sulfhydryl]-groups, which are readily oxidized by the latter ROS and RNS. Overall, this additional information suggests that the mechanism underlying neuroprotective properties of tempol, and the associated reduction of glutamate release, involves superoxide or the superoxide-derived intermediate that is poorly scavenged by edaravone. 

That edaravone may be superior to tempol in the treatment of Alzheimer's disease is hinted at in the following study.

 2015 Apr 21;112(16):5225-30. doi: 10.1073/pnas.1422998112. Epub 2015 Apr 6.

Edaravone alleviates Alzheimer's disease-type pathologies and cognitive deficits.

Abstract

Alzheimer's disease (AD) is one of most devastating diseases affecting elderly people. Amyloid-beta (Abeta) accumulation and the downstream pathological events such as oxidative stress play critical roles in pathogenesis of AD. Lessons from failures of current clinical trials suggest that targeting multiple key pathways of the AD pathogenesis is necessary to halt the disease progression. Here we show that Edaravone, a free radical scavenger that is marketed for acute ischemic stroke, has a potent capacity of inhibiting Abeta aggregation and attenuating Abeta-induced oxidation in vitro. When given before or after the onset of Abeta deposition via i.p. injection, Edaravone substantially reduces Abeta deposition, alleviates oxidative stress, attenuates the downstream pathologies including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, synaptic dysfunction, and rescues the behavioral deficits of APPswe/PS1 mice. Oral administration of Edaravone also ameliorates the AD-like pathologies and memory deficits of the mice. These findings suggest that Edaravone holds a promise as a therapeutic agent for AD by targeting multiple key pathways of the disease pathogenesis.

On the other hand there are other peroxynitrite scavengers that do the very same thing and are safer.

Lane Simonian
Posted: Saturday, February 11, 2017 9:47 PM
Joined: 12/12/2011
Posts: 4986


Here is yet another part of it:

PN [peroxynitrite] interacts with NMDARs leading to nitration of the tyrosine residues present on NR1 subunits. This event is an irreversible reaction that leads to constant potentiation of the synaptic currents and calcium influx, overt activation of NMDARs and ultimately excitotoxicity.

And one more part:

The depletion of GSH [glutathione] enhances oxidative stress leading to neuronal degeneration as shown in several studies. Glutathione is a tripeptide composed of glutamate, cysteine and glycine residues with an unusual peptide bond between the alpha-amine of cysteine and the side chain carboxylate of glutamate. In neurons, cysteine is the rate-limiting substrate for GSH synthesis and in neurons approximately 90% of total cysteine uptake is mediated by GTs [glutamat transporters] and in particular EAAC1. Thus, EAAC1 transports cysteine at a rate comparable to that of glutamate... Recent studies have shown that PN [peroxynitrite]-mediated nitration of EAAC1 in neurons reduces the uptake capacity of cysteine leading to a depletion of intracellular GSH and neuronal cell death. Integrating these findings, central sensitization could also develop due to excitotoxicity from increased synaptic concentrations of glutamate and a decrease in neuronal thiol redox state due to decreased intracellular levels of cysteine and thus GSH.

Peroxynitrite scavengers partially reverse nitration.  Thus directly and indirectly (by allowing for the transport of glutamate and its uptake) they would greatly reduce the overactivation of NMDA receptors that leads to the death of neurons.  There would be a greater uptake of cysteine which would lead to more production of glutathione--the key peroxynitrite scavenger in the brain.

The hippocampi – the brain centres for learning and memory – are one of the earliest regions to be sabotaged by Alzheimer’s pathology. Our data revealed that GSH levels plummet in the hippocampi of patients with Alzheimer’s as well as those with MCI (Fig.1). The frontal cortices – brain CEOs responsible for a variety of executive functions – are chronologically affected later in Alzheimer’s. GSH levels mimic this chronology with no changes in the cortices of MCI patients, but significant reduction in those of Alzheimer’s patients (Fig.1). Interestingly, GSH remains unaffected in the cerebellum – a brain region unaffected by Alzheimer’s till late stages. It appears GSH decline is not ubiquitous but rather a region-specific phenomenon that appears to precisely map the progression of Alzheimer’s in our brains.

Could it then be that GSH levels would be able to act like a detector test for MCI and Alzheimer’s? It appears that may well be the case. Using only GSH levels in the hippocampi and frontal cortices as indicators, we were able to differentiate between healthy subjects and MCI patients as well as between patients with MCI and Alzheimer’s with a remarkably high accuracy.

 

Glutathione depletion alone had no effect on any of the measured parameters. It is concluded that glutathione is an important intracellular defence against peroxynitrite and that when glutathione levels are compromised the mitochondrial respiratory chain is a vulnerable target and cell death ensues. In view of the relative paucity of neuronal glutathione, it is possible that astrocyte-derived peroxynitrite may, in certain pathological conditions, be released and diffuse into neighboring neurones where mitochondrial damage may occur.

Maybe the end to Alzheimer's disease is in sight.


The_Sun_Still_Rises
Posted: Sunday, February 12, 2017 10:42 AM
Joined: 7/24/2015
Posts: 3020


Some of this is going way beyond my ability read....BUT....I find this VERY interesting because I over-produce glutamate and under-produce GABA.   For a long while, before I dx'd, they gave me baclofen that dealt with the resulting muscle tightness and rigidity caused by this.  I was able study understand enough back then completely understand how we make and unmake GABA and Glutamate....and I narrowed it down 2 enzymes my body that must be dysfunctioning. 

While I was having confusion before the muscle tightness....but when the tightness started, much more pronounced brain/cognitive dysfunction. 

Once I was dx'd with Mysathenia Gravis....and given Mesitinon (which a bromide that worsens dementia), I did no need the Baclofen anymore...or, not near as often.  I maybe take it 1x every 2 months keep down the tightness.  So....I wondered if my tightness was due the opposing muscle having gone weak. 

Anyways....just some thoughts questions.  My doctor ordered some the Bredesen labs...I just have go in get blood drawn.  And I will be asking her re Singulair....I will likely have re-do my lung test....but aside from be bother that should be no issue have need....as my O2 levels have been dropping lately....as have my blood pressure.   I did just encounter someone who say Alz can attack the autonomic function controller in brain...although I had never heard this before. 

Hope you doing well and you back better.

<3

 


Lane Simonian
Posted: Sunday, February 12, 2017 4:59 PM
Joined: 12/12/2011
Posts: 4986


Glutamate is indeed likely a key player in Alzheimer's disease.  It does not get transported and removed so it just stays there activating NMDA receptors which leads to the death of neurons.

It appears that both Baclofen and mestinon when combined with bromide are bad for dementia.  Singulair may help to some degree as it reduces inflammation and to a lesser degree oxidation.  If you feel comfortable doing so, let me know what the Bredesen lab results show when you have them.

Thanks for remembering my back.  I can move and sleep again with just a little bit of pain, although I feel like I am one wrong move away from being in bad shape again. 

Serenoa
Posted: Saturday, February 18, 2017 5:14 AM
Joined: 4/24/2012
Posts: 484


  This seems relevant...

Oxidative stress and cerebrovascular dysfunction in mouse
models of Alzheimer’s disease

 

 http://onlinelibrary.wiley.com/doi/10.1113/expphysiol.2007.038729/pdf


Lane Simonian
Posted: Saturday, February 18, 2017 11:39 AM
Joined: 12/12/2011
Posts: 4986


Yes quite relevant.  I think that maybe the key question going forward is how much and what type of damage can be reversed by the most potent antioxidants.