1229 replies to this topic

[ta5]

H2S keeps looking more interesting.

 

 

Mol Neurobiol. 2015 May 28. [Epub ahead of print]
Hydrogen Sulfide Ameliorates Homocysteine-Induced Alzheimer's Disease-Like Pathology, Blood-Brain Barrier Disruption, and Synaptic Disorder.
Kamat PK1, Kyles P, Kalani A, Tyagi N.
Elevated plasma total homocysteine (Hcy) level is associated with an increased risk of Alzheimer's disease (AD). During transsulfuration pathways, Hcy is metabolized into hydrogen sulfide (H2S), which is a synaptic modulator, as well as a neuro-protective agent. However, the role of hydrogen sulfide, as well as N-methyl-D-aspartate receptor (NMDAR) activation, in hyperhomocysteinemia (HHcy) induced blood-brain barrier (BBB) disruption and synaptic dysfunction, leading to AD pathology is not clear. Therefore, we hypothesized that the inhibition of neuronal NMDA-R by H2S and MK801 mitigate the Hcy-induced BBB disruption and synapse dysfunction, in part by decreasing neuronal matrix degradation. Hcy intracerebral (IC) treatment significantly impaired cerebral blood flow (CBF), and cerebral circulation and memory function. Hcy treatment also decreases the expression of cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) in the brain along with increased expression of NMDA-R (NR1) and synaptosomal Ca2+ indicating excitotoxicity. Additionally, we found that Hcy treatment increased protein and mRNA expression of intracellular adhesion molecule 1 (ICAM-1), matrix metalloproteinase (MMP)-2, and MMP-9 and also increased MMP-2 and MMP-9 activity in the brain. The increased expression of ICAM-1, glial fibrillary acidic protein (GFAP), and the decreased expression of vascular endothelial (VE)-cadherin and claudin-5 indicates BBB disruption and vascular inflammation. Moreover, we also found decreased expression of microtubule-associated protein 2 (MAP-2), postsynaptic density protein 95 (PSD-95), synapse-associated protein 97 (SAP-97), synaptosomal-associated protein 25 (SNAP-25), synaptophysin, and brain-derived neurotrophic factor (BDNF) showing synapse dysfunction in the hippocampus. Furthermore, NaHS and MK801 treatment ameliorates BBB disruption, CBF, and synapse functions in the mice brain. These results demonstrate a neuro-protective effect of H2S over Hcy-induced cerebrovascular pathology through the NMDA receptor. Our present study clearly signifies the therapeutic ramifications of H2S for cerebrovascular diseases such as Alzheimer's disease.
PMID: 26019015

[ta5]

The study below discusses these antioxidants for Alzheimer's:

• NAC
• Vitamin D
• Vitamin E
• Ferulic Acid
• D609 (Tricyclodecan-9-yl-xanthogenate)
• Selenium
• Melatonin
• CoQ10
• MitoQ
• Lipoic Acid
• SS-31 (Bendavia)

The full text is available

 

Expert Rev Neurother. 2015 Jan;15(1):19-40.
Strategy to reduce free radical species in Alzheimer's disease: an update of selected antioxidants.
Di Domenico F1, Barone E, Perluigi M, Butterfield DA.
Alzheimer's disease (AD), characterized by progressive loss of memory, language, reasoning and other cognitive functions, including dementia, is characterized pathologically by the presence of senile plaques, neurofibrillary tangles and synapse loss. Increased oxidative/nitrosative stress, decreased antioxidants, mitochondrial damage and other factors play major roles in the development and progression of AD. Strategies to reduce pro-oxidant species to ameliorate AD pathology have been proposed with mixed results. In this review, we focus on the most recent in vitro and in vivo antioxidant approaches for removing oxidant species with relevance to AD, including N-acetyl-l-cysteine, vitamin D, vitamin E, ferulic acid, tricyclodecan-9-yl-xanthogenate, selenium and melatonin as therapeutic stratagems in AD management. In addition, we reviewed the most effective mitochondria targeted antioxidants such as coenzyme Q10 and lipoic acid. We suggest the use of multitargeted approaches by formulas containing one or more antioxidant compounds may be more promising than single-agent approaches.
PMID: 25243342

[Bryan_S]

Injections may have passed on Alzheimer's 'seeds': study September 9, 2015

 

http://medicalxpress...imer-seeds.html

[Area-1255]

Liver health also has a lot to do with Alzheimer's development; you see this a lot in Chronic Alcoholism - when the liver breaks down - amyloid plagues generate easier and make their way through the bloodstream.

[niner]

Injections may have passed on Alzheimer's 'seeds': study September 9, 2015

 

http://medicalxpress...imer-seeds.html

 

Any chance this could happen with cerebrolysin?

[Bryan_S]

 

Injections may have passed on Alzheimer's 'seeds': study September 9, 2015

 

http://medicalxpress...imer-seeds.html

 

Any chance this could happen with cerebrolysin?

 

 

Scary situation to be sure. Cerebrolysin is a mixture of peptides purified from pig brains so I'd say its remotely possible. Look if this proves out many medical tissue transfers will be looked at in a new light. This is reminiscent of the infectious prion disease in Papua New Guinea except no one is being eaten. I think there is a certain acceptable risk for many procedures, we've known for some time pathogens can be passed from one living organism to another, even across species. Now that its known that this can happen at a molecular level new safeguards will have to be put in place.

[Avatar of Horus]

Two recent discoveries about changes in the preclinical stage of the disease, in the preceding 1-10 years:

Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease
Goetzl EJ1, Boxer A2, Schwartz JB2, Abner EL2, Petersen RC2, Miller BL2, Kapogiannis D2.

Neurology. 2015 Jul 7;85(1):40-7. doi: 10.1212/WNL.0000000000001702. Epub 2015 Jun 10.

http://www.ncbi.nlm....pubmed/26062630

Abstract

...

Step-wise discriminant modeling of the protein levels correctly classified 100% of patients with AD. Exosomal levels of all proteins were similarly significantly different from those of matched controls in 20 patients 1 to 10 years before and at diagnosis of AD (p 0.0003).
CONCLUSIONS: Levels of autolysosomal proteins in neurally derived blood exosomes distinguish patients with AD from case controls and appear to reflect the pathology of AD up to 10 years before clinical onset. These preliminary results confirm in living patients with AD the early appearance of neuronal lysosomal dysfunction and suggest that these proteins may be useful biomarkers in large prospective studies.

and

Low neural exosomal levels of cellular survival factors in Alzheimer's disease
Goetzl EJ1, Boxer A2, Schwartz JB3, Abner EL4, Petersen RC5, Miller BL2, Carlson OD6, Mustapic M6, Kapogiannis D6.

Ann Clin Transl Neurol. 2015 Jul;2(7):769-73. doi: 10.1002/acn3.211. Epub 2015 May 13.

http://www.ncbi.nlm....pubmed/26273689

Abstract

Transcription factors that mediate neuronal defenses against diverse stresses were quantified in plasma neural-derived exosomes of Alzheimer's disease or frontotemporal dementia patients and matched controls. Exosomal levels of low-density lipoprotein receptor-related protein 6, heat-shock factor-1, and repressor element 1-silencing transcription factor all were significantly lower in Alzheimer's disease patients than controls (P < 0.0001). In frontotemporal dementia, the only significant difference was higher levels of repressor element 1-silencing transcription factor than in controls. Exosomal transcription factors were diminished 2-10 years before clinical diagnosis of Alzheimer's disease. Low exosomal levels of survival proteins may explain decreased neuronal resistance to Alzheimer's disease neurotoxic proteins.

Edited by Avatar of Horus, 15 September 2015 - 07:07 PM.

[Avatar of Horus]

Major breakthrough in understanding Alzheimer's disease
Date: September 18, 2015
Source: Trinity College Dublin
http://www.scienceda...50918152000.htm

...
The research, published this week in leading international journal, Science Advances, was supported by Science Foundation Ireland (SFI) and the US-based charity, Brightfocus Foundation.
Alzheimer's disease is characterized, in part, by the build-up of a small protein ('amyloid-beta') in the brains of patients. Impaired clearance of this protein appears to be a major factor in the build-up of plaques, and then in the disease process itself. While the mode by which amyloid-beta is cleared remains unclear, it is evident that it needs to be removed from the brain via the bloodstream.
Unlike blood vessels anywhere else in the body, those in the brain have properties that strictly regulate what gets in and out of the delicate tissue -- this is what is known as the blood-brain barrier (BBB). The BBB functions as a tightly regulated site of energy and metabolite exchange between the brain tissue and the bloodstream.
"We have shown that distinct components of these blood vessels termed tight junctions are altered in Alzheimer's disease. We think that this alteration could be an entrained mechanism to allow for the clearance of toxic amyloid-beta from the brain in those living with Alzheimer's disease," said postdoctoral researcher in Trinity's School of Genetics and Microbiology, Dr James Keaney, who spearheaded the study.
Working with the Dublin Brain Bank, which is based in Beaumont Hospital, the researchers from Trinity examined brain tissues of individuals who were affected by Alzheimer's disease during their lifetime and then compared results to those observed in model systems in the laboratory.
Research Assistant Professor in Genetics at Trinity, Dr Matthew Campbell, added: "Our recent findings have highlighted the importance of understanding diseases at the molecular level. The concept of periodic clearance of brain amyloid-beta across the BBB could hold tremendous potential for Alzheimer's patients in the future. The next steps are to consider how this might be achieved.
...

Journal Reference:

Autoregulated paracellular clearance of amyloid-β across the blood-brain barrier.
Keaney et al. Science Advances, 2015 DOI: 10.1126/sciadv.1500472
Abstract
The blood-brain barrier (BBB) is essential for maintaining brain homeostasis and protecting neural tissue from damaging blood-borne agents. The barrier is characterized by endothelial tight junctions that limit passive paracellular diffusion of polar solutes and macromolecules from blood to brain. Decreased brain clearance of the neurotoxic amyloid-β (Aβ) peptide is a central event in the pathogenesis of Alzheimer’s disease (AD). Whereas transport of Aβ across the BBB can occur via transcellular endothelial receptors, the paracellular movement of Aβ has not been described. We show that soluble human Aβ(1–40) monomers can diffuse across the paracellular pathway of the BBB in tandem with a decrease in the tight junction proteins claudin-5 and occludin in the cerebral vascular endothelium. In a murine model of AD (Tg2576), plasma Aβ(1–40) levels were significantly increased, brain Aβ(1–40) levels were decreased, and cognitive function was enhanced when both claudin-5 and occludin were suppressed. Furthermore, Aβ can cause a transient down-regulation of claudin-5 and occludin, allowing for its own paracellular clearance across the BBB. Our results show, for the first time, the involvement of the paracellular pathway in autoregulated Aβ movement across the BBB and identify both claudin-5 and occludin as potential therapeutic targets for AD. These findings also indicate that controlled modulation of tight junction components at the BBB can enhance the clearance of Aβ from the brain.

[ceridwen]

An article I read about this said the amyloid could be cleared very very quickly

[mag1]

Any suggestions on strategies that might be used with the tight junction idea to clear amyloid?

[tunt01]

Any suggestions on strategies that might be used with the tight junction idea to clear amyloid?

 

I think MMP-9 inhibitors.  I think it gets back to the same issue of Cyclophilin A and its downstream effect (MMP9) which ultimately leads to degradation of tight junctions and blood brain barrier breakdown.

[niner]

Two recent discoveries about changes in the preclinical stage of the disease, in the preceding 1-10 years:

Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease
Goetzl EJ1, Boxer A2, Schwartz JB2, Abner EL2, Petersen RC2, Miller BL2, Kapogiannis D2.

Neurology. 2015 Jul 7;85(1):40-7. doi: 10.1212/WNL.0000000000001702. Epub 2015 Jun 10.

http://www.ncbi.nlm....pubmed/26062630

 

Step-wise discriminant modeling of the protein levels correctly classified 100% of patients with AD. Exosomal levels of all proteins were similarly significantly different from those of matched controls in 20 patients 1 to 10 years before and at diagnosis of AD (p 0.0003).
CONCLUSIONS: Levels of autolysosomal proteins in neurally derived blood exosomes distinguish patients with AD from case controls and appear to reflect the pathology of AD up to 10 years before clinical onset. These preliminary results confirm in living patients with AD the early appearance of neuronal lysosomal dysfunction and suggest that these proteins may be useful biomarkers in large prospective studies.

and

Low neural exosomal levels of cellular survival factors in Alzheimer's disease
Goetzl EJ1, Boxer A2, Schwartz JB3, Abner EL4, Petersen RC5, Miller BL2, Carlson OD6, Mustapic M6, Kapogiannis D6.

Ann Clin Transl Neurol. 2015 Jul;2(7):769-73. doi: 10.1002/acn3.211. Epub 2015 May 13.

http://www.ncbi.nlm....pubmed/26273689

 

Transcription factors that mediate neuronal defenses against diverse stresses were quantified in plasma neural-derived exosomes of Alzheimer's disease or frontotemporal dementia patients and matched controls. Exosomal levels of low-density lipoprotein receptor-related protein 6, heat-shock factor-1, and repressor element 1-silencing transcription factor all were significantly lower in Alzheimer's disease patients than controls (P < 0.0001). In frontotemporal dementia, the only significant difference was higher levels of repressor element 1-silencing transcription factor than in controls. Exosomal transcription factors were diminished 2-10 years before clinical diagnosis of Alzheimer's disease. Low exosomal levels of survival proteins may explain decreased neuronal resistance to Alzheimer's disease neurotoxic proteins.

 

This is pretty good news.  It means we can identify people in the very initial stages of AD when therapy will be able to do the most for them.   I think that a significant fraction of the 300-odd failed AD drug trials was probably due to only treating people who already had a huge pathological burden.

[Der Springende Punkt]

 

Any suggestions on strategies that might be used with the tight junction idea to clear amyloid?

 

I think MMP-9 inhibitors.  I think it gets back to the same issue of Cyclophilin A and its downstream effect (MMP9) which ultimately leads to degradation of tight junctions and blood brain barrier breakdown.

 

 

At Alzforum Berislav Zlokovic specifically emphasizes MMP-3 inhibitors.

[mag1]

Could the tight junctions ideas have implications for the trials with antibodies?

Clearing the amyloid from brain might merely clog up the tight junctions. (?)

[Bryan_S]

Injections may have passed on Alzheimer's 'seeds': study September 9, 2015

 

http://medicalxpress...imer-seeds.html

 

 

Here we go, this one is far from conclusive but is also remotely related in concept. 

 

Does fungus cause Alzheimer's?

http://medicalxpress...er-experts.html

[platypus]

Lifestyle modifications have reversed some of the memory deficits seen in Alzheimer's:

 

http://superhumanrad...a-nutshell.html

[resveratrol_guy]

 

Injections may have passed on Alzheimer's 'seeds': study September 9, 2015

 

http://medicalxpress...imer-seeds.html

 

 

Here we go, this one is far from conclusive but is also remotely related in concept. 

 

Does fungus cause Alzheimer's?

http://medicalxpress...er-experts.html

 

 

Even if this is true, I don't think killing the fungus cells will change the course of disease. There are plenty of mouse models of the disease in which Alzheimer's is artificially induced, for example, by injecting amyloid. But perhaps this has preventative value. I wonder, for instance, if the link between cheese consumption and high Alzheimer's rates in France has more to do with fungus than methionine.

 

As to the BBB considerations... apart from TERT therapy which suggests that it may be possible to motivate microglia and/or neurons to metabolize phosphotau (but is currently a figment of BioViva's imagination), Samuel Cohen thinks that we don't need to worry about disaggregation or tight junction issues at all, insofar as prevention is concerned; rather, all we need to do is prevent the prionlike chain reaction of amyloid oligomers begetting more of themselves (and presumably, the same with phosphotau). His team has already done that (especially see 5:30 in the video below) in worms afflicted with genetic predisposition to amyloid oligomer formation. In a nutshell, misfolded proteins can corrupt correctly folded proteins in an explosive chain reaction. If we can interfere with that process alone, then the only way to form Alzheimer's plaque is by quantum luck, one molecule at a time; the resulting damage would be incidental and easily obviated by routine neuroplasticity. In theory, this could be done even well along the course of the disease, provided that enough neurons were left intact to provide adequate cognition after the disease were halted.

 

BBB clearance of amyloid seems unlikely to be useful, except in the early stages of pathology where doing so (e.g. with lipidated curcumin or nilvadepine) might prevent the chain reactions involving both amyloid and phosphotau. In particular, the one article linked above suggested that anything over 8 KDa is difficult to excrete out the tight junction, whereas various phosphotau oligomers weigh in excess of 200 KDa. Ironically, precisely because of the TJ damage which occurs in Alzheimer's, it's possible that these larger molecules could be excreted, at the price of allowing toxins to flow into the brain. But that problem might be mooted by the aforementioned anti-chain-reaction compounds. So all hope is not lost for BBB clearance strategies.

 

Ideally, I would want to find a natural substance of low toxicity which has anti-chain-reaction properties, rather than merely disaggregation properties. I know of no such molecule.

 

Edited by resveratrol_guy, 16 October 2015 - 12:58 PM.

[mag1]

http://www.ncbi.nlm....pubmed/26444777

[ceridwen]

I thought this had already failed

[mag1]

2 clinical trials have been conducted. One of them is supposed to report soon.

 

It has been years since the initial research was published and there is still only 1 published human AD patient treated.

[resveratrol_guy]

http://www.ncbi.nlm....pubmed/26444777

 

Thanks for this.

 

"After 6 months of treatment with Targretin® 300 mg/day, memory improved by about 40%" I wonder how they measured that. Such an improvement in basic memory games would be virtually inconceivable, dementia or not. Too bad it's paywalled.

 

But I wouldn't spend money to read the study unless you're wealthy and at high risk of dementia, because it turns out that a 300 mg dose of bexarotene costs on the order of $1000 in the West. Either that, or you're willing to roll the dice with dodgy vendors on Alibaba, in which case it can be had for about $1/day. (You really have to wonder who is scamming you more.)

 

BTW these results seem to contradict those discussed here. However, it sounds like the difference is that this particular patient was early stage. Nevertheless the side effect warnings are still valid.

 

All in all, this approach sounds very much like the nilvadepine strategy, which is also in trials and is also a repurposed drug.

[ceridwen]

I wonder what happened to the patient. I wonder if they stopped the disease

[mag1]

http://newsroom.myla...gretin-Capsules

[ceridwen]

How do we get this?

[ceridwen]

Alzheimer's might be caused by upset circadian rhythms. Polyamines can help shorten these in people who show no sign of the disease yet

[mag1]

Targretin?

[ceridwen]

Yes is it possible?

[mag1]

I don't see why not, this would be considered off-label use.

 

There are a few considerations, though. There is a question of APOE genotype. There has been ongoing discussion whether

increasing APOE in epsilon 4s would be a helpful and safe idea. Might be good to check the above article to see what genotype the patient who responded was.

 

Also,

http://www.ncbi.nlm....pubmed/26085639

 

As well, there would, for me, be a question of dosing. The original research was suggesting lowish human dosing of 50-100 mg per day as being the most effective range.

The above patient was treated at 300 mg / day. 

 

Another patient report with moderately severe AD did not respond to 3 months of treatment at 150 mg per day.

Alzheimer’s Dementia. 2013;9(4):P301

 

A clinical trial for bexarotene should be published soon. Might be good idea to wait and see what is reported.

 

 

The recent genericization of Targretin might add obstacles to further reports of positive responses in AD patients.

Anyone have a quote on the current cost of Targretin? It seems as though it might be quite inexpensive now. 

Edited by mag1, 16 October 2015 - 09:06 PM.

[ceridwen]

I can't wait. Maybe 300mg is too low? Perhaps the patient would have made a better recovery if dosage was even higher?
Anyone think Astrogaloside 1v might be the way forward. Lengthen telomeres and hope for the best?

[mag1]

The original research in mice seemed to suggest that more was not better.

 

It probably is not that surprising that there might be improvements seen in mild and not moderately severe AD with Bexarotene.