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Different forms of amyloid in Alzheimer's disease
Lane Simonian
Posted: Friday, October 21, 2016 10:06 AM
Joined: 12/12/2011
Posts: 4863


One of the problems in Alzheimer's research is that amyloid is considered to be the cause of the disease whereas the cause of the disease is nitro-oxidative stress.

The first cut in the amyloid precursor protein is by beta secretase and beta secretase is stabilized by caspase-3, an enzyme that also contributes to the death of neurons. Caspase-3 is upregulated by the oxidant peroxynitrte.  One of the best ways to inhibit BACE1 (the beta secretase) is with peroxynitrite scavengers.

The first cut in the amyloid precursor protein leads to the c-terminal fragment of the amyloid precursor protein.  This fragment results in further oxidative stress by increasing g protein signalling and its toxicity can be inhibited by peroxynitrite scavengers.

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.

The second cut in the amyloid precursor protein (the gamma secretase cut) depends on the release of intracellular calcium.  This leads to the formation of amyloid monomers which would be neuroprotective except for the fact that the receptor signalling that they work through (receptor tyrosine kinases) is damaged in Alzheimer's disease.

Here we show that synthetic Abeta 1-42 monomers support the survival of developing neurons under conditions of trophic deprivation and protect mature neurons against excitotoxic death, a process that contributes to the overall neurodegeneration associated with AD. The neuroprotective action of Abeta 1-42 monomers was mediated by the activation of the PI-3-K (phosphatidylinositol-3-kinase) pathway, and involved the stimulation of IGF-1 (insulin-like growth factor-1) receptors and/or other receptors of the insulin superfamily. Interestingly, monomers of Abeta 1-42 carrying the Arctic mutation (E22G) associated with familiar AD (Nilsberth et al., 2001) were not neuroprotective. We suggest that pathological aggregation of Abeta 1-42 may also cause neurodegeneration by depriving neurons of the protective activity of Abeta 1-42 monomers. 


Oxidants lead to the intracellular release of copper and zinc which result in the aggregation of monomers into oligomers.  Amyloid oligomers cause oxidative stress via g protein-coupled receptor signalling and their damage can also be limited by peroxynitrite scavengers.

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

The peroxynitrite-mediated nitration of amyloid oligomers leads to the production of plaques.  Plaques do not cause oxidative damage, although they can get lodged into blood vessels, potentially causing problems in blood flow and cognition.

If peroxynitrite is being sufficiently scavenged, it is possible to have amyloid plaques in the brain but not have Alzheimer's disease.  This was the case with the famous nun study where they had a diet high in antioxidants.

http://www.publishersweekly.com/978-0-553-80163-7 

On the other hand, if the release of intracellular calcium is limited (by compounds such as caffeine and heparin, for instance), it is possible to have few amyloid plaques and still have Alzheimer's disease.  Again it is not amyloid per se that causes the disease, it is oxidants that cause the disease (hydrogen peroxide early on and peroxynitrite throughout the disease).

In mice, the different forms of amyloid are the main cause of oxidative stress, so if you remove these forms of amyloid you treat the disease.  But in humans there are many factors that cause oxidative stress, so if you remove different forms of amyloid you often put very little dent into the disease.  The same goes for less than robust antioxidants (some of which can become pro-oxidants in certain circumstances).

The following quote is really the key to understanding Alzheimer's disease and how to treat it.

[Clinical trials with over-the-counter supplements have concentrated either on items which suppress inflammation, or on antioxidants which scavenge oxygen derived free radicals. Most of these have proved worthless in the treatment of Alzheimer's disease. Similarly most of the drugs used to treat Alzheimer's disease do little to slow down the deterioration, but instead offer a mild temporary symptom relief.  However, evidence has been accumulating that the primary drivers of Alzheimer's disease is the nitrogen derived free radical called peroxynitrite, which may mediate both amyloid and tau accumulation as well as their toxicity.  Excellent results have been obtained with peroxynitrite scavengers, with reversals of Alzheimer's disease in human clinical trials being repeatedly demonstrated.  IMHO, the only thing preventing the abolition of Alzheimer's disease is the mental inertia of scientists, as well as the bureaucrats who fund them.  Unfortunately, most bureaucrats keep throwing money into repeatedly testing discredited interventions, while ignoring successful ones. Common sense is anything but...]


Lane Simonian
Posted: Monday, October 24, 2016 3:32 PM
Joined: 12/12/2011
Posts: 4863


Added to this are genes which increase amyloid and oxidative stress in Alzheimer's disease.  The presenilin gene 1 mutation cuts off the neuroprotective phosphatidylinositol 3-kinase.  Presenlin gene 2 mutations increase intracellular calcium release.  Amyloid precursor protein mutations and the ApoE4 gene increase g protein signalling.  

Wild-Type But Not FAD Mutant Presenilin-1 Prevents Neuronal Degeneration by Promoting Phosphatidylinositol 3-Kinase Neuroprotective Signaling

Presenilin-2 mutations modulate amplitude and kinetics of inositol 1, 4,5-trisphosphate-mediated calcium signals.

Neuronal Apoptosis by Apolipoprotein E4 through Low-Density Lipoprotein Receptor-Related Protein and Heterotrimeric GTPases [ApoE4 is not a mutation].

Stimulation of G-proteins in human control and Alzheimer's disease brain by FAD mutants of APP(714-723): implication of oxidative mechanisms.

Mutations in amyloid precursor protein and presenilin-1 genes increase the basal oxidative stress in murine neuronal cells and lead to increased sensitivity to oxidative stress mediated by amyloid beta-peptide (1-42), HO and kainic acid: implications for Alzheimer's disease.

 

Now amyloid beta is likely to be a greater percentage of the source of oxidative stress in mutations that lead to early onset of Alzheimer's disease than amyloid beta in late onset Alzheimer's disease, but in any case scavenging oxidants is likely to be the most effective treatment of Alzheimer's disease whether early or late onset.  


Lane Simonian
Posted: Tuesday, December 20, 2016 11:23 PM
Joined: 12/12/2011
Posts: 4863


 

There are also differences in where amyloid plaques end up in the brain.  Most of the amyloid precursor protein mutations lead to more amyloid in blood vessels rather than in neurons

How these findings relate to AD is unclear. The Dutch and Iowa mutations are known to cause primarily cerebral amyloid angiopathy, or CAA (see ARF related news story), and as Kumar-Singh and colleagues point out, their mouse data is more reminiscent of Flemish familial AD, characterized by many large, dense-core plaques and CAA, than it is of sporadic AD or Down syndrome, in which plaques are more diffuse and CAA minimal.

Nonetheless, these results would seem to cement the relationship between vessel walls and Abeta deposits. And as Kumar-Singh and colleagues write, “the present study, for the first time, demonstrates that dense amyloid plaques in Tg2576 and PSAPP mice are centered on vessel walls. If a similar mechanism is also operative in AD, therapeutics targeting Abeta clearance from the vascular compartment may be most beneficial.”

 

http://www.alzforum.org/news/research-news/amyloid-v-or-wall

 

The genetic argument for amyloid being a cause of Alzheimer's disease may be flawed: amyloid that accumulates in blood vessels may contribute to cognitive decline in some cases of early onsest Alzheimer's disease but the amyloid that accumulates in neurons may not contribute to cognitive decline in late onset Alzheimer's disease.  Indeed, the amyloid plaques that accumulate in neurons may help limit the plaques that form in blood vessels.

In the case of presenilin 1 gene mutations, the mutations lead to amyloid plaques in neurons but they also cut off a pathway that is neuroprotective (the phosphatidylinositol 3-kinase/Akt pathway).  A Japanese family with the same presenilin 1 gene mutation developed Alzheimer's disease on average eight years later than family members with the same gene in Colombia--at 57 years old rather than 49 years old (the Spanish brought the gene to both countries).  It just happens that the Colombian extended family lives in one of the areas most contaminated by mercury in the world. Maybe if you remove other oxidative stresses and employee antioxidants, a person with a presenilin gene 1 mutation might not develop Alzheimer's disease into their 60s.  

The genetic "evidence" has thrown many researchers off track.  They thought if they could remove oligomers and plaques from neurons or prevent their development in the they could cure Alzheimer's disease and prevent it from developing in the first place whereas the best they could do was to delay its onset and slightly slow down its progression.  But the right combination of antioxidants can be used to partially reverse Alzheimer's disease and potentially prevent its onset.


Lane Simonian
Posted: Saturday, December 24, 2016 12:49 AM
Joined: 12/12/2011
Posts: 4863


The amyloid plaques that develop in blood vessels may contribute to nitro-oxidative stress in some genetic forms of Alzheimer's disease by oxygen and glucose deprivation.

...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 (gp91ds-tat), NOS inhibition (L-NNA) and by the peroxynitrite decomposition catalyst FeTPPS or PARP inhibition (PJ34; Fig. 4c–e). Thus, Abeta leads to endothelial DNA damage and PARP activation via oxidative–nitrosative stress.

Removing this form of amyloid may help people with these particular mutations.

In the case of presenilin gene mutations and late onset Alzheimer's disease, amyloid oligomers contribute to oxidative stress early in the disease process.   Removing them may help slow the progression of the disease early on.

But it does not matter whether it is early onset Alzheimer's disease or late Alzheimer's disease, if you scavenge peroxynitrite and reverse part of the damage that it does to the brain you effectively treat the disease. 


Serenoa
Posted: Sunday, December 25, 2016 6:42 AM
Joined: 4/24/2012
Posts: 484


I admire your determination Lane. I wish I had the depth of knowledge to contribute more to furthering your conclusions. The complexity of this disease does seem overwhelming at times.

But, here's a question for you (which I have probably asked before), why not try to prevent the formation of peroxynitrite before it forms? Would this be possible? 


Lane Simonian
Posted: Sunday, December 25, 2016 10:11 AM
Joined: 12/12/2011
Posts: 4863


 

This is a critical question and it is certainly possible.  Polyphenolic compounds both scavenge and inhibit the formation of peroxynitrite.  This is why a Mediterranean diet high in polyphenols can both delay or prevent the onset of Alzheimer's disease and treat the disease.  

https://www.ncbi.nlm.nih.gov/pubmed/16622828

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673956/

https://www.ncbi.nlm.nih.gov/pubmed/12676458

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980563/

https://www.ncbi.nlm.nih.gov/pubmed/17074427

http://onlinelibrary.wiley.com/doi/10.1196/annals.1329.054/full

http://aje.oxfordjournals.org/content/164/9/898.short

 

Phospholipase C inhibitors and Protein kinase C alpha inhibitors would also inhibit the formation of peroxynitrite, but these would be difficult targets since too much inhibition would also have a negative effect on memory and learning (by overinhibiting NMDA receptors).



Serenoa
Posted: Sunday, December 25, 2016 3:27 PM
Joined: 4/24/2012
Posts: 484


I've been reading your post and learning things Lane. Here is a clue you mention above, and that I have read somewhere before. You said:

"The peroxynitrite-mediated nitration of amyloid oligomers leads to the production of plaques.  Plaques do not cause oxidative damage, although they can get lodged into blood vessels, potentially causing problems in blood flow and cognition."

 

Now here is a quote from Wikipedia:

"When blood flow is suppressed, glutamate is released from presynaptic neurons causing NMDA and AMPA receptor activation more so than would normally be the case outside of stress conditions, leading to elevated Ca2+ and Na+ entering the post synaptic neuron and cell damage....Glutamate receptors are one of four categories, three of which are ligand-gated ion channels and one of which is a G-protein coupled receptor."

Here is why this clue may be very important. The Alz medication Namenda inhibits the NMDA receptor thereby limiting exitotoxicity. We know that Namenda improves symtoms of Alz, therefore the overactivation of the NMDA receptor (excitotoxicity) is real and not just a hypothesis tested on mice. So, we can surmize that lack of blood flow is a primary factor in the disease. My mother has been diagnosed with "microvascular eschemia" which is basically a lack of blood flow in micro vessels of the brain (the blood-brain barrier). She has also always had low blood pressure.


Lane Simonian
Posted: Sunday, December 25, 2016 8:58 PM
Joined: 12/12/2011
Posts: 4863


I think this is a very important clue indeed.  I had not previously considered the link between reduced blood flow and overactivation of NMDA receptors.

I am looking for several connections now and will post as I find them.

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

It is possible that continuous accumulation of oxidative stress products, such as peroxynitrite accumulation (via the overexpression of the iNOS and/or nNOS), appear to be secondary and accelerating factors for damage and for compromising the blood brain barrier (BBB) in hypoxia/hypoperfusion or AD.

peroxynitrite formation in cerebral blood vessels is needed for the cerebrovascular effects of Abeta (one from above).

Our experiments reveal that total cerebral blood flow was 20% lower in the AD group than in the NDC [non-demented control] group, and that these values were directly correlated with pulse pressure and cognitive measures. The AD group had a significantly lower pulse pressure (mean AD 48, mean NDC 71; P = 0.0004).



Lane Simonian
Posted: Sunday, December 25, 2016 9:16 PM
Joined: 12/12/2011
Posts: 4863


I have been looking for an actual cycle in Alzheimer's disease and this might be close to it: oxidative stress restricts blood flow in the brain and restricted blood flow in the brain increases oxidative stress.  Thanks, Serenoa.
Lane Simonian
Posted: Monday, December 26, 2016 10:02 AM
Joined: 12/12/2011
Posts: 4863


Another part of this cycle is the depletion of ATP.  Overactivation of NMDA receptors leads to ATP depletion and ATP depletion inhibits the transport and thus removal of extracellular glutamate which causes the continuous activation of NMDA receptors.  ATP depletion deprives cells of energy which leads to the death of neurons.



Serenoa
Posted: Monday, December 26, 2016 1:55 PM
Joined: 4/24/2012
Posts: 484


This is good stuff. Thanks Lane. I will keep reading...
Serenoa
Posted: Tuesday, December 27, 2016 5:07 AM
Joined: 4/24/2012
Posts: 484


I found this link to your previous post in Alz Connected Lane: "Glutamate and Alzheimer's Disease"

https://www.alzconnected.org/WorkArea/threadeddisc/print_thread.aspx?id=77&g=posts&t=2147524617

And here's another possibly relevant article:

Capillary cerebral amyloid angiopathy identifies a distinct APOE e4-associated subtype of sporadic Alzheimer’s disease

http://link.springer.com/article/10.1007/s00401-010-0707-9


Lane Simonian
Posted: Tuesday, December 27, 2016 9:48 AM
Joined: 12/12/2011
Posts: 4863


Thank you for finding the old thread and for the new article.

I found this very interesting article that also ties ApoE4 to cerebral amyloid angiopathy. It also includes a number of other observations that may help provide further insights.

Cerebral amyloid angiopathy: pathogenetic mechanisms and link to dense amyloid plaques

http://onlinelibrary.wiley.com/doi/10.1111/j.1601-183X.2007.00380.x/pdf 


Lane Simonian
Posted: Tuesday, December 27, 2016 10:09 AM
Joined: 12/12/2011
Posts: 4863


A fascinating finding from the above article.  

...most of the antibodies used in mice and human vaccination trials target Ab N-terminus and thus would not remove N-terminally truncated Ab species. Moreover, such intervention would also remove Ab40, and recent data suggest that Ab40 could be protective. This is because (1) Ab40 inhibits Ab42 fibril formation in vitro (Snyder et al. 1994). (2) Ab40 might also inhibit Ab42 plaque deposition in vivo in mice.

 

Amyloid beta 40 may inhibit the formation of dense amyloid plaques in blood vessels in the brain and thus may be neuroprotective.  Dense amyloid plaques in neurons only appear to develop late in Alzheimer's disease and their role if any in the progression of the disease is unclear.  


Lane Simonian
Posted: Tuesday, December 27, 2016 11:29 AM
Joined: 12/12/2011
Posts: 4863


At least one more for now:

Human Apolipoprotein E4 Alters the Amyloid-Beta 40:42 Ratio and Promotes the Formation of Cerebral Amyloid Angiopathy in an Amyloid Precursor Protein Transgenic Model

These findings demonstrate that, once Abeta fibrillogenesis occurs, apoE4 favors the formation of CAA over parenchymal plaques and suggest that molecules or treatments that increase the ratio of Abeta 40:42 may favor the formation of CAA versus parenchymal plaques.


The more amyloid beta 40 produced the more plaque that ends up in blood vessels; the more amyloid beta 42 produced the more plaque that end up in neurons.  The fact that people with the ApoE4 gene have more amyloid beta 40 and thus more dense core plaques in blood vessels may help explain why they progress more rapidly during the early stages of Alzheimer's disease and why amyloid plaque antibodies directed at amyloid 42 often lead to microbleeds and brain swelling (as the antibodies allow more amyloid to end up in blood vessels).  The dense core amyloid plaques in blood vessels lead to oxidative stress early in Alzheimer's disease whereas the late development of dense core plaques in neurons appears to contribute little if anything to Alzheimer's disease.


Serenoa
Posted: Thursday, December 29, 2016 5:40 AM
Joined: 4/24/2012
Posts: 484


Brilliant Lane. Your clue pointing to cereberal amyloid angiopathy has been eye-openning. So many connections here. It reminds me of the research Dr. Potter (Leukine) was doing. Several years ago (when we were trying Leukine) his assistant showed me a presentation on how the plaques and the die off of neurons was centered around the small blood vessels in the brain. I wasn't convenced at the time. But these posts are changing my thinking.

I like the connections to ApoE4, LRP-1, the ratio of Ab40/Ab42, dysfunction with transport of Ab accross BBB, etc. Lots here to try and wrap my brain around.


Lane Simonian
Posted: Friday, December 30, 2016 11:14 AM
Joined: 12/12/2011
Posts: 4863


Thank you, Serenoa.  I have not paid enough attention to the role of plaques in or around blood vessels over the years, so going back over it has been an eye opener for me, too.

Various forms of amyloid (c-terminal fragments of the amyloid precursor protein, amyloid monomers, amyloid oligomers, and amyloid plaques especially in or around blood vessels) contribute to oxidative stress, but there are many other factors that contribute to that stress as well.  Among a family in Colombia, a presenilin gene mutation leads to the onset of Alzheimer's disease at an average age of 49, but in Japan the same exact gene mutation leads to the onset of Alzheimer's disease at the age of 57. One of the main differences is that particular region of Colombia has some of the highest levels of mercury exposure in the world.

Most mouse models incorporate only one cause of oxidative stress: genes that increase the production of amyloid.  But when other causes of oxidative stress are incorporated the onset of the disease is accelerated.

Smoking exacerbates amyloid pathology in a mouse model of Alzheimer’s disease

We exposed transgenic mouse models of Alzheimer’s disease to cigarette smoke and analysed the neuropathological alterations in comparison with animals not subjected to smoke inhalation. Our results showed that smoking increases the severity of some abnormalities typical of Alzheimer’s disease, including amyloidogenesis, neuroinflammation and tau phosphorylation. Our findings suggest that cigarette smoking may increase Alzheimer’s disease onset and exacerbate its features and thus, may constitute an important environmental risk factor for Alzheimer’s disease.

The flip side to amyloid and other factors leading to oxidative stress is that if you remove one or more of these factors, you likely delay and somewhat slow down the progression of the disease early on.  But later on one has to not only reduce oxidative stress but reverse the damage that has already been done.  This is where peroxynitrite scavengers come in.

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 (gp91ds-tat), 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-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).



Serenoa
Posted: Saturday, December 31, 2016 5:41 AM
Joined: 4/24/2012
Posts: 484


And here is more evidence for dysfunction in nitric oxide and blood flow.

Towards use of MRI-guided ultrasound for treating cerebral vasospasm

"Among the proposed mechanisms is alteration of several nitric oxide (NO) pathways, where NO is a known vasodilator. While in vivo studies do not point to a specific physical mechanism, results of in vitro studies favor cavitation induction by ultrasound, where the associated shear stresses likely induce NO production."

https://www.ncbi.nlm.nih.gov/pubmed/26929821

 


Serenoa
Posted: Saturday, December 31, 2016 9:29 AM
Joined: 4/24/2012
Posts: 484


There's a lot of research out there on blood flow and Alz. This one says they targeted Ab40 to clear plaques. This avenue was suggested in a previously posted article.

 Passive immunotherapy targeting amyloid-beta reduces cerebral amyloid angiopathy and improves vascular reactivity

http://brain.oxfordjournals.org/content/139/2/563.abstract


Serenoa
Posted: Saturday, December 31, 2016 9:37 AM
Joined: 4/24/2012
Posts: 484


Just found that the above study was on Ponezumab which failed to improve clinical endpoints in phase II trials. But now Pfizer is testing again:

"Development of ponezumab for Alzheimer's disease was discontinued. Pfizer is, however, conducting a Phase 2 study of ponezumab in patients with cerebral amyloid angiopathy (CAA)."


Lane Simonian
Posted: Saturday, December 31, 2016 10:34 AM
Joined: 12/12/2011
Posts: 4863


I am interested to learn about this drug.  I will be curious and anxious to see if there is success when Ponezumab is used by people who have cerebral amyloid angiopathy.  It may be that the treatment has to start early to limit the damage done by oxidation, nitration, and nitric oxide depletion in cerebral amyloid angiopathy.

https://www.ncbi.nlm.nih.gov/pubmed/21294650


Lane Simonian
Posted: Saturday, December 31, 2016 11:04 AM
Joined: 12/12/2011
Posts: 4863


In general, this is likely the right approach to all forms of Alzheimer's disease:

 2015;863:79-94. doi: 10.1007/978-3-319-18365-7_4.

Natural Phenolic Compounds as Therapeutic and Preventive Agents for Cerebral Amyloidosis.

Abstract

Epidemiological studies have suggested that diets rich in phenolic compounds may have preventive effects on the development of dementia or Alzheimer's disease (AD). We investigated the effects of natural phenolic compounds, such as myricetin (Myr), rosmarinic acid (RA), ferulic acid (FA), curcumin (Cur) and nordihydroguaiaretic acid (NDGA) on the aggregation of amyloid beta-protein (Abeta), using in vitro and in vivo models of cerebral Abeta amyloidosis. The in vitro studies revealed that these phenolic compounds efficiently inhibit oligomerization as well as fibril formation of Abeta through differential binding, whilst reducing Abeta oligomer-induced synaptic and neuronal toxicity. Furthermore, a transgenic mouse model fed orally with such phenolic compounds showed significant reduction of soluble Abeta oligomers as well as of insoluble Abeta deposition in the brain. These data, together with an updated review of the literature, indicate that natural phenolic compounds have anti-amyloidogenic effects on Abeta in addition to well-known anti-oxidative and anti-inflammatory effects, hence suggesting their potential as therapeutic and/or preventive agents for cerebral Abeta amyloidosis, including AD and cerebral amyloid angiopathy (CAA). Well-designed clinical trials or preventive interventions with natural phenolic compounds are necessary to establish their efficacy as disease-modifying agents.


Lane Simonian
Posted: Saturday, December 31, 2016 9:46 PM
Joined: 12/12/2011
Posts: 4863


I have a feeling that there are some huge hints in this dog study, although perhaps one cannot extrapolate to far.  One hint is that diffuse plaques are a sign of a brain under some oxidative stress but not so much that it causes major problems in cognition.

Research Brief: Combination Therapy Does the Trick for Old Dogs

Maybe you can teach old dogs new tricks—and reduce their amyloid-beta burden. In the July 21 Journal of Neuroscience, researchers led by Carl Cotman at the University of Irvine, California, report a synergistic effect of environmental enrichment and antioxidants on reducing amyloid-beta load in the brains of aged beagles. “The findings are not at all what we expected when we started this study,” Cotman told ARF. The finding hints that in humans, too, combination therapy might work better than monotherapies, which, in the case of antioxidants like vitamins C and E, have proved unable to stave off impending dementia [although the Vitamin E findings have come under some question].

The antioxidant supplement included vitamins E and C, L-carnitine, and alpha-lipoic acid. The environmental enrichment included social (shared caging), physical (two 20-minute outdoor walks per week), environmental (availability of toys), and cognitive (20-30-minute testing per day) stimulation. The eight- to 12-year-old animals, eight per group, were treated for 2.69 years.

At the end of the trial, animals treated with antioxidants had reduced plaque burden in their brain. This was further reduced in the animals that received both interventions. In animals that received the antioxidant, Abeta plaques were predominantly diffuse, rather than the dense-core plaques associated with more advanced pathology. “It could be that the treatments are slowing plaque evolution and in that way helping maintain neuronal health,” suggested Berchtold.

A potentially critical finding is that while this combination therapy helped reduce different forms of amyloid and improve cognition in the dogs, the two were independent from each other.

While the reduction in brain amyloid may be welcome news, it did not herald any change in cognition. The researchers previously found that dogs on the combination therapy improved performance in a range of cognitive measures, including spatial memory, discrimination errors, and discrimination reversal errors. None of these measures correlated with any Abeta measure, including plaque load, soluble Abeta levels, number of oligomers, or alpha-secretase activity. “These dogs are like humans and show great variability in cognitive performance when they age, but when you look at things that correlate to that, amyloid is not a dependent variable,” said Cotman. A previous Abeta immunization study in dogs, supports this idea, since the immunotherapy lowered brain Abeta load but had little effect on cognition.

One of the possible reasons for this is that most forms of amyloid do their initial damage via g protein signalling and subsequent protein kinase C activation, but in most cases this pathway is inhibited past the early stages of Alzheimer's disease.

"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."

Cerebral microvessels in Alzheimer's have reduced protein kinase C activity

Attenuated protein kinase C activity and translocation in Alzheimer's disease brain.

The main damage done to the brain after the initiation of Alzheimer's disease is via NMDA receptor activation (first by protein kinase C and then by inhibition of glutamate transport), peroxynitrite formation (ONOO-), and caspase 3 activation and this damage can be inhibited and reversed in part via selected antioxidants.

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


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.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4470891/



Lane Simonian
Posted: Monday, January 2, 2017 9:16 PM
Joined: 12/12/2011
Posts: 4863


An important study to start the new year.

Cerebrovascular disease linked to Alzheimer's

Study finds association between diseases in brain blood vessels and dementia

Date: July 1, 2016 Source: Rush University Medical Center Summary: While strokes are known to increase risk for dementia, much less is known about diseases of large and small blood vessels in the brain, separate from stroke, and how they relate to dementia. Diseased blood vessels in the brain itself, which commonly is found in elderly people, may contribute more significantly to Alzheimer's disease dementia than was previously believed, according to new study.

https://www.sciencedaily.com/releases/2016/07/160701183319.htm


Lane Simonian
Posted: Tuesday, January 3, 2017 3:46 PM
Joined: 12/12/2011
Posts: 4863


Another good study for the new year:

Reactive species play an important role in physiological functions. Overproduction of reactive species, notably reactive oxygen (ROS) and nitrogen (RNS) species along with the failure of balance by the body’s antioxidant enzyme systems results in destruction of cellular structures, lipids, proteins, and genetic materials such as DNA and RNA. Moreover, the effects of reactive species on mitochondria and their metabolic processes eventually cause a rise in ROS/RNS levels, leading to oxidation of mitochondrial proteins, lipids, and DNA. Oxidative stress has been considered to be linked to the etiology of many diseases, including neurodegenerative diseases (NDDs) such as Alzheimer diseases, Amyotrophic lateral sclerosis, Friedreich’s ataxia, Huntington’s disease, Multiple sclerosis, and Parkinson’s diseases. In addition, oxidative stress causing protein misfold may turn to other NDDs include Creutzfeldt-Jakob disease, Bovine Spongiform Encephalopathy, Kuru, Gerstmann-Straussler-Scheinker syndrome, and Fatal Familial Insomnia. An overview of the oxidative stress and mitochondrial dysfunction-linked NDDs has been summarized in this review.


Serenoa
Posted: Wednesday, January 4, 2017 5:30 AM
Joined: 4/24/2012
Posts: 484


Looking back over these posts, I was focusing on the PS-1 mutation and found this, "Heterozygosity for the PS-1 knock in mutation [mouse model] decreased production of Abeta40 and Abeta42, increased the Abeta42/Abeta40 ratio, and exacerbated Abeta deposition."

Presenilin-1 Knockin Mice Reveal Loss-of-Function Mechanism for Familial Alzheimer’s Disease

This supports what we posted previously about the Ab42/Ab40 ratio being critical.
Serenoa
Posted: Wednesday, January 4, 2017 6:28 AM
Joined: 4/24/2012
Posts: 484


Lodged in Late Endosomes, Presenilin 2 Churns Out Intraneuronal Abeta

According to a study published in Cell on June 9, presenilin 2 contains a sorting sequence that directs it to endolysosomal vesicles, where it produces intracellular Abeta peptides that are enriched for Abeta42. According to this new study, PS2’s highly specific localization stands in stark contrast to that of PS1.

http://www.alzforum.org/news/research-news/lodged-late-endosomes-presenilin-2-churns-out-intraneuronal-av


Lane Simonian
Posted: Wednesday, January 4, 2017 11:19 AM
Joined: 12/12/2011
Posts: 4863


These are good finds, Serenoa.  I think part of it may be that different genes and gene mutations differential affect gamma secretase activity.  Intracellular calcium release increases both gamma secretase activity and protein kinase C activity, increasing the secretion of the amyloid precursor protein and the ratio of amyloid beta 42 relative to amyloid beta 40.  Conversely inhibiting gamma secretase leads to a decrease in amyloid precursor protein secretion, a decrease in amyloid beta 42, and an even greater decrease in amyloid beta 40.

Presenilin 1 gene mutations lead to a loss of function (although not a complete loss of function) in the gamma secretase activity whereas presenilin 2 gene mutations lead to an increase in gamma secretase activity.

The Presenilin-1 DeltaE9 mutation results in reduced gamma-secretase activity, but not total loss of PS1 function, in isogenic human stem cells

Presenilin-2 mutations modulate amplitude and kinetics of inositol 1, 4,5-trisphosphate-mediated calcium signals. 

Both ApoE4 and various genetic mutations linked to Alzheimer's disease also decrease gamma secretase activity and increase the Abeta 42/Abeta 40 ratio.

Apolipoprotein E modulates gamma-secretase cleavage of the amyloid precursor protein.

These data suggest that apoE reduces gamma-secretase cleavage of APP, lowering secreted Abeta levels, with stronger effects on Abeta40. 

Alzheimer’s disease-associated mutations increase amyloid precursor protein resistance to gamma-secretase cleavage and the Abeta42/Abeta40 ratio

But even when the ratio of Abeta 40 is lowered compared to Abeta 42 more Abeta 40 often still ends up in blood vessels worsening cognitive decline.

Inhibition of gamma-secretase worsens memory deficits in a genetically congruous mouse model of Danish dementia



Lane Simonian
Posted: Wednesday, January 4, 2017 4:20 PM
Joined: 12/12/2011
Posts: 4863


I am running into seemingly contradictory findings regarding Abeta 42:Abeta 40 ratios in various forms of Alzheimer's disease, but it appears that in genes or gene mutations that inhibit gamma secretase activity more amyloid ends up in or around blood vessels than in or around neurons.  Perhaps this explains why in some people the use of gamma secretase inhibitors actually made their condition worse and why antibodies removing abeta 42 led to microbleeds and brain swelling.
Lane Simonian
Posted: Friday, January 6, 2017 5:28 PM
Joined: 12/12/2011
Posts: 4863


Peroxynitrite has somewhat opposing effects on the supposed hallmarks of Alzheimer's disease: hyperphosphorylated tau (tau tangles) and amyloid plaques.  Peroxynitrite can contribute to the hyperphosphorylation of tau, but it may also inhibit it through nitration.

The same is also true for plaques.

Peroxinitrite in the brain promotes the development of alzheimer's

Oligomers and beta-amyloid fibers induce nitro oxidative stress, triggering the production of nitric oxide and free radicals in the extracellular environment. When they combine, peroxynitrite is produced, a highly reactive molecule that can modify proteins and alter their function. The study led by Francisco José Muñoz reveals that when peroxynitrite reacts with beta-amyloid oligomers, it facilitates its stabilization and prevents the formation of mature fibers [plaques]. Thus, the more beta-amyloid protein there is, the more peroxynitrite formation is promoted and the latter, in turn, makes the beta-amyloid oligomers to remain stabilized, perpetuating the characteristic neuronal damage of Alzheimer's disease.

On the other hand, as Alzheimer's disease progresses the g protein-coupled receptor via which oligomers contribute to the disease is damaged.

In addition, peroxynitrite can potentially contribute to dense core plaques by inhibiting de-phosphorylation.  In contrast, diffuse plaques may be a sign that peroxynitrite-mediated damage is limited by antioxidants.  This may account for why some people have considerable amounts of diffuse plaques in their brain but do not have Alzheimer's disease. 

The most important correlation in the disease is between peroxynitrite-mediated damage and memory loss.

 1999 Jul 2;269(1):52-4.

Alterations of 3-nitrotyrosine concentration in the cerebrospinal fluid during aging and in patients with Alzheimer's disease.

Abstract

To investigate the significance of nitric oxide (NO)-mediated neuron death in aging and Alzheimer's disease (AD), the 3-nitrotyrosine concentration in the cerebrospinal fluid (CSF) was investigated in neurologically normal controls and patients with AD. The 3-nitrotyrosine concentration and the 3-nitrotyrosine/tyrosine ratio significantly increased with advancing age, whereas the tyrosine concentration was unaltered. In patients with AD, the 3-nitrotyrosine concentration and the 3-nitrotyrosine/tyrosine ratio increased significantly (>six-fold) compared with controls of similar age, and increased significantly with decreasing cognitive functions, whereas the tyrosine concentration did not change. These findings suggest that an activation of tyrosine nitration, increase in nitrated tyrosine-containing proteins, and/or its degradation may be involved in brain aging and play an important role in the pathogenesis of AD.


Serenoa
Posted: Monday, January 9, 2017 8:46 AM
Joined: 4/24/2012
Posts: 484


Found something right up your alley Lane. Oxidation of the Ca2+ sensor calmodulin by ROS like H2O2 through the oxidation of methionine residues stops calmodulin from activating adenlyly cyclase, which is known to be low in AD brain. This could be another way peroxynitrite is acting as a root cause. Adenlyly cyclase has many connections including to cAMP and has been very interesting to me of late.

Membranous adenylyl cyclase 1 activation is regulated by oxidation of N- and C-terminal methionine residues in calmodulin

http://www.sciencedirect.com/science/article/pii/S0006295214006881


Lane Simonian
Posted: Monday, January 9, 2017 10:27 AM
Joined: 12/12/2011
Posts: 4863


This is another good find, Serenoa.  Peroxynitrite along with hydrogen peroxide does seem to be involved in the decrease of adenylyl cyclase activity.

Peroxynitrite inhibits the expression of G(i)alpha protein and adenylyl cyclase signaling in vascular smooth muscle cells.

These results suggest that ONOO(-) decreased the expression of G(i) proteins and associated functions in VSMC [vascular smooth muscle cells] through a cGMP-independent mechanism and may involve the MAP kinase signaling pathway.

Although somewhat oddly to me, this does not seem to affect protein kinase A activity. Nor does it seem to affect cyclic-AMP/protein kinase A regulation of NMDA receptors.

Impaired G-protein-stimulated adenylyl cyclase activity in Alzheimer's disease brain is not accompanied by reduced cyclic-AMP-dependent protein kinase A activity.

 

This study may be critical:

Signal Transduction Mechanisms in Alzheimer's Disease (199

Recent years have seen the publication of many studies describing the integrity of various compounds of the "classical" G-protein-mediated phosphatidylinositol hydrolysis and adenylyl cyclase signal transduction pathways in Alzheimer's disease postmortem brains.  Such disturbances have been proposed to both limit the successful outcomes of neurotransmitter replacement strategies in Alzheimer's disease and to contribute to disease pathogenesis by altering calcium homeostasis, processing of the Beta-amyloid precursor protein, and the state of tau phosphorylation.


Serenoa
Posted: Monday, January 9, 2017 3:57 PM
Joined: 4/24/2012
Posts: 484


An external file that holds a picture, illustration, etc.
Object name is BMB-47-369-g0001.jpg
Serenoa
Posted: Monday, January 9, 2017 4:00 PM
Joined: 4/24/2012
Posts: 484


The above figure is from:

Neuroprotective roles of pituitary adenylate cyclase-activating polypeptide in neurodegenerative diseases

"In most studies, the neurotrophic and neuroprotective actions of PACAP occur through the activation of the cAMP-protein kinase A (PKA) pathway. Additionally, PACAP can influence the mitogen activated protein kinase (MAPK) pathway. A direct protective effect of PACAP on neurons is often accompanied by the inhibition of caspase-3, a key apoptotic enzyme. Induction of transcriptional target gene expression, such as BDNF, mediates the neuroprotective action of PACAP in rat cortical neurons. In some cases, PACAP inhibits the expression of proapoptotic factors, such as Bcl-2-associated X protein (Bax), and activates the phosphatidylinositol 3'-OH kinase (PI3K) pathway(Fig. 1)."

 

 


Serenoa
Posted: Monday, January 9, 2017 5:54 PM
Joined: 4/24/2012
Posts: 484


Another clue. From Wikipedia:

"Glucagon like protein 1 receptor (GLP1R) is known to be expressed in pancreatic beta cells. Activated GLP1R stimulates the adenylyl cyclase pathway which results in increased insulin synthesis and release of insulin.[12] Consequently, GLP1R has been a target for developing drugs usually referred to as GLP1R agonists to treat diabetes.[13]

GLP1R is also expressed in the brain where it is involved in the control of appetite.[14] Furthermore, mice which over express GLP1R display improved memory and learning.[15]