Research on Amyloid Clotting Pathways

Research on Amyloid Clotting Pathways

natural tools for amyloid clotting

 

So…are there tools and pathways we can look at to reduce risk and affect clotting especially around the amyloid type that DON'T build tolerance?


Of course, work with your doctor or naturopath…this is not medical advice. Some of these players essentially thin blood so other meds (like blood thinners) must be taken into account.


We'll focus on three interconnected lines with amyloid clot pathways being primary:

  • Natural tools that affect clots, specifically amyloid formation
  • Natural tools for brain and systemic inflammation
  • Key pathways for removal of toxins, damage, and more

A great deal of the research will come from amyloid formations in dementia, prions, etc since that's where the research is more fleshed out.


Let's get started with these topics:

  • A quick intro to the amyloid clotting pathway in play
  • Tip 1 - Glutathione and NAC
  • Tip 2 - Nattokinase
  • Tip 3 - Myricetin
  • Tip 4 - CBD Isolate
  • Tip 5 - Omega 3's
  • Tip 6 - Cold Exposure
  • Tip 7 - Medicinal mushrooms
  • Tip 8 - Melatonin
  • Tip 9 - steroidal hormones
  • Tip 10 - Sleep - the waste removal machine
  • A final note on aspirin, turmeric, and cinnamon

Let's get started! First, know thy enemy! 

A quick intro to the amyloid clotting pathway in play 

The goal is to protect from dysfunctional clotting and help the body remove foreign entities. An endeavor not that different from dementia (see big review on dementia).


We're going to focus on amyloid fibril clotting. Amyloid beta is the primary accumulating substance with dementia.


Essentially, amyloid is a result of our immune system's arsenal against bacteria. It will stab bacteria with a long lance called a fibril.

However, in new work, Kumar et al. show that Aβ is a natural antibiotic that protects the brain from infection. Most surprisingly, Aβ aggregates trap and imprison bacterial pathogens.

https://www.science.org/doi/abs/10.1126/scitranslmed.aaf1059


The problem is that it can clump together and form long tendrils…like a balled-up fishing wire.

Amyloid fibrils are formed by normally soluble proteins, which assemble to form insoluble fibers that are resistant to degradation.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2634529/


Another big player is fibrinogen which starts the blot clot cascade of responses.


In fact, the interaction of fibrinogen and amyloid may be critical:

Aβ interacts with fibrinogen and FXII. These interactions can lead to increased clotting, abnormal clot formation, persistent fibrin deposition, and generation of pro-inflammatory molecules.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540762/


Abnormal clot formation indeed.


So…are there tools that can help us address amyloid accumulation and the associated clotting?


Let's get to it!   We'll start with clearance mechanisms first. Our money is on nattokinase, glutathione, myricetin, and CBD isolate but the research will tell the tale below.

Tip 1 - Glutathione and NAC

Our primary detox system in the body is called glutathione. It's known as our default anti-oxidant (C and E figure into its recycling), but it's also the primary way to address toxins, chemicals (alcohol eats it up in the liver), and even….amyloid formation!


We'll piggyback Alzheimer's research:

Lower glutathione levels were associated with greater brain amyloidosis in the temporal (P = .03) and parietal (P = .05) regions, adjusted for apolipoprotein E ε4 carrier status.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471116/


More importantly to our discussion…boosting its level can directly affect this clotting pathway:

Supplementation with γ-GC can reduce amyloid pathology and improve learning and memory deficits in an AD mouse model.

https://www.sciencedirect.com/science/article/abs/pii/S0197018620303223?via%3Dihub


Turns out that glutathione function directly manages fibrinogen activity:

Relative to normal fibrinogen, the addition of GSH, GSSG, or GSNO leads to prolonged lag times, slower rates of protofibril lateral aggregation and the formation of clots with lower final turbidities

https://pubmed.ncbi.nlm.nih.gov/18570468/


So…more glutathione, less clot-forming initiation by fibrinogen.


Go figure.


You can take glutathione directly and we use this one (after bouts of infection, etc.).


More on oxidative stress or glutathione.


Another way to support glutathione is NAC.


NAC has gained recent fame for countering the effects of infection and more. We've loved NAC for quite some time due to its effect on oxidative stress and mental health.


NAC directly supports glutathione as it supplies a rate-limiting player (cysteine) in its creation.


NAC also acts as a sink for excess glutamate which just gushes out when the immune system is hyperactive and can be toxic to neurons and tissue.

 

immune response and glutamate


As for the amyloid building process:

NAC blocks Cystatin C amyloid complex aggregation in a cell system and in skin of HCCAA patients

https://www.nature.com/articles/s41467-021-22120-4


That's a heart issue where amyloid accumulates due to a genetic issue and eventually causes heart attacks.


Interestingly, NAC supports glutathione which "breaks oligomers into monomers."


Literally, deconstructing the buildup at the chemical chain level.


And as for fibrinogen and the clotting cascade when excessive:

(NAC) partly prevented the deposition of fibrin in the lungs and the disappearance of fibrinogen from the blood

https://pubmed.ncbi.nlm.nih.gov/3716022/


Read more on NAC. We use this one.


Next up…an exciting option from Japan.

Nattokinase and clotting

A very popular tool used in Japan from fermented beans is about to become really common in the US and Europe.


Nattokinase is a well known player in anti-thrombosis (reducing blot clots):

Nattokinase dissolves blood clots by directly hydrolyzing fibrin and plasmin substrate

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372539/



And the amyloid question??

Nattokinase is capable of degrading amyloid fibrils at neutral pH and normal body temperature, suggesting a role in the treatment of amyloid-related diseases such as Alzheimer's disease (AD).

https://journals.sagepub.com/doi/full/10.1177/1177271918785130


Goodness…Strike 2 for clots!


We're really leveraging the powerful effects of the bacteria strain used to ferment the beans but we all know that the gut and its microbiome are key to almost every pathway these days.


We use this one here


Comparing the side effect profile and effectiveness, it's hard to understand why this isn't first line treatment. Work with your doctor or naturopath…nattokinase is a powerful anti-clotting player on par with standard medications.


Another powerful player.

Tip 3 - Myricetin

Big write-up on myricetin but we discovered this gem from a different pathway involving dopamine and obesity (plus just about every addiction out there).


Myricetin is a bit of a workhorse though as a GLP1 agonist (more on that in the review).


One interesting aspect of the research involves its neuroprotective effects and is in line with this...

Myricetin inhibits amyloid fibril formation of globular proteins by stabilizing the native structures

    https://www.sciencedirect.com/science/article/abs/pii/S0927776519307842


    Bam!


    It suppressed the formation to begin with but more importantly...


    Myricetin was also observed to promote disassembly of mature amyloid fibrils.


    More research is starting to bare this out:

    We demonstrate that myricetin significantly inhibits the fibrillation of HEWL and the inhibitory effect is dose-dependent.

    https://mural.maynoothuniversity.ie/6864/1/GJ-Myricetin.pdf

     

    HEWL is a hen-based platform to study clots.

     

    Myricetin appears to block the formation of new amyloid as well:

    Myricetin Inhibits α-Synuclein Amyloid Aggregation by Delaying the Liquid-to-Solid Phase Transition

    https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/cbic.202200216

     

    So...it prevents the transition to a stable structure for the clot.

     

    And the primary clotting aspect (fibrinogen):

    Myricetin inhibits adhesion to collagen and thrombus formation in vitro.

    https://www.researchgate.net/figure/Myricetin-inhibits-adhesion-to-collagen-and-thrombus-formation-in-vitro-Washed_fig5_338956313


    Thrombus…clotting!


    Again…check out the review. Myricetin also displays neuroprotective effects.


    Next up…close to our heart.

    Tip 4 - CBD Isolate

    Big reviews on CBD and dementia or CBD and neuroinflammation but let's zoom into the amyloid formation piece.


    CBD directly affects this pathway by stimulating the endocannabinoid system and a particular pathway called PPAR:

    Results indicated the CBD capability to induce the ubiquitination of APP protein which led to a substantial decrease in APP full length protein levels in SHSY5Y(APP+) with the consequent decrease in Aβ production.

    https://pubmed.ncbi.nlm.nih.gov/24288245/


    Let's translate the Klingon, please.


    APP is short for amyloid precursor protein…it's needed to get the amyloid party started.


    CBD reduced this key ingredient which causes a decrease in amyloid (beta in this case) formation.


    Here's the critical piece in terms of our bodies!


    Moreover, CBD promoted an increased survival of SHSY5Y(APP+) neurons, by reducing their long-term apoptotic rate.


    So…CBD helped neurons which are genetically programmed to build lots of amyloid and then die (like brain tissue with dementia)...survive!


    After all…that's the real outcome that matters since amyloid removal itself is not coming through in dementia research and medication.


    It needs to reflect in actual behavior, right??


    Okay then…

    Importantly, vehicle-treated APPxPS1 mice were characterized by object recognition deficits and delayed spatial learning, which were reversed by CBD treatment.

    https://www.frontiersin.org/articles/10.3389/fphar.2020.587604/full


    "Deficits reversed by CBD" in mice that are genetically programmed to make amyloid in spades.


    This is in the brain…across the blood-brain barrier. Hard to get to. Harder to affect.


    We use this one here. Hold under the tongue up to 60 seconds and 300mg daily is peak neurogenesis (brain repair process) as a benchmark.


    The immune balancing aspect is just a bonus since amyloid is driven by that system.


    Next up…an old standby.

    Tip 5 - Omega 3's

    You're probably tired of the fish oil list of benefits but it really is pretty impressive.


    We did a giant review of omega 3 versus omega 6. The inflammatory effects between the two are night and day and we're swimming in omega 6s (seed oils, processed foods, etc).


    So…what about those amyloid clots?

    Omega-3 polyunsaturated fatty acids promote amyloid-β clearance from the brain through mediating the function of the glymphatic system

    https://pubmed.ncbi.nlm.nih.gov/27789520/


    Oh goodness…our favorite "system". We'll cover the glymphatic system below in the sleep section but put a bookmark by that one.


    So…Omega 3's support the process that removes the waste from our body and brains…including amyloid particles.


      Look what happens when you combine omega-3 fat and Vitamin D:

      Both 1alpha, 25-dihydroxyvitamin D3 and resolvin D1 improved the ability of the Alzheimer's disease patients' macrophages to gobble-up amyloid-beta, and they inhibited the cell death that is induced by amyloid-beta.

      https://newsroom.ucla.edu/releases/vitamin-d-omega-3-may-help-clear-242465


      We have a massive review on Vitamin D which directly manages our immune response along with steroidal hormones:  testosterone, estradiol, and progesterone.


      It's so much more than reproduction! The immune system is front and center.


      Remember…part of the equation is righting the immune ship so that we don't keep making more amyloid material. This is all immune!


      As for the clotting aspect:

      Intake of fish oil reduced fibrinogen and factor V levels as well as thrombin generation in plasma.

      https://pubmed.ncbi.nlm.nih.gov/15217806/


      Here's the exciting part there:

      Interestingly, the lowering effect of fish oil on thrombin generation and fibrinogen clustered around subjects with high fibrinogen carrying a structural fibrinogen alpha-chain polymorphism.


      Some people have clotting issues in response to a cue or pathogen….others don't.


      This may speak to that difference! Too bad we're swimming in omega 6 acids which are compete with omega 3 for processing. 


      Let's turn to a behavior we can do.

      Tip 6 - Cold Exposure

      The research is just crazy on this front. We're going to do a deep dive next for mental health and cold exposure.


      Even 10 minutes in a cold bath (around 60 degrees) affords most of the benefits.


      Daily before noon ideally. Run it by your doctor and take magnesium glycinate (or mag salts in the bath) and B vitamin complex.


      Cold exposure has a powerful effect on rebalancing and strengthening our immune system.


      So…first, the poor mice:

      Overall, BAT stimulation through RSCE improved metabolic deficits and completely blocked cold-induced tau hyperphosphorylation in the 3xTg-AD mouse model of AD neuropathology.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437631/


      Mice who are genetically designed to get the animal version of Alzheimer's show reduced induction of tau and amyloid formation as well as the resulting behavior deficits after cold exposure.


      There's a known connection between immune dysregulation, amyloid formation, and metabolic health.


      Obesity drives these formations…especially in the bloodstream:

      Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410081/


      Vascular dysfunction. The stuff that leads to heart attacks and strokes.


      Cold exposure fine-tunes metabolism and as a result…a direct effect on the formation of these micro-clots.


      It goes deeper than that (we're complicated after all).


      There's a cold-shock protein called RMB3 which may be conserved from distant relatives (such as bears) who lose a lot of brain matter during hibernation only to regrow it when they wake up!


      Big review here:

      https://www.bbc.com/news/health-54531075


      The net net for our discussion??

      In both prion-infected and 5×FAD (Alzheimer-type) mice7, the capacity to regenerate synapses after cooling declined in parallel with the loss of induction of RBM3.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338605/

       

      So...this cold shock protein was key to the repair/rebuild of the brain.


      Okay…prion infection. Another flavor of amyloid tangles that can actually grow:

      Prions are considered a subclass of amyloids in which protein aggregation becomes self-perpetuating and infectious.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4601216/



      Watch for research on fgf21 pathway which cold exposure boosts...

      Prophylactic and therapeutic administration of FGF-21 significantly improved the degree of vascular stenosis and reduced the thrombus area, volume and burden.

      https://www.nature.com/articles/s41598-021-00906-2


      "Vascular stenosis" - narrowing of veins/arteries due to damage.


      Look…read our dopamine rescue guide.

       

      how to rescue dopamine


      Any discomfort or pain you experience with cold exposure will directly translate to even more satisfaction/pleasure afterward. It's just how we're built.


      You're buying future pleasure on account!


      Let's turn to getting the immune system in check.

      Tip 7 - Medicinal mushrooms

      Huge review on medicinal mushrooms and mental health with a focus on the immune system's effect.


      Medicinal mushrooms have powerful effects of rebalancing our immune system and it's clearly driving the amyloid clotting activity.


      It has also been reported that edible mushrooms (basidiocarps/mycelia extracts or isolated bioactive compounds) may reduce beta-amyloid-induced neurotoxicity.

      https://www.sciencedirect.com/science/article/pii/S0753332221001621


      This immune "setting" (TH1 versus TH2) is critical to why some people's immune systems over respond versus other people's immune systems which don't.


      It also goes to the formations themselves…

      In aging rats, IOE can decrease the production of amyloid precursor protein (APP) and the levels of Aβ plaques in the hippocampus after IOE treatment in the brain by an action that is associated with a lowering of the of IL-1β, TNF-α levels.


      IOE is an extract of the Chaga mushroom.

      • So…it reduced APP, the basic ingredient for amyloid
      • It reduced the resulting plaques
      • It lowered key inflammatory assassins like TNF and IL1b

      And the clotting factor fibrinogen?

      The data we present suggest that the fibrinolytic enzyme derived from the edible and medicinal mushroom Cordyceps militaris has fibrin binding activity, which allows for the local activation of the fibrin degradation pathway.

      https://pubmed.ncbi.nlm.nih.gov/17205040/


      "Fibrin degradation pathway". Breakdown and remove. That's just one species!


      We have a massive review of medicinal mushrooms. We take this one here to get different species.


      Let's turn to an unsuspecting player.

      Tip 8 - Melatonin

      We all think of melatonin for sleep and yes, it's a key manager of sleepiness.


      Made from serotonin (which is boosted by estrogen and conversely, testosterone in the male brain), melatonin is getting recognition for a wide range of neuroprotective benefits.


      It makes sense since most repair is done when we're sleeping (more on that below…so important).


      Mother nature likes to multitask.


      Okay..so both formation and protection from effects:

      Melatonin efficiently protects neuronal cells from Aβ-mediated toxicity via antioxidant and anti-amyloid properties: it not only inhibits Aβ generation, but also arrests the formation of amyloid fibrils by a structure-dependent interaction with Aβ.

      https://www.nature.com/articles/aps20063


      Goodness. Just sleep indeed.


      But does this translate into effects we can feel??

      These findings suggest that melatonin may improve the soluble Aβ1–42-induced impairment of spatial learning and memory, synaptic plasticity, and astrogliosis via the Musashi1/Notch1/Hes1 signaling pathway.

      https://alzres.biomedcentral.com/articles/10.1186/s13195-016-0206-x


      As for fibrinogen and clotting??:

      A single dose of oral melatonin was associated with lower plasma levels of procoagulant factors 60 min later.

      https://pubmed.ncbi.nlm.nih.gov/18289163/


      Next up…your steroids matter.

      Tip 9 - steroidal hormones

      We have massive reviews on testosterone, estrogen, and progesterone.


      Every cell in the body has receptors and they directly govern our immune system.


      These are just a few examples.

      17β-Estradiol and Progesterone Regulate Expression of β-Amyloid Clearance Factors in Primary Neuron Cultures and Female Rat Brain

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3473201/

       

      Goodness…they manage the removal of waste including amyloid formation.


      That's not great news since progesterone drops by 50% by age 40 and estradiol drops through the floor late 40s (we learned the hard way - that story is here).


      T's no slouch:

      Testosterone reduces neuronal secretion of Alzheimer's β-amyloid peptides

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC15568/


      Look what happens when testosterone is just cut off:

      These findings indicate that acute or chronic androgen depletion by gonadectomy might lead to susceptibility of the male brain to Aβ deposition.

      https://academic.oup.com/endo/article/159/12/3885/5094961


      And why aren't you supplementing with bio-identical since it's dropping 1% a year starting around age 20??


      Estradiol is even more severe but progesterone is a monster calming agent for immune response and inflammation.


      Autoimmune hits women 8:1 and the '40s (when P is really dropping) spikes this effect.


      In fact, autoimmune will go into remission during pregnancy when P is highest.


      Get your levels tested and watch out for the "your levels are fine for your age."


      And situations where clotting is hyperactive?

      For patients receiving steroids, the fibrinogen level dropped from >600 to <400 mg/dL 66% faster [median 6 days (95% CI 3.6, 8.4) compared to a median of 18 days (95% CI 13.7, 22.3) for those not receiving steroids (P=0.017)].

      https://www.jhltonline.org/article/S1053-2498(16)00244-8/fulltext


      Bioidentical:


      Read the reviews…there's no band-aiding loss of steroids.


      Finally…we have to talk about sleep.

      Tip 10 - Sleep - the waste removal machine

      Whether the lymphatic system (body) or glymphatic system (brain - newly discovered), this is the key to the removal of waste material and malformed entities.


      It primarily happens in the last half of sleep (4 am on) and during stages 3-4 of deep sleep (generally 1 ½ hour cycles).


      Just look at bad sleep:

      β-Amyloid accumulation in the human brain after one night of sleep deprivation

      https://www.pnas.org/doi/10.1073/pnas.1721694115


      Goodness.

       

      The waste removal systems work when we sleep (deeply) and this is why it's important:

      The mice with impaired lymphatic systems had greater buildup of amyloid-beta plaques and immune cells that cause inflammation.

        https://www.nih.gov/news-events/nih-research-matters/boosting-brains-waste-removal-system-could-improve-alzheimers-outcomes


        So…how's your sleep? Thought so.

        • Benzo and sleep aids cause tolerance (get worse off with time)
        • Anti-histamine (Benadryl; Tylenol PM) rip acetylcholine and worse (gut and heart)
        • Many supplements also cause tolerance (slower than benzos), and histamine response (key to insomnia) afterward
        • THC dysregulates the sleep architecture (the deep sleep piece above)

        We have to address sleep for our bodies to naturally remove the substances that eventually congregate to form clots.


        We have a whole review on sleep but here's our sleep toolkit. We need a deeper dive on this front since it's so critical to the clotting issue.

         

        sleep toolkit


        Of course…one more feather in Vitamin D's cap:

        Dietary Vitamin D Increases Percentages and Function of Regulatory T Cells in the Skin-Draining Lymph Nodes and Suppresses Dermal Inflammation.

        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031886/


        Aim for 60ng/ml based on the endocrinologist's data (see big review). Get levels tested.


        A few final notes that need to be addressed.


        We focused on tools that don't build tolerance or have potential longer-term issues.

        What about aspirin, turmeric, and cinnamon

        There's conflicting research on aspirin (even baby aspirin) a known anti-coagulant.


        Specifically, as it applies to amyloid driven disease for stroke and heart:

        Recurrence of lobar ICH is associated with previous microbleeds or macrobleeds and posterior CT white matter hypodensity, which may be markers of severity for underlying cerebral amyloid angiopathy. Use of an antiplatelet agent following lobar ICH may also increase recurrence risk.

        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2931649/


        Essentially, substances that affect COX pathways (NSAIDs, etc.) may cause micro-bleeds in these individuals.


        We just need more info.

        As for turmeric (which is very interesting across many pathways), there's some conflicting research around increased bleeding we would like ironned out first.

        And cinnamon…discount aspirin!


        Interesting results there but there's a liver toxin naturally found in cinnamon called coumarin.


        Longer term, we would like to see more research. Remember that glutathione is the primary detox agent in the liver so we don't want to draw that down.


        Of course, work with your doctor or naturopath especially if you take other medications.

         

        Always work with a doctor or naturopath with any supplement!

        The information provided here is not intended to treat an illness or substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.

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