This will be part science and part essay. Among my many interdisciplinary research interests, one of the longest-running ones at a personal level has been “misfolded proteins”. I will link some of the most meaningful articles and an AI podcast that summarizes and simplifies the content, which is more helpful to a large portion of the readers, and also a good refresher. The first two are the most impactful and important to our discussion today.
Altered amyloid plasma profile in patients with disabling headaches after SARS-CoV-2 infection and vaccination
We found a strong and persistent upregulation of APP in patients with headache after COVID-19 as compared to the two other groups. At both inclusion and after 6 months APP levels were also increased in those with accompanying cognitive symptoms. In contrast, plasma levels of PZP were elevated in both headache groups as compared to healthy controls at inclusion and after 6 months follow-up, but with no relation to cognitive symptoms. CTSL was only elevated in those with COVID-19 associated headache at baseline, whereas SAA1 showed levels comparable in all groups. Conclusion: Altered plasma levels of soluble markers potentially reflecting changes in amyloid processing was found in patients with persistent headache after SARS-CoV-2 vaccine and particular in those with persistent headache after COVID-19 disease where we also found some association with cognitive symptoms.
When specific enzymes are produced in the body in response to numerous types of injury, such as an infection, the body can “cut” APP and form the “toxic” form of Amyloid. The S2 part of the Spike itself can do it, along with many other methods. Chronic or persistent inflammation and persistent fragments of the virus will also affect this, especially persist Spike fragments.
Neurological symptoms following Covid infections, especially severe infections are common, but the underlying causes or systemic changes remain to be fully understood. APP is a necessary protein that plays a significant role in many cellular processes and even developing the brain, but it is also one of the “bad boys” of neurodegeneration.
A similar trend to many other studies is observed here, severe Covid cases had a higher number of persistent headache patients, and specific degrees of headache are used as a good initial diagnostic tool for neuroinflammation or degenerative processes. An analysis of different biomarkers, both related to amyloid formation and responses to inflammation found an upregulate of Amyloid Precursor Protein (APP) in unvaccinated, but not in vaccinated patients (both groups suffering from the headaches), yet in vaccinated individuals with persistent headache there is an upregulation of a protein called PZP.
PZP, literally Pregnancy Zone Protein was first thought to play mostly and an essential role during pregnancy, it is considered an immunosuppressive protein often playing a role in suppressing T-cell responses. PZP is also a proteinase-trapping protein, meaning PZP traps enzymes that break down proteins, and this changes which type of proteins the proteinases can break down. Effectively it is a way of the body to regulate protein breakdown.
Both APP and PZP remained elevated at the 6-month mark, meaning 6 months after the initial measurement, they still remained high in the patients with cognitive symptoms (headache). APP in unvaccinated, APP and PZP in vaccinated. This points towards persistent inflammation and a persistent production or compromised capacity to clear Amyloid byproducts.
Cathepsin L (CTSL) is an interesting protein that helps degrade other proteins, cutting them into smaller parts. It is one of the “hidden hands” in SARS-CoV-2 infections by creating a novel cleavage site, facilitating the virus's entry into cells. (Fun fact, inhibiting Cathepsin L already blocked SARS-CoV-1 infection 20 years ago…). CTSL plays roles in many important, yet paradoxical functions. It can degrade α-Synuclein (amyloid fibrils), and it can degrade specific parts of APP.
PZP stabilizes misfolded proteins, it is produced a lot less in diabetes (and diabetics, and people with metabolic diseases produce a lot more APP, Galectin-3, and all the other nasty proteins I have covered), its abundance in these states helps improve the metabolic dysregulation. PZP participates in NETs, Neutrophil traps outside the cell used to “catch and trap” pathogens and other things. The protein is present at higher levels in Alzheimer’s…
Given the incredibly complex changes even Omicron infections set off, let alone mRNA vaccine + multiple breakthrough infections, it is safe to deduce the PZP upregulation is a protective response of the body on dealing with a substantial increase in amyloid-esque proteins, a failure to clear them, and limiting inflammation. Infection and vaccination are inducing significant changes in “protein break down”.
And one of my long-lasting questions is “What is inside the cloooooooot” (a reference to the movie 7).
The clots removed from ischaemic stroke patients by mechanical thrombectomy are amyloid in nature
By analyzing clots from ischemic stroke patients, the authors built upon an already good body of evidence on how clots are not all the same, not just in shape, and structure but also in composition and effects on the body and those are amyloid-rich in nature. This paper cites important evidence for our subject matter, such as bacterial cell wall and SARS-CoV-2 Spike Protein catalyzing amyloid clot formation, sepsis, diabetic complications, and other inflammatory conditions that also contribute to amyloid-esque microclot formation.
The authors argue that many thrombi form from amyloid via an incremental process of accretion, in simple terms the slow build-up of amyloidogenic proteins, amyloid fibrils, and proteins that interact with both, like building an eldrich Lego block. From the initial stages to moderate size during this process, these clots are resistant to being broken down. It is also remarkable the authors mention these amyloid clots may contain actual bacteria inside, giving evidence to my proposition this is a protective response against foreign pathogens or foreign “material”.
There is a lingering question, and my litmus test early in the pandemic was to block an absurdly large number of people (algorithmically =) ) if they got the answer wrong. Not everyone has a bacterial infection problem, and not everyone has the very distinct molecular responses, or problem discussed, yet microclots and clots that are resistant to being broken down are widespread. The amyloid must be coming from somewhere.
Elevated Liver Damage Biomarkers in Long COVID: A Systematic Review and MetaAnalysis
Long Covid is one of the most complex post-viral states or otherwise physiological states there is, and my focus on Long Covid was multifold. Not only it is a multi-organ battle, systemic, but it has always been a great non-orthodox analytical framework to analyze mRNA-damage. And at the core of both, and overall long-term low-grade dysfunction of yearly Covid infections, is the liver.
LC patients exhibit persistent liver enzyme abnormalities, with ALT, AST, GGT, and LDH levels significantly elevated compared to controls. The liver damage index further confirms this pattern, underscoring the chronic nature of LC-related liver injury. While albumin levels remain unchanged, total protein is notably reduced, reflecting impaired protein synthesis. Elevated ferritin levels, a marker of inflammation and iron metabolism disruption, stand out as a consistent theme. Coagulation markers reveal prolonged prothrombin time, indicating a bleeding risk, and elevated D-dimer levels suggest ongoing microvascular damage.
And once again we are back at “Linguistic Convergence”.
This great paper makes a strong point, with good analysis of the evidence of the long-term dysfunction of the liver in Long Covid, but as we will find out in the coming months (if you work in healthcare and are attentive to details and biomarkers, you have been seeing it, minor fluctuations of each of these markers throughout the last 24 months) different levels of continued dysfunction in people infected with SARS-CoV-2.
Per the author’s own words, one of the “problems” of liver dysfunction is how easy to miss it is, it often only shows itself when a serious condition or problem arises, making it hard to track down and address in a timely manner. All these changes lead to a chronically inflammatory state, and metabolic dysfunction thus hindering immune responses, contributing in multiple ways to coagulation abnormalities, and the creation of microclots.
Similar to the recent paper on microvascular damage in the kidneys leading to renal dysfunction and impaired metabolism and use of Vitamin D, here it would create a similar loop. Microclots lead to damage to the microvasculature, and impaired oxygen and blood flow, thus leading to a little bit of organ damage, repeating the cycle.
ALT, AST and ALP are often elevated in chronic liver damage, and in Alzheimer’s Disease, so is sugar, and so is Amyloid Precursor Protein. High Ferritin has been a hallmark of SARS-CoV-2 and during the first 2 doses of the vaccine, widespread on social media, and parts of Ferritin interact with APP forming the “bad Amyloid” although they both have a paradoxical dance, APP can be a compensatory response to maintain iron levels in the brain (after all, bacteria loves iron…). The liver’s persistent biomarker abnormalities and its interplay with vascular and neurological damage make it a central player in anything related to SARS-CoV-2.
See you tomorrow in my short Thanksgiving message. I appreciate your continued support.
Happy thanksgiving and thank you for this.
Thank you for explaining how long covid is responsible for my elevated ALT and AST liver values, as well as for my tendency to bleed easily post-covid (since April 2020). Dang.