Right on the heals of the recent publication that shows that beta-amyloid in the brain specifically wraps around HerpesViral particles in order to prevent them from spreading!
Turns out, a great many viruses use low-density-lipoproteins (LDLs, of heart disease fame) to travel around the body, and some even enter our cells by binding to LDL receptors. The APOE gene, associated with alzheimers, binds and transports herpes in the brain and hepatitis viruses in the liver!
If I understand correctly, APOE helps viruses enter neurons. How does APOE4 behave differently than other isoforms in this regard? APOE itself isn't implicated in AD risk, just the APOE4 isoform. And I couldn't tell from your post or a brief lit search, what's the current thinking on the relationship btw APOE and amyloid beta?
I think APOE4 is associated with higher levels of beta amyloid but I don't know why. You mention a study showing beta amyloid traps herpes simplex? Is there a mechanism by which APOE4 drives more beta amyloid aggregation to fight viral infections, but as an unintended result leads to AD?
I've briefly followed some of the recent papers on a viral link to AD but haven't spent much time on it, your post has inspired me to do some more research!
* APO-E isoform, that predicts alzheimers risk, correlates with how much beta amyloid is present in the brain
* It also correlates with how much Herpes Virus is present : https://www.theatlantic.com/science/archive/2018/07/herpes-v...
"Readhead and his colleagues have shown that the more E4 copies someone has, the more HHV–6A and HHV–6B viruses they are likely to have in their brains."
* We also know that if you knock APOE out in a mouse, and then infect it, there is WAY less HSV penetration in the brain (see figure 1, and note that the Y-axis is logarithmic!) : http://jvi.asm.org/content/76/23/12394.full
* Also, APOE isoforms predict whether or not Hepatitis B virus will give you liver cancer. Note that its the E3 genotype that is risky for this, yet its the E4 genotype thats bad for Alzheimers. I take this to be evidence that hepatitis viruses and herpes viruses likely have different binding affinities to these two isoforms.
https://www.ncbi.nlm.nih.gov/pubmed/26823800
* Someone should do some drug screening to eliminate binding between known viral capsids and APOE variants. cough YC Bio
Seems like there is still a lot to learn about the underlying biology, though very provocative findings thus far. I may be misunderstanding but I'd think that if beta amyloid traps herpes, then higher levels of beta amyloid would correlate with lower levels of virus, but it seems that isn't the case?
Would antiviral therapy be more effective that blocking capsid-APOE interaction? It's my understanding that blocking protein protein interactions is challenging, although inhibiting that interaction would be a nice specific way to block the mechanism
It's a fair point, for sure. I'm not so sure how antivirals work but that is probably a more direct pathway to target.
Alternatively, maybe we could train our immune systems to detect when a lipoprotein is transporting malicious cargo. Ideally, if we could realiably distinguish between healthy LDL particles and lipoviral particles, maybe we can find surface epitopes!
I wonder if the reason foam cells are forming in atherosclerosis is because the immune system suspects that they may be infected and carrying payloads.
Certainly seems like an interesting avenue, though I don't know enough to speculate as to whether there are surface epitopes (i dont even know how / where on the LDL the virus binds haha)
The relationship btw HSV, APOE, amyloid beta and AD is certainly intriguing but it seems quite messy at this point. Would imagine there's a lot of work to do to unravel the mechanism before we get to the point where we can think about how best to drug whatever target emerges. Unfortunately mouse models in AD are terrible, so studying the biology may be very tough, although it seems iPSC derived neurons are proving to be decent models.
One thing I like about a lot of HN discussions, as opposed to those on many other sites on the web, is that the people involved have a clear sense of what they do and don't know.
> the people involved have a clear sense of what they do and don't know.
As someone who has, on more than one occasion, called out top-posts that were flat-out wrong, but conformed to HN's biases (I was 100% certain of this because the posts concerned either my area of expertise or my first-hand experiences) - I will disagree with you. The occasions made me wonder about the other HN posts where I'm not an expert.
HN isn't anywhere near as free of the usual human love of gossip, valuing social pecking order over objective facts, etc as it imagines itself to be.
But it's a little like that saying about democracy being "the worst thing ever -- except for everything else". In spite of HNs serious delusions about how objective etc it is, it still remains vastly more objective, rational etc than anything else I've found.
Perhaps the presence of the virus causes the beta amyloid to be produced, or to not be cleared (because it's being used to trap the virus)? I'm no biologist but spitballing on why you might see a direct relationship vs an inverse one.
your question: higher levels of beta amyloid would correlate with lower levels of virus. A metaphor for answering it: if the protection arrives late and the harm is done then the number of protectors can't be used to predict the harm. So to anaylize the correlation one has to know if the effect of the protection happen before it makes the harm or not. That is the speed here is an essential ingredient.
Emperator caveat: I applied abstract reasoning and a metaphor, don't know about the specific details of how beta amyloid is generated.
Hah! I've spent the last several years studying dementia at UCSF actually, and I'm well known in the building for compulsively making puns CONSTANTLY...
I once told my boss, who studies sociopaths, that I have "sociopuny" ... and she facepalmed harder than you can imagine .... This one wasn't intentional. I have a problem.
No. The beta amyloid protein is the primary 'cause' of Alzheimer's. It builds up in the brain and kills neurons and synapses. Tens of billions of dollars have been spent developing drugs to reduce the amount of amyloid in the brain to try and combat Alzheimer's, none of which has led to an effective treatment.
This newer theory is that the cause of the amyloid build-up is an immune response to the herpes virus increasingly infiltrating the brain (as you get older the blood/brain barrier that protects your brain from infections weakens) so a possible treatment is to try and reduce the levels of herpes infection rather than attacking the amyloid protein which is your body's immune response to the herpes infection.
The APOE4 gene is infamous for increasing amyloid production and being a major risk factor for early-onset Alzheimers and so carriers of the gene are often used in studies to see the effect of treatments. (@subcosmos below has a good explanation of what this gene actually does)
The thing about viral infections of the nervous system is that you don't even need to consider the blood brain barrier. Viruses travel backwards through neurons by hijacking microtubule transport networks, and many groups have hypothesized in the literature that it could be getting into the brain by simply infecting a peripheral nerve and traveling up the spinal chord.
Check out Figure 1 in this paper. The model effectively is that HSV infects a great many people in early life, and becomes latent in neurons until old age. Then it suddenly wakes up again and travels to the brain. All it takes is an infected muscle or other tissue, allowing the virus to get into the nerve.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3546524/
Some VERY notable statistics mentioned in the paper : "Such studies have revealed endemic infection rates of 31% in children aged 6–14, rising to 49% in adults aged 14–49, and to a high of 80–90% in the population over 65. In one study of 40 autopsied TGs, HSV-1 sequences were amplified from DNA or RNA extracted from 81% of TGs from demented subjects, and 74% of controls"
I blogged about these connections here, for I think that this retrograde transport phenomenon might explain Tau phosphorylation, which is a secondary hallmark of Alzheimer's and other dementias : https://medium.com/@InfinoMe/cholesterol-have-we-shot-the-me...
As its name implies, the blood brain barrier protects the brain from whatever happens to flow in the blood stream. The herpes virus enters the brain by another channel : the peripheral, somatosensory nerve cells whose axon has a T shape. One prong of the top bar goes to the peripheral tissue, and the other prong goes up to the brainstem.
Expanding further: the blood brain barrier is made of cytoplasmic expansions of astrocytes in the central nervous system. The T-shape sensory cells are part of the peripheral nervous system, their axon ends up in the encephalon.
After reading a bit about it, I think the hypothesis is more that Alzheimer’s is the side effect of the body’s own anti-viral systems acting to contain viruses in the brain.
Most of the latest studies are showing a reduction in Alzheimer’s risk after treating patients who have some form of herpes with anti-viral medication.
Correct, as humans evolved, parasitic infections increased. The APOE gene was a method of slowing down or stopping parastic infection to the brain.
"Among the Tsimane as a whole, adults with APOE4 got poorer scores in these tests. But when the team focused on the people with high parasite levels, they saw that the APOE4 carriers had better mental skills, even outperforming APOE3 carriers who were parasite-free."
No.... APOE is a lipoprotein that transports cholesterol, and viruses jump onto it to get into cells. Amyloid-Beta is what seems to be wrapping around the virus particles to block their transit.
https://www.cell.com/neuron/fulltext/S0896-6273(18)30526-9
Turns out, a great many viruses use low-density-lipoproteins (LDLs, of heart disease fame) to travel around the body, and some even enter our cells by binding to LDL receptors. The APOE gene, associated with alzheimers, binds and transports herpes in the brain and hepatitis viruses in the liver!
https://medium.com/@InfinoMe/cholesterol-have-we-shot-the-me...