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Cold sore virus might cause Alzheimer's
Posted: Thursday, November 15, 2012 9:27 AM
Joined: 4/24/2012
Posts: 484

After researching the information in several posts, including the Autism and AD post, and the Brushing Your Teeth post, I saw ample evidence for the link to infections, bacteria and viruses as causal agents for the onset of Alzheimer's. We understand much about the pathways that lead to AD and the genetic predispositions that contribute to it. We also know about the many environmental factors that contribute to it or possibly cause it (i.e. metal toxicity, infections, stress, diet, drugs, etc.). 


Researching more about the connection to viruses as well as autoimmunity, I came across a 2010 article in the International Journal of Alzheimer's Disease that just blew me away (I don't know if it has been posted previously). This hypothesis and the supporting evidence is amazing and makes so much sense to me that I feel like it is the missing link we have been searching for that ties everything together. I hope that you all can give me some feedback on this, positive or negative. Are they on to something here or not?


First read this news article from 2008 as a general introduction to the concept.


Cold sore virus might cause Alzheimer's

The virus that causes cold sores - Herpes simplex type 1 - was found in 90% of plaque samples from six patients who had died of Alzheimer's disease.

The virus was also found in 80% of the plaques in brain tissue from five "control" patients who didn't die of Alzheimer's, although they had far fewer plaques overall than the patients.

However, the most convincing evidence that the virus is linked with the disease came from scans mapping the whereabouts of the virus across the whole brain. These showed that, in the Alzheimer's patients, 72% of the virus found was in the plaques, compared with just 24% in the non-Alzheimer's brains.

"It's very specifically located in the plaques, so it strongly supports the likelihood that the virus is a major cause of plaque formation," says Itzhaki.

In earlier studies, Itzhaki's team demonstrated that when healthy brain cells are grown in culture and infected with HSV-1, they accumulate the same amyloid beta protein that is found in plaque.

Itzhaki's team followed that up by showing that amyloid beta plaques formed in the brains of mice deliberately infected with the virus.

Now the new results provide direct evidence that the same happens in the brains of people with Alzheimer's.



 Then read the 2010 study that takes it much further into the realm of viruses mimicing gene protiens like ApoE4 and much more.


Alzheimer's Disease: A Pathogenetic Autoimmune Disorder Caused by Herpes Simplex in a Gene-Dependent Manner

Herpes simplex is implicated in Alzheimer's disease and viral infection produces Alzheimer's disease like pathology in mice. The virus expresses proteins containing short contiguous amino acid stretches (5–9aa “vatches” = viralmatches) homologous to APOE4, clusterin, PICALM, and complement receptor 1, and to over 100 other gene products relevant to Alzheimer's disease, which are also homologous to proteins expressed by other pathogens implicated in Alzheimer's disease. Such homology, reiterated at the DNA level, suggests that gene association studies have been tracking infection, as well as identifying key genes, demonstrating a role for pathogens as causative agents. Vatches may interfere with the function of their human counterparts, acting as dummy ligands, decoy receptors, or via interactome interference. They are often immunogenic, and antibodies generated in response to infection may target their human counterparts, producing protein knockdown, or generating autoimmune responses that may kill the neurones in which the human homologue resides, a scenario supported by immune activation in Alzheimer's disease. These data may classify Alzheimer's disease as an autoimmune disorder created by pathogen mimicry of key Alzheimer's disease-related proteins. It may well be prevented by vaccination and regular pathogen detection and elimination, and perhaps stemmed by immunosuppression or antibody adsorption-related therapies.



I feel like this might explain why AD is age-related, why some people get it and others don't, why immune system therapy (vaccine, IgIV, Leukine) have shown benefits. But what about aromatherapy, antibiotics and blood transfusion? Do these treatments being beneficial point to a virus as the cause of AD? Could this be the smoking gun? And, does this change anything about how we should be directing our search for a treatment? Thanks for any thoughts you all may have, pro or con.


Lane Simonian
Posted: Thursday, November 15, 2012 10:39 AM
Joined: 12/12/2011
Posts: 4833

As you note, Serenoa, there may be multiple causes for Alzheimer's disease (and other forms of dementia).  The end cause, however, is almost always the same--peroxynitrites.   


Clinical Studies Injury to human skin
Human skin is know to produce the high amounts of Nitric Oxide and skin cells also produce hydrogen peroxide. This causes a problem in that high levels of peroxynitrite are also produced. Burned, damaged or infected skin produces even higher levels of peroxynitrite, which damages non damaged cells and immune cells and drugs needed to treat the damaged skin. An example of this is the use of Acyclovir on cold sore lesions. Acyclovir is effective when taken orally or intervenously, but topically its effect has been minimal. Infections with herpes simplex virus I (HSV-1) induces a persistent nuclear translocation of NF-kappa B, which is dramatically enhanced by peroxynitrite. The activation of NF-kappa B promotes efficient replication by HSV. In epithelial cells HSV-1 induces NF-kappa B causing persistent activation of NF-kappa B, which is a critical regulator of HSV-1 replication in skin. In AIDs patients, HIV-1 also triggers and activates NF-kappa B and AIDS patients have elevated levels of peroxynitrite, which contributes to the etiology of AIDS related dementia, persistent immunosuppression and Kaposi’s sarcoma. Peroxynitrite have also been shown to be very destructive to CD4 and CD8 cells. We have discovered that alpha-keto acids can decrease the levels and production of peroxynitrite, while protecting Nitric Oxide which can enhance the viral kill rate, while protecting drugs like Acyclovir. 


Peroxynitrites may also play a role in various autoimmune diseases, as well as other diseases. 


Biochemical and cellular toxicology of peroxynitrite: implications in cell death and autoimmune phenomenon.


Department of Biochemistry, Sardar Bhagwan Singh Post-Graduate Institute of Biomedical Sciences and Research, Balawala, Dehradun 248161, India.


Reactive nitrogen species include nitric oxide (.NO), peroxynitrite (ONOO(-)) and nitrogen dioxide radical (NO2*). Peroxynitrite is a reactive oxidant, produced from nitric oxide (*NO) and superoxide anion (O(2*-), that reacts with a variety of biological macromolecules. It is produced in the body in response to physiological stress and environmental toxins. It is a potent trigger of oxidative protein and DNA damage-including DNA strand breakage and base modification. It activates the nuclear enzyme poly-ADP ribose polymerase (PARP) resulting in energy depletion and apoptosis/necrosis of cells. Peroxynitrite generation is a crucial pathological mechanism in stroke, diabetes, inflammation, neurodegeneration, cancer, etc. Peroxynitrite modified DNA may also lead to the generation of autoantibodies in various autoimmune disorders such as systemic lupus erythematosus (SLE). In chronic inflammatory diseases, peroxynitrite formed by phagocytic cells may cause damage to DNA, generating neoepitopes leading to the production of autoantibodies. Hence, understanding the pathophysiology of peroxynitrite could lead to important therapeutic interventions.


The development of amyloid plaques and peroxynitrites takes a much shorter period of time in the case of autism, because autistic individuals lack the levels of glutathione needed to protect themselves against mercury and other toxins and infections which generate peroxynitrites.  In Alzheimer's disease, it takes a much longer time to deplete glutathione which has been called the body's master antioxidant.  In addition changes in blood chemistry also appear capable of triggering Alzheimer's disease and various antibodies in blood transfussions may help to alter this.   


In regards to the APOE gene it inhibits the phosphatidylinositol-3 kinase, which increases the substrate for phospholipase C (phosphatidylinositol 4,5 biphosphate--PIP2).  Certain bacteria and viruses can increase phospholipase C activity.  Any combination like this is bad.  In my mother's case, it was high levels of glucose (swimming stopped her from becoming diabetic) which increases myo-inositol levels and phospholipase C activity and Fosamax (an alendronate) which inhibits the phosphatidylinositol-3 kinase. 


Many of the genetic factors linked to Alzheimer's disease (the APOE4 gene, presenilin gene mutations, and TREM2 deficiency) inhibit the phostphatidylinositol-3 kinase/Akt pathway.  This is a cell survival pathway. The pathway started by phospholipase C in the brain is a cell death pathway.   


Posted: Monday, September 2, 2013 7:58 AM
Joined: 4/24/2012
Posts: 484

I just ran across an article by C.J. Carter describing the possibility that neurodegenerative diseases are caused by the interaction of a virus/bacteria and certain human genes known as susceptibility genes. In other words, the virus causes the activation or expression of specific genes that promote the disease-causing pathways in the brain. Then I realized that I had posted it before, see above. However, I thought it was worth another posting. Here is another article by Carter:



J Pathog. 2013;2013:965046. doi: 10.1155/2013/965046. Epub 2013 Mar 4.

Toxoplasmosis and Polygenic Disease Susceptibility Genes: Extensive Toxoplasma gondii Host/Pathogen Interactome Enrichment in Nine Psychiatric or Neurological Disorders.


Toxoplasma gondii is not only implicated in schizophrenia and related disorders, but also in Alzheimer's or Parkinson's disease, cancer, cardiac myopathies, and autoimmune disorders. During its life cycle, the pathogen interacts with ~3000 host genes or proteins. Susceptibility genes for multiple sclerosis, Alzheimer's disease, schizophrenia, bipolar disorder, depression, childhood obesity, Parkinson's disease, attention deficit hyperactivity disorder (P  from  8.01E - 05  (ADHD)  to  1.22E - 71) (multiple sclerosis), and autism (P = 0.013), but not anorexia or chronic fatigue are highly enriched in the human arm of this interactome and 18 (ADHD) to 33% (MS) of the susceptibility genes relate to it. The signalling pathways involved in the susceptibility gene/interactome overlaps are relatively specific and relevant to each disease suggesting a means whereby susceptibility genes could orient the attentions of a single pathogen towards disruption of the specific pathways that together contribute (positively or negatively) to the endophenotypes of different diseases. Conditional protein knockdown, orchestrated by T. gondii proteins or antibodies binding to those of the host (pathogen derived autoimmunity) and metabolite exchange, may contribute to this disruption. Susceptibility genes may thus be related to the causes and influencers of disease, rather than (and as well as) to the disease itself.

Lane Simonian
Posted: Monday, September 2, 2013 10:32 AM
Joined: 12/12/2011
Posts: 4833

This is further evidence for the protein kinase C pathway being critical for the development of Alzheimer's disease. 







2006 Nov 1;119(Pt 21):4565-73.

Host cell Ca2+ and protein kinase C regulate innate recognition of Toxoplasma gondii.


Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.



In healthy hosts, acute infection with the opportunistic pathogen Toxoplasma gondii is controlled by innate production of IL-12, a key cytokine crucial for the development of protective immunity. Previous work has established that the mitogen-activated protein kinases (MAPK), particularly p38 and ERK1/2, are important regulators of T. gondii-induced IL-12 synthesis. Here we report that host cell Ca(2+) is required for activation of MAPK by T. gondii, as well as LPS and CpG, and for parasite-induced synthesis of IL-12. In addition, pharmacological mobilization of Ca(2+) stores in macrophages treated with parasites or LPS enhanced MAPK phosphorylation initiated by these stimuli. Investigation of the upstream mechanism by which Ca(2+) regulates MAPK activation revealed that T. gondii induced acute activation of conventional, Ca(2+)-dependent PKCalpha and PKCbeta, which are required for infection-induced MAPK activation and production of IL-12. Despite these findings, neither acute parasite infection nor LPS initiated a measurable Ca(2+) response in macrophages, suggesting that low levels of Ca(2+) are permissive for initiation of pro-inflammatory signaling. Together these data identify host cell Ca(2+) and PKC as crucial regulators of the innate immune response to microbial stimuli, including T. gondii. 


It is important to identify which bacterial and viruses contribute to the activation of this pathway because they need to be treated if possible otherwise they can lead to Alzheimer's disease. 





Lane Simonian
Posted: Monday, September 2, 2013 12:35 PM
Joined: 12/12/2011
Posts: 4833

One of the great ironies in Alzheimer's disease is that the body's immune system designed to protect against infections can play a role in triggering the disease. 


In Toxoplasma gondii infection, the induction of iNOS serves as a nonspecific immune response that prevents parasite invasion.


While iNOS induction can protect brain from certain infectious diseases, excessive levels of NO can also be toxic to neurons. 

Posted: Tuesday, September 3, 2013 3:47 PM
Joined: 12/21/2011
Posts: 62

In topic

you can find: 16. HERPES ENCEPHALITIS

Because of it in

I wrote about possibility of using a combination of aromatherapy and treating of brain insulin resistance or herpesviral encephalitis (caused by herpes simplex virus 1 and 2 - HSV-1 and HSV-2, also known as Human herpes virus 1 and 2 - HHV-1 and -2).

Posted: Friday, September 27, 2013 10:08 AM
Joined: 4/24/2012
Posts: 484

I want to add a couple of articles to this post because viral infection is a very plausible explanation for triggering AD. The infection hypothesis describes amyloid beta as a defense mechanism against herpes simplex or other viruses. This would account for why removing amyloid does not improve AD in human clinical trials. Also, high blood sugar is a trigger for activating the virus, and it is also a risk factor for AD. If this hypothesis holds water then wouldn't we have some anecdotal evidence that anti-viral medications have improved symptoms in AD patients?


In addition to what is posted above, here's a good article from way back in 1997, and a more recent one addressing the use of anti-virals for AD.


Herpes simplex virus type 1 in brain and risk of Alzheimer's disease


These findings suggest that the combination of HSV1 in brain and carriage of an APOE-ε4 allele is a strong risk factor for AD, whereas either of these features alone does not increase the risk of AD. The findings in people with cold sores support our hypothesis that APOE-ε4 and HSV1 together are damaging in the nervous system.




The helicase-primase inhibitor BAY 57–1293 reduces the Alzheimer’s disease-related molecules induced by herpes simplex virus type 1

Herpes simplex virus type 1 (HSV1) infection of cultured cells causes the formation of β-amyloid (Aβ) and abnormal tau (P-tau). These molecules comprise the main components of the abnormal protein deposits, amyloid plaques and neurofibrillary tangles, respectively, in Alzheimer’s disease (AD) brains, and they have been implicated in disease development. The formation of P-tau, but not of Aβ, depends on viral DNA replication, but nonetheless, three antiviral agents that inhibit HSV1 DNA replication, including acyclovir (ACV), were found to reduce greatly the level of Aβ as well as P-tau, the former probably through prevention of viral spread. Previous studies showed that HSV1 DNA is present and is active in the brain of many elderly people, including AD patients, and that in combination with the type 4 allele of the apolipoprotein E gene, it is likely to play a role in the disease, perhaps via Aβ and P-tau production. With the aim of finding the most suitable antiviral for inhibiting Aβ and P-tau formation as well as HSV1 DNA replication, for future use in a clinical trial for treating AD, we compared the efficacy of ACV with that of another antiviral, BAY 57–1293, which acts by a different mechanism from ACV. We found that BAY 57–1293 is more efficient than ACV not only in inhibiting HSV1 replication, confirming previous studies, but also in decreasing Aβ and P-tau formation. Also, the cell clusters that are formed during infection are reduced in size much more efficiently by BAY 57–1293 than by ACV. These data suggest that BAY 57–1293 would be a more effective agent than ACV for treating AD.




Posted: Tuesday, September 18, 2018 8:29 PM
Joined: 7/3/2017
Posts: 31

I want to update the links between herpes and Alzheimer's. Importantly, the studies are in humans (not mice models).

"In the herpes group, the risk of dementia was over 2.5 times higher than in the control group.

Significantly, the study also revealed that aggressive antiviral treatment reduced the relative risk of dementia by 10 times."

Herpes Viruses and Senile Dementia: First Population Evidence for a Causal Link

Multiscale Analysis of Independent Alzheimer’s Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus

Investigators have long suspected that pathogenic microbes might contribute to the onset and progression of Alzheimer’s disease (AD) although definitive evidence has not been presented. Whether such findings represent a causal contribution, or reflect opportunistic passengers of neurodegeneration, is also difficult to resolve. We constructed multiscale networks of the late-onset AD-associated virome, integrating genomic, transcriptomic, proteomic, and histopathological data across four brain regions from human post-mortem tissue. We observed increased human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) from subjects with AD compared with controls. These results were replicated in two additional, independent and geographically dispersed cohorts. We observed regulatory relationships linking viral abundance and modulators of APP metabolism, including induction of APBB2, APPBP2, BIN1, BACE1, CLU, PICALM, and PSEN1 by HHV-6A. This study elucidates networks linking molecular, clinical, and neuropathological features with viral activity and is consistent with viral activity constituting a general feature of AD.

Lane Simonian
Posted: Friday, September 21, 2018 1:07 PM
Joined: 12/12/2011
Posts: 4833

Thank you for providing recent information about the potential link between herpes viruses and dementia.