Dr. Weeks’ Comment: Alzheimer’s can be productively seen as an inflammatory response to a post infective state with Herpes being the infectious agent. At the center of all neurofibrillatory tangles and plaques we find a herpes virus being sequestered and quarantined as a suboptimal adaption. This is not new info. We reported this over the past 2 decades at www.weeksmd.com (search terms “herpes” and “Alzheimer’s”). But now the science is stronger and we know that Alzheimer’s – like all psychiatric ailments – is made worse – it is driven by inflammation. An inflammatory response to the infection. And mindful that the bSo take the omega 6
- Neurobiol Aging. 2018 Mar 29;68:5-17. doi: 10.1016/j.neurobiolaging.2018.03.025.[Epub ahead of print] The lysosome system is severely impaired in a cellular model of neurodegeneration induced by HSV-1 and oxidative stress. Kristen H(1), Sastre I(1), Muñoz-Galdeano T(2), Recuero M(3), Aldudo J(4), Bullido MJ(5).
The causal agent(s) and molecular mechanisms of Alzheimer’s disease (AD) remain unclear. Mounting evidence suggests that herpes simplex virus type 1 (HSV-1) infection is involved in the AD pathogenesis.
Oxidative stress (OS) may also be crucial in the AD development.
Our group previously reported that both HSV-1 and OS trigger the appearance of AD-type neurodegeneration markers. The main aim of the present study was to identify the mechanisms involved in this triggering. Expression studies revealed the involvement of a set of OS-regulated genes in HSV-1-infected cells and in cells harboring the Swedish mutation of the amyloid beta precursor protein gene. Functional annotation of these genes revealed the lysosome system to be impaired, suggesting that the interaction of OS with both HSV-1 and amyloid beta precursor protein mutations affects lysosomal function. Functional studies revealed HSV-1 infection and OS to increase the lysosome load, reduce the activity of lysosomal hydrolases, affect cathepsin maturation, and inhibit the endocytosis-mediated degradation of the epidermal growth factor receptor.These findings suggest alterations in the lysosome system to be involved in different forms of AD.
- Neural Regen Res. 2018 Feb;13(2):211-221. doi: 10.4103/1673-5374.226380. Contributions of neurotropic human herpesviruses herpes simplex virus 1 and human herpesvirus 6 to neurodegenerative disease pathology.Hogestyn JM(1), Mock DJ(2), Mayer-Proschel M(3).
Human herpesviruses (HVs) have developed ingenious mechanisms that enable them to traverse the defenses of the central nervous system (CNS). The ability of HVs to enter a state of latency, a defining characteristic of this viral family, allows them to persist in the human host indefinitely. As such, HVs represent the most frequently detected pathogens in the brain.Under constant immune pressure, these infections are largely asymptomatic in healthy hosts. However, many neurotropic HVs have been directly connected with CNS pathology in the context of other stressors and genetic risk factors. In this review, we discuss the potential mechanisms by which neurotropic HVs contribute to neurodegenerative disease (NDD) pathology by highlighting two prominent members of the HV family, herpes simplex virus 1 (HSV-1) and human herpesvirus 6 (HHV-6). We (i) introduce the infectious pathways and replicative cycles of HSV-1 and HHV-6 and then (ii) review the clinical evidence supporting associations between these viruses and the NDDs Alzheimer’s disease (AD) and multiple sclerosis (MS), respectively. We then (iii) highlight and discuss potential mechanisms by which these viruses exert negative effects on neurons and glia. Finally, we (iv) discuss how these viruses could interact with other disease-modifying factors to contribute to the initiation and/or progression of NDDs.
- J Alzheimers Dis. 2017;60(3):1055-1063. doi: 10.3233/JAD-170520. Modulation of Immune Responses to Herpes Simplex Virus Type 1 by IFNL3 and IRF7 Polymorphisms: A Study in Alzheimer’s Disease. Costa AS(1), Agostini S(1), Guerini FR(1), Mancuso R(1), Zanzottera M(1), Ripamonti E(1), Racca V(1), Nemni R(1)(2), Clerici M(1)(2).
Herpes simplex virus type 1 (HSV-1) has long been suspected to play a role in Alzheimer’s disease (AD), the most common form of dementia.IFN-lambda (IFN-λ) is one of the key cytokine in innate antiviral defenses and, in particular, has an appreciable antiviral activity against HSV-1 infection. IFN-λexpression is regulated by the interaction between two different proteins: Mediator Complex 23 (MED23) and Interferon-Responsive Transcription Factor 7 (IRF7); single nucleotide polymorphisms (SNPs) in these genes as well as in IFNL3 were shown to be differently distributed in AD patients. In this study, allelic discrimination analysis for IFNL3 rs12979860, MED23 rs3756784, and IRF7 rs6598008, as well as IFN-λserum concentration and anti-HSV-1 antibody (Ab) titers were performed in 79 AD patients, 57 mild cognitive impairment (MCI) individuals, and 81 healthy controls (HC) who were HSV-1-seropositive. Results showed that INF-λserum concentration was increased in AD and MCI carrying the IFNL3 T allele compared to HC (AD versus HC: p = 0.014; MCI versus HC: p = 0.029), with the highest anti-HSV-1 Ab titers seen in AD patients carrying the IFNL3 CC genotype (p = 0.012 versus HC). Notably, anti-HSV-1 Ab titers were higher in AD and MCI individuals carrying the IRF7 AA genotype compared to HC (p = 0.018 for both). MED23 polymorphisms did not show any statistical association either with serum IFN-λor with anti-HSV-1 Ab. Data herein suggest that the IFNL3 rs12979860 and IRF7 rs6598008 polymorphisms modulate immune responses against HSV-1 via their effect on the IFN-λpathway. These results help to clarify the possible role of HSV-1 infection in AD pathogenesis.
- FASEB J. 2017 Aug;31(8):3216-3226. doi: 10.1096/fj.201700360. Herpes simplex virus type 1 and Alzheimer’s disease: possible mechanisms and signposts. Itzhaki RF(1).
Support for the concept that herpes simplex virus type 1 (HSV1), when present in the brains of apolipoprotein E-ε4 carriers, is a major risk for Alzheimer’s disease (AD) is increasing steadily, with over 120 publications providing direct or indirect evidence relevant to the hypothesis. No articles have contested the concept, apart from 3 published 13-18 yr ago. This review describes very recent studies on the role of HSV1 but refers also to older studies that provide background for some lesser-known related topics not covered in other recent reviews; these include the relevance of herpes simplex encephalitis and of epilepsy to AD, the action of IFN, and the possible relevance of the different types of DNA damage to AD-in particular, those caused by HSV1-and mechanisms of repair of damage. New epidemiologic data supporting previous studies on mild cognitive impairment and progression to AD are reviewed, as are those examining the relationship between total infectious burden (additive seropositivity to various microbes) and cognition/AD. The latter indicates the involvement of HSV1 and cytomegalovirus (and the necessity of taking into account any marked differences in sensitivity of antibody detection). Recent studies that provide further support for the occurrence of repeated reactivation of latent HSV1 in the brain in AD pathogenesis are also discussed.
- PLoS One. 2016 Dec 19;11(12):e0168816. doi: 10.1371/journal.pone.0168816. eCollection 2016.Usefulness of DNA Methylation Levels in COASY and SPINT1 Gene Promoter Regions as Biomarkers in Diagnosis of Alzheimer’s Disease and Amnestic Mild Cognitive Impairment. Kobayashi N(1), Shinagawa S(2), Nagata T(2)(3), Shimada K(1), Shibata N(4), Ohnuma T(4), Kasanuki K(4), Arai H(4), Yamada H(3), Nakayama K(2), Kondo K(1).
In order to conduct early therapeutic interventions for Alzheimer’s disease (AD), convenient, early diagnosis markers are required. We previously reported that changes in DNA methylation levels were associated with amnestic mild cognitive impairment (aMCI) and AD. As the results suggested changes in DNA methylation levels in the COASY and SPINT1 gene promoter regions, in the present study we examined DNA methylation in these regions in normal controls (NCs, n = 30), aMCI subjects (n = 28) and AD subjects (n = 30) using methylation-sensitive high resolution melting (MS-HRM) analysis. The results indicated that DNA methylation in the two regions was significantly increased in AD and aMCI as compared to NCs (P < 0.0001, P < 0.0001, ANOVA). Further analysis suggested that DNA methylation in the COASY gene promoter region in particular could be a high sensitivity, high specificity diagnosis biomarker (COASY: sensitivity 96.6%, specificity 96.7%; SPINT1: sensitivity 63.8%, specificity 83.3%). DNA methylation in the COASY promoter region was associated with CDR Scale Sum of Boxes (CDR-SB), an indicator of dementia severity. In the SPINT1 promoter region, DNA methylation was negatively associated with age in NCs and elevated in aMCI and AD subjects positive for antibodies to Herpes simplex virus type 1 (HSV-1). These findings suggested that changes in DNA methylation in the COASY and SPINT1 promoter regions are influenced by various factors. In conclusion, DNA methylation levels in the COASY and SPINT1 promoter regions were considered to potentially be a convenient and useful biomarker for diagnosis of AD and aMCI.
- J Alzheimers Dis. 2016 Oct 18;54(4):1273-1281. Herpes and Alzheimer’s Disease: Subversion in the Central Nervous System and How It Might Be Halted. Itzhaki RF.
The last 8 or so years have seen a large increase in the number of studies supporting the concept of a major role for herpes simplex virus type 1 (HSV1) in Alzheimer’s disease (AD). The main advances have been made through studies in humans and in mice, investigating the likelihood of reactivation of the latent virus in brain. Others have aimed to explain the mechanisms in cells whereby the increase in amyloid-beta (Aβ) production on HSV1 infection of cells and mouse brains occurs, and the reason that infected cells make this increase. The possibility that other herpesviruses are involved in the development of AD has been explored, and human herpesvirus type 6, Epstein-Barr virus, and cytomegalovirus, in particular, have been implicated. Epidemiological studies have further supported the role specifically of HSV1 and its reactivation in the disease. Antiviral studies have continued, comparing those acting by different mechanisms, such as restricting viral replication, or blocking viral entry into cells, to treat HSV1-infected cell cultures, and then examining the extent to which the virus-induced increases in Aβand AD-like tau are reduced. All the studies support the usage of antiviral treatment to slow or halt the progression of AD.