Murine roseolovirus does not accelerate amyloid-β pathology and human roseoloviruses are not over-represented in Alzheimer disease brains

Bigley, Tarin M.; Xiong, Monica; Ali, Muhammad; Chen, Yun; Wang, Chao; Serrano, Javier Remolina; Eteleeb, Abdallah M.; Harari, Oscar; Yang, Liping; Patel, Sanket; Cruchaga, Carlos; Yokoyama, Wayne M.; Holtzman, David M.

doi:10.1186/s13024-021-00514-8

Cited by 13 publications

(21 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Rizzo et al [ 16 ] found a correlation between KIR2DS2/KIR2DL2/C1, a lower MMSE score (representative for AD), and an increased susceptibility to HHV-6A infection. On the other hand, a very recent study on AD murine models (5XFAD mice) did not support the role of murine or human roseola viruses in the development of AD-specific Aβ senile plaque formation [ 26 ]. The authors do, however, demonstrate HHV-6 involvement in generating and maintaining neuroinflammation, but the fact that the pathological formation of Aβ agglomeration is not achieved is further evidence that there are other mechanisms—still incompletely elucidated—involved in this complex neurodegenerative process.…”

Section: Evidence Of Hhv-6 Infection and Alzheimer’s Diseasementioning

confidence: 99%

The Role of Human Herpesvirus 6 Infection in Alzheimer’s Disease Pathogenicity—A Theoretical Mosaic

Romanescu

Schreiner

Mukovozov

2022

JCM

View full text Add to dashboard Cite

Alzheimer’s disease (AD), a neurodegenerative disorder generally affecting older adults, is the most common form of dementia worldwide. The disease is marked by severe cognitive and psychiatric decline and has dramatic personal and social consequences. Considerable time and resources are dedicated to the pursuit of a better understanding of disease mechanisms; however, the ultimate goal of obtaining a viable treatment option remains elusive. Neurodegenerative disease as an outcome of gene–environment interaction is a notion widely accepted today; a clear understanding of how external factors are involved in disease pathogenesis is missing, however. In the case of AD, significant effort has been invested in the study of viral pathogens and their role in disease mechanisms. The current scoping review focuses on the purported role HHV-6 plays in AD pathogenesis. First, early studies demonstrating evidence of HHV-6 cantonment in either post-mortem AD brain specimens or in peripheral blood samples of living AD patients are reviewed. Next, selected examples of possible mechanisms whereby viral infection can directly or indirectly contribute to AD pathogenesis are presented, such as autophagy dysregulation, the interaction between miR155 and HHV-6, and amyloid-beta as an antimicrobial peptide. Finally, closely related topics such as HHV-6 penetration in the CNS, HHV-6 involvement in neuroinflammation, and a brief discussion on HHV-6 epigenetics are examined.

show abstract

Section: Evidence Of Hhv-6 Infection and Alzheimer’s Diseasementioning

confidence: 99%

The Role of Human Herpesvirus 6 Infection in Alzheimer’s Disease Pathogenicity—A Theoretical Mosaic

Romanescu

Schreiner

Mukovozov

2022

JCM

View full text Add to dashboard Cite

show abstract

“…Together with several recent studies [38, 62, 63], our work raises serious doubts as to whether a direct causal relationship between viral infections and Aβ pathology exists. Analysis of brain tissues from latently HSV‐1 infected patients and individuals with HSE did not reveal Aβ or hyperphosphorylated tau pathology [62].…”

Section: Discussionmentioning

confidence: 65%

“…Similarly, in hAβ mice with acute HSE, the levels of APP/Aβ in individual neurons did not change upon HSV‐1‐infection. In another recent study, a series of experiments examined 5XFAD mice infected with murine roseolovirus (MRV) via two different routes (peripheral/intracranial) at various time points (before/after spontaneous formation of Aβ plaques); the mice were analyzed at multiple time‐points post infection (acute/chronic) [ 63 ]. In young 5XFADs, MRV infection did not induce the formation of Aβ plaques de novo [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

“…In another recent study, a series of experiments examined 5XFAD mice infected with murine roseolovirus (MRV) via two different routes (peripheral/intracranial) at various time points (before/after spontaneous formation of Aβ plaques); the mice were analyzed at multiple time‐points post infection (acute/chronic) [ 63 ]. In young 5XFADs, MRV infection did not induce the formation of Aβ plaques de novo [ 63 ]. In older 5XFAD mice with Aβ pathology, MRV infection did not increase the plaque density nor facilitate the progression of Aβ pathology [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Aβ plaques do not protect against HSV‐1 infection in a mouse model of familial Alzheimer's disease, and HSV‐1 does not induce Aβ pathology in a model of late onset Alzheimer's disease

et al. 2022

View full text Add to dashboard Cite

The possibility that the etiology of late onset Alzheimer's disease is linked to viral infections of the CNS has been actively debated in recent years. According to the antiviral protection hypothesis, viral pathogens trigger aggregation of Aβ peptides that are produced as a defense mechanism in response to infection to entrap and neutralize pathogens. To test the causative relationship between viral infection and Aβ aggregation, the current study examined whether Aβ plaques protect the mouse brain against Herpes Simplex Virus 1 (HSV‐1) infection introduced via a physiological route and whether HSV‐1 infection triggers formation of Aβ plaques in a mouse model of late‐onset AD that does not develop Aβ pathology spontaneously. In aged 5XFAD mice infected via eye scarification, high density of Aβ aggregates did not improve survival time or rate when compared with wild type controls. In 5XFADs, viral replication sites were found in brain areas with a high density of extracellular Aβ deposits, however, no association between HSV‐1 and Aβ aggregates could be found. To test whether HSV‐1 triggers Aβ aggregation in a mouse model that lacks spontaneous Aβ pathology, 13‐month‐old hAβ/APOE4/Trem2*R47H mice were infected with HSV‐1 via eye scarification with the McKrae HSV‐1 strain, intracranial inoculation with McKrae, intracranial inoculation after priming with LPS for 6 weeks, or intracranial inoculation with high doses of McKrae or 17syn + strains that represent different degrees of neurovirulence. No signs of Aβ aggregation were found in any of the experimental groups. Instead, extensive infiltration of peripheral leukocytes was observed during the acute stage of HSV‐1 infection, and phagocytic activity of myeloid cells was identified as the primary defense mechanism against HSV‐1. The current results argue against a direct causative relationship between HSV‐1 infection and Aβ pathology.

show abstract

“…Moreover, administration of nonlethal viral dose to these mice led to Aβ deposits surrounding the viruses [ 161 ]. These observations were questioned by some subsequent studies [ 172 , 173 ]. However, this discrepancy could be explained by viral particle doses or viral strains/species used, which may differ in their sensitivity to Aβ.…”

Section: Protective Role Of Amyloid Betamentioning

confidence: 98%

Infectious origin of Alzheimer’s disease: Amyloid beta as a component of brain antimicrobial immunity

Vojtěchová

Macháček²,

Krištofiková³

et al. 2022

PLoS Pathog

View full text Add to dashboard Cite

The amyloid cascade hypothesis, focusing on pathological proteins aggregation, has so far failed to uncover the root cause of Alzheimer’s disease (AD), or to provide an effective therapy. This traditional paradigm essentially explains a mechanism involved in the development of sporadic AD rather than its cause. The failure of an overwhelming majority of clinical studies (99.6%) demonstrates that a breakthrough in therapy would be difficult if not impossible without understanding the etiology of AD. It becomes more and more apparent that the AD pathology might originate from brain infection. In this review, we discuss a potential role of bacteria, viruses, fungi, and eukaryotic parasites as triggers of AD pathology. We show evidence from the current literature that amyloid beta, traditionally viewed as pathological, actually acts as an antimicrobial peptide, protecting the brain against pathogens. However, in case of a prolonged or excessive activation of a senescent immune system, amyloid beta accumulation and aggregation becomes damaging and supports runaway neurodegenerative processes in AD. This is paralleled by the recent study by Alam and colleagues (2022) who showed that alpha-synuclein, the protein accumulating in synucleinopathies, also plays a critical physiological role in immune reactions and inflammation, showing an unforeseen link between the 2 unrelated classes of neurodegenerative disorders. The multiplication of the amyloid precursor protein gene, recently described by Lee and collegues (2018), and possible reactivation of human endogenous retroviruses by pathogens fits well into the same picture. We discuss these new findings from the viewpoint of the infection hypothesis of AD and offer suggestions for future research.

show abstract

Murine roseolovirus does not accelerate amyloid-β pathology and human roseoloviruses are not over-represented in Alzheimer disease brains

Cited by 13 publications

References 82 publications

The Role of Human Herpesvirus 6 Infection in Alzheimer’s Disease Pathogenicity—A Theoretical Mosaic

The Role of Human Herpesvirus 6 Infection in Alzheimer’s Disease Pathogenicity—A Theoretical Mosaic

Aβ plaques do not protect against HSV‐1 infection in a mouse model of familial Alzheimer's disease, and HSV‐1 does not induce Aβ pathology in a model of late onset Alzheimer's disease

Infectious origin of Alzheimer’s disease: Amyloid beta as a component of brain antimicrobial immunity

Contact Info

Product

Resources

About