Corroboration of a Major Role for Herpes Simplex Virus Type 1 in Alzheimer’s Disease

Itzhaki, Ruth F.

doi:10.3389/fnagi.2018.00324

Cited by 187 publications

(164 citation statements)

References 75 publications

(82 reference statements)

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“…It has been postulated that accumulation of damage from HSV infection and major neuroinflammatory effects can lead to the development of AD, and that apoE4 carriers suffer either greater viral damage or have poorer repair of such damage 54 . Previous studies have demonstrated that ITPKB expression is increased in human AD brains and exacerbates AD pathology in an animal model 64 .…”

Section: Discussionmentioning

confidence: 99%

Sex-Specific Cross Tissue Meta-Analysis Identifies Immune Dysregulation in Women with Alzheimer’s Disease

Paranjpe

Belonwu

Wang

et al. 2020

Preprint

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In spite of evidence of females having a greater lifetime risk of developing Alzheimer's Disease (AD) and greater apolipoprotein E4-related (apoE4) AD risk compared to males, molecular signatures underlying these findings remain elusive. We took a meta-analysis approach to study gene expression in the brains of 1,084 AD patients and age-matched controls and whole blood from 645 AD patients and age-matched controls. Gene-expression, network-based analysis and cell type deconvolution approaches revealed a consistent immune signature in the brain and blood of female AD patients that was absent in males. Machine learning-based classification of AD using gene expression from whole blood in addition to clinical features revealed an improvement in classification accuracy upon stratifying by sex, achieving an AUROC of 0.91 for females and 0.80 for males. These results help identify sex and apoE4 genotype-specific transcriptomic signatures of AD and underscore the importance of considering sex in the development of biomarkers and therapeutic strategies for AD.Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia 1,2 . It is pathologically characterized by the deposition of extracellular amyloid β (Aβ) and intracellular tau, otherwise referred to as plaques and neurofibrillary tangles, respectively 3-5 . AD is also marked by neuronal loss, impaired neurotransmitter signaling, neuroinflammation, and dysregulation of neuronal metabolism and immune response in the central nervous system 6-8 . AD prevalence increases dramatically with age, where the majority of cases are in individuals above the age of 65 1,9 . Although AD was identified more than a century ago 10 , its cause and pathophysiology are not fully understood, and there are no available treatments that aid in halting or reversing the disease 11 . Accordingly, it is of high priority to tackle AD, as it is projected to triple in incidence by 2050 as a consequence of population aging 6,8,12 and, to date, has no disease-modifying therapies.While the exact cause and pathophysiology remain unknown, a number of mutations and genetic risk factors have been identified as associated with AD. Apolipoprotein E (apoE) is the most common genetic risk factor for late onset AD 8,13-18 . ApoE is a lipid binding protein, that plays a central role in lipid transport and metabolism. It is highly expressed in the brain, and is important for maintaining neuronal membranes during inflammation and damage. In humans, apoE has three isoforms, apoE2, apoE3, and apoE4, which are encoded by the three alleles, ε2, ε3, and ε4, of the apoE gene, respectively. The ε2 isoform has been shown to be protective against AD, while the ε4 isoform (apoE4) is associated with increasing the risk and lowering the age of onset for developing late onset AD in a gene dose-dependent manner 19,20 . Specifically, one copy of the ε4 isoform confers a 3 to 4-fold increased risk and 7 year decrease in age of onset, while two copies confers a 12 to 15-fold increased r...

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Section: Discussionmentioning

confidence: 99%

Sex-Specific Cross Tissue Meta-Analysis Identifies Immune Dysregulation in Women with Alzheimer’s Disease

Paranjpe

Belonwu

Wang

et al. 2020

Preprint

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“…Given the large body of data that amyloid is not causal to AD but rather the result of a protective response (Krstic & Knuesel, ) where amyloid may function as an endogenous antimicrobial peptide (AMP; Moir, Lathe, & Tanzi, ) in response to microbial infection (Itzhaki, ; Dominy et al., ), the current focus on amyloid‐based transgenics may actually be antithetical to AD causality, instead leading to the creation of models of the overexpression of an AMP. Amyloid‐based transgenics also have conceptual limitations when they are used as animal models for non‐amyloid approaches to AD causality like those focused on neuronal network dysfunction, innate immune dysfunction, and chronic inflammation, neurotoxic protein accumulation, cerebrovascular disease, and metabolically‐related diseases that involve mitochondrial dysfunction (Mullane & Williams, ).…”

Section: Beyond Amyloid and Taumentioning

confidence: 99%

Preclinical Models of Alzheimer's Disease: Relevance and Translational Validity

Mullane

Williams

2019

CP Pharmacology

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The only drugs currently approved for the treatment of Alzheimer's Disease (AD) are four acetylcholinesterase inhibitors and the NMDA antagonist memantine. Apart from these drugs, which have minimal to no clinical benefit, the 40‐year search for effective therapeutics to treat AD has resulted in a clinical failure rate of 100% not only for compounds that prevent brain amyloid deposition or remove existing amyloid plaques but also those acting by a variety of other putative disease‐associated mechanisms. This indicates that the preclinical data generated from current AD targets to support the selection, optimization, and translation of new chemical entities (NCEs) and biologics to clinical trials is seriously compromised. While many of these failures reflect flawed hypotheses or a lack of adequate characterization of the preclinical pharmacodynamic and pharmacokinetic (PD/PK) properties of lead NCEs—including their bioavailability and toxicity—the conceptualization, validation, and interrogation of the current animal models of AD represent key limitations. The overwhelming majority of these AD models are transgenic, based on aspects of the amyloid hypothesis and the genetics of the familial form of the disease. As a result, these generally lack construct and predictive validity for the sporadic form of the human disease. The 170 or so transgenic models, perhaps the largest number ever focused on a single disease, use rodents, mainly mice, and in addition to amyloid also address aspects of tau causality with more complex multigene models including other presumed causative factors together with amyloid. This overview discusses the current animal models of AD in the context of both the controversies surrounding the causative role of amyloid in the disease and the need to develop validated models of cognitive function/dysfunction that more appropriately reflect the phenotype(s) of human aged‐related dementias. © 2019 by John Wiley & Sons, Inc.

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“…To this end, we investigated HSV-1 and the Aβ42 peptide, whose aggregation is a major hallmark of AD. Recently, there has been an increasing body of reports suggestive of a correlation between HSV-1 infection and AD, reviewed in 21 . However, evidence of a direct role of HSV-1 in the process of amyloid nucleation and subsequent fibril growth is currently lacking.…”

Section: Hsv-1 Catalyzes Aβ42 Amyloid Aggregation In-vitro and In-vivomentioning

confidence: 99%

The Viral Protein Corona Directs Viral Pathogenesis and Amyloid Aggregation

Ezzat

Pernemalm

Pålsson

et al. 2018

Preprint

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Nanoparticles accumulate a plethora of host factors on their surface (protein corona) in biological fluids, which influence the nanoparticle activity. Here we provide evidence for the existence of a rich viral protein corona and show its implications for viral infectivity, immune cell activation and catalysis of amyloid aggregation. We demonstrate that respiratory syncytial virus (RSV), a major cause of respiratory tract infections, accumulates a distinctive protein corona in different biofluids including: human plasma, human bronchoalveolar lavage fluid, non-human primate plasma and fetal bovine serum. Additionally, corona pre-coating differentially affects viral infectivity and its ability to activate human monocyte-derived dendritic cells (moDCs) depending on the biofluid.Furthermore, we demonstrate that cell-free RSV can bind and catalyze the amyloid aggregation of an amyloidogenic peptide derived from the islet amyloid polypeptide (IAPP) via surface-assisted nucleation.Similarly, we show that herpes simplex virus 1 (HSV-1) catalyzes the amyloid aggregation of the amyloid-beta (Aβ 42 ) peptide which is the major constituent of amyloid plaques in Alzheimer's disease. Our results provide a proof-of-concept for the presence of a viral protein corona layer that is dependent on the microenvironment and influences viral-host interactions. Additionally, the demonstration of viral nanosurface driven amyloid catalysis in an extracellular environment illustrates convergence between viral and amyloid pathologies suggesting a novel mechanistic link that warrants further investigation.

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Corroboration of a Major Role for Herpes Simplex Virus Type 1 in Alzheimer’s Disease

Cited by 187 publications

References 75 publications

Sex-Specific Cross Tissue Meta-Analysis Identifies Immune Dysregulation in Women with Alzheimer’s Disease

Sex-Specific Cross Tissue Meta-Analysis Identifies Immune Dysregulation in Women with Alzheimer’s Disease

Preclinical Models of Alzheimer's Disease: Relevance and Translational Validity

The Viral Protein Corona Directs Viral Pathogenesis and Amyloid Aggregation

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