Alzheimer's disease gene signature says: beware of brain viral infections

Porcellini, Elisa; Carbone, Ilaria; Ianni, Manuela; Licastro, Federico

doi:10.1186/1742-4933-7-16

Cited by 52 publications

(44 citation statements)

References 42 publications

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“…The findings show that genetic background is important for the development of HSV1‐associated AD. This corresponds with AD as a multifactorial disease, caused by genetic susceptibility in combination with environmental factors [1,2,7,16,30]. One plausible explanation could be that AD development with amyloid deposition is fueled by persistent and low‐grade infection in the CNS over long periods of time.…”

Section: Discussionmentioning

confidence: 99%

“…The squared GRS was associated with increased risk of AD, with a higher estimated risk effect than the non‐squared GRS. This might indicate that there are gene‐gene interactions between different risk genes, where concomitant carriage of many risk variants results in a genetic pattern which further increases the risk of HSV1‐associated AD by multiplicative effects [7,30].…”

Section: Discussionmentioning

confidence: 99%

“…It has been hypothesized that concomitant carriage of several AD‐related genes and their subsequent synergistic interactions might result in a genetic signature, which predisposes a person to HSV1‐associated AD [7,30]. In postmortem studies, the combination of having APOEε 4 and HSV1 in the brain was more highly associated with AD than having only one of these factors [15,31].…”

Section: Introductionmentioning

confidence: 99%

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A genetic signature including apolipoprotein Eε4 potentiates the risk of herpes simplex–associated Alzheimer's disease

Lindman

Weidung

Olsson

et al. 2019

A&D Transl Res & Clin Interv

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Introduction Herpes simplex virus type 1 (HSV1) in combination with genetic susceptibility has previously been implicated in Alzheimer's disease (AD) pathogenesis. Methods Plasma from 360 AD cases, obtained on average 9.6 years before diagnosis, and their age‐ and sex‐matched controls, were analyzed for anti–HSV1 immunoglobulin (Ig) G with enzyme‐linked immunosorbent assays (ELISAs). APOE genotype and nine other selected risk genes for AD were extracted from a genome‐wide association study analysis by deCODE genetics, Reykjavik, Iceland. Results The interaction between APOEε4 heterozygosity (APOEε2/ε4 or ε3/ε4) and anti–HSV1 IgG carriage increased the risk of AD (OR 4.55, P = .02). A genetic risk score based on the nine AD risk genes also interacted with anti–HSV1 IgG for the risk of developing AD (OR 2.35, P = .01). Discussion The present findings suggest that the APOEε4 allele and other AD genetic risk factors might potentiate the risk of HSV1‐associated AD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A genetic signature including apolipoprotein Eε4 potentiates the risk of herpes simplex–associated Alzheimer's disease

Lindman

Weidung

Olsson

et al. 2019

A&D Transl Res & Clin Interv

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show abstract

“…These observations strongly suggest that AD development could be the result of a complex transcriptional regulatory structure modulating regional gene expression (Fitzsimons et al., 2014) supported by clustering of alleles in the molecular signatures identified in the APOE region. Given the functional role of BCAM , NECTIN2 , TOMM40 , APOE , and APOC1 genes and the regulatory activity of variants in these genes, the molecular signatures elucidated in the present study could be associated with increased risk of developing an AD by increasing susceptibility to brain infections (Itzhaki et al., 2016; Porcellini, Carbone, Ianni & Licastro, 2010). …”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E region molecular signatures of Alzheimer's disease

et al. 2018

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SummaryAlthough the APOE region is the strongest genetic risk factor for Alzheimer's diseases (ADs), its pathogenic role remains poorly understood. Elucidating genetic predisposition to ADs, a subset of age‐related diseases characteristic for postreproductive period, is hampered by the undefined role of evolution in establishing molecular mechanisms of such diseases. This uncertainty is inevitable source of natural‐selection–free genetic heterogeneity in predisposition to ADs. We performed first large‐scale analysis of linkage disequilibrium (LD) structures characterized by 30 polymorphisms from five genes in the APOE 19q13.3 region (BCAM,NECTIN2,TOMM40,APOE, and APOC1) in 2,673 AD‐affected and 16,246 unaffected individuals from five cohorts. Consistent with the undefined role of evolution in age‐related diseases, we found that these structures, being highly heterogeneous, are significantly different in subjects with and without ADs. The pattern of the difference represents molecular signature of AD comprised of single nucleotide polymorphisms (SNPs) from all five genes in the APOE region. Significant differences in LD in subjects with and without ADs indicate SNPs from different genes likely involved in AD pathogenesis. Significant and highly heterogeneous molecular signatures of ADs provide unprecedented insight into complex polygenetic predisposition to ADs in the APOE region. These findings are more consistent with a complex haplotype than with a single genetic variant origin of ADs in this region.

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“…Recently, the presence of IgM anti-HSV antibodies in serum - a marker of recent HSV reactivation - was also correlated with an increased risk of developing AD [13]. In addition, the analysis of data gathered in genome-wide association studies involving thousands of Europeans with AD and controls [14] identified a set of AD-linked gene variants that might increase the susceptibility of the brain to HSV-1 infection [15].…”

Section: Introductionmentioning

confidence: 99%

Oxidative Stress Enhances Neurodegeneration Markers Induced by Herpes Simplex Virus Type 1 Infection in Human Neuroblastoma Cells

et al. 2013

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Mounting evidence suggests that Herpes simplex virus type 1 (HSV-1) is involved in the pathogenesis of Alzheimer’s disease (AD). Previous work from our laboratory has shown HSV-1 infection to induce the most important pathological hallmarks of AD brains. Oxidative damage is one of the earliest events of AD and is thought to play a crucial role in the onset and development of the disease. Indeed, many studies show the biomarkers of oxidative stress to be elevated in AD brains. In the present work the combined effects of HSV-1 infection and oxidative stress on Aβ levels and autophagy (neurodegeneration markers characteristic of AD) were investigated. Oxidative stress significantly potentiated the accumulation of intracellular Aβ mediated by HSV-1 infection, and further inhibited its secretion to the extracellular medium. It also triggered the accumulation of autophagic compartments without increasing the degradation of long-lived proteins, and enhanced the inhibition of the autophagic flux induced by HSV-1. These effects of oxidative stress were not due to enhanced virus replication. Together, these results suggest that HSV-1 infection and oxidative damage interact to promote the neurodegeneration events seen in AD.

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Alzheimer's disease gene signature says: beware of brain viral infections

Cited by 52 publications

References 42 publications

A genetic signature including apolipoprotein Eε4 potentiates the risk of herpes simplex–associated Alzheimer's disease

A genetic signature including apolipoprotein Eε4 potentiates the risk of herpes simplex–associated Alzheimer's disease

Apolipoprotein E region molecular signatures of Alzheimer's disease

Oxidative Stress Enhances Neurodegeneration Markers Induced by Herpes Simplex Virus Type 1 Infection in Human Neuroblastoma Cells

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