Genetic and Epidemiological Factors in Cognitive Impairment and Dementia

Raschi, Elena (2016) Genetic and Epidemiological Factors in Cognitive Impairment and Dementia, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Oncologia e patologia sperimentale, 28 Ciclo. DOI 10.6092/unibo/amsdottorato/7323.
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Alzheimer's disease (AD) is a multifactorial and progressive form of dementia with a senile onset that affects specific areas of the brain. Recent genome wide association (GWA) studies reported that the allele 4 of apolipoprotein E (APOE) and single nucleotide polymorphisms (SNPs) in other genes that regulate inflammatory pathways, such as the gene coding for clusterin (CLU), are associated with AD. The hypothesis is that all of these genes may be involved in different mechanisms mediated by herpes viruses and we argued that the concomitant presence of SNPs in these genes in the same individual may represent a genetic signature predisposing to AD. The present study is focused on SNPs in CLU, interferon (IFN)-λ3/IL-28B, Med23 and the transcription factor IRF7, which are genes involved in antiviral responses and their association with AD and cognitive deterioration. Moreover, the effects of IL-28B, Med23 and IRF7 genotypes upon the presence of epstein-barr virus (EBV) and human herpes virus 6 (HHV-6) in the peripheral blood of AD and controls (CTR) have been also investigated. The activation of the innate immune system has a key role as a promoting factor for AD and in AD patients activated microglia release cytokines that induce neuro-inflammation. In this thesis gene variants and different expression of genes involved in the innate immune response in case-control population studies and in a mouse model of AD were investigated. Results from these experiments suggest that individuals with a particular genetic makeup in defensive mechanisms of the innate immunity may be at risk of defective immune responses. Impaired immunity against persistent viruses such as those of herpes family, might result in chronic and inappropriate activation of microglia, abnormal Aβ production and increased amyloid deposition. Cycles of virus latency and infections may therefore contribute to neurodegeneration associated with AD in genetically predisposed elderly.

Tipologia del documento
Tesi di dottorato
Raschi, Elena
Dottorato di ricerca
Scuola di dottorato
Scienze biologiche, biomediche e biotecnologiche
Settore disciplinare
Settore concorsuale
Parole chiave
Alzheimer's disease; single nucleotide polymorphisms; clusterin; IL-28B, Med23 and IRF7; herpes viruses; gene expression; inflammation-associated pathways; sustained microglial activation
Data di discussione
9 Maggio 2016

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