Molecular characterisation of the role of systemic infections in Alzheimer’s disease brain

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder arising from the interplay of amyloid and tau pathology, glial activation, vascular dysfunction, and systemic influences. This thesis investigates how systemic infection reshapes the molecular architecture of the AD brain and introduces Genedex, a framework to contextualise transcriptional findings within the broader AD continuum. Using post-mortem prefrontal cortex samples from the UK Brain Bank Network, bulk RNA sequencing revealed that systemic infection elicits distinct molecular responses in AD compared with controls. Differential expression and co-expression network analyses identified infection-dependent alterations in immune, vascular, and metabolic pathways, including epithelial cell apoptotic and viral processes. These findings indicate that systemic infection amplifies neuroinflammatory and endothelial signalling already perturbed in AD, potentially compromising blood–brain barrier (BBB) integrity and facilitating peripheral–central immune crosstalk. Extending these analyses to microRNAs, small RNA sequencing identified miR-375-3p as uniquely dysregulated in AD brains with concurrent infection. Functional enrichment of validated miR-375-3p targets revealed associations with vascular regulation, and antiviral response pathways, suggesting a role in maintaining blood–brain barrier integrity under inflammatory stress. Integration of miRNA co-expression modules with transcriptomic data further highlighted convergent dysregulation of vascular and glial networks, reinforcing the notion that systemic infection exacerbates AD pathology through coordinated disruption of neurovascular and immune homeostasis. Finally, Genedex, an ontology-driven Shiny platform, was developed to integrate and compare gene signatures across AD facets, including neuroinflammation, synaptic dysfunction, and resilience. Analysis of the transcriptomic signatures within Genedex revealed that systemic infection may disrupt astrocyte-mediated resilience and amplify neuronal susceptibility in AD. These results highlight the complex role of systemic infection in AD, which appears to potentiate glial and vascular pathogenic programmes while diminishing neuronal protective mechanisms Together, these studies demonstrate how systemic inflammation reconfigures molecular networks in AD, highlight miR-375-3p as a putative mediator of infection-related dysfunction, and establish a framework for contextualising infection-driven molecular signatures within the AD continuum.<p></p>

Author dc:creator

• Giulia Pegoraro (21042221)

• Alzheimer's Disease
• Blood-brain barrier
• Neurovascular dysfunction
• Systemic infection
• Transcriptomics

Statement dc:rights

• All rights reserved
• Open Access after 2027-09-23

Identifier

10779/exe.31843645.v1

OAI identifier oai:identifier

oai:figshare.com:article/31843645