Neuropathological Networks of Alzheimer’s disease: Blood-brain barrier dysfunction and neuroinflammation unveiled

Alzheimer’s disease (AD) characterized by amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) is increasingly recognized to involve significant contributions from cerebrovascular dysfunction and neuroinflammation. This thesis investigated the roles of blood-brain barrier (BBB) dysfunction and neuroinflammation in AD pathophysiology. We demonstrated that modeling age-related DNA damage through reduced ERCC1 expression in vitro and in vivo induced significant BBB dysfunction, mirroring changes observed in aging and AD, suggesting a potential contribution of age-related BBB breakdown to AD pathogenesis. Furthermore, we identified a novel mechanism by which liver X receptor alpha (LXRα) maintains BBB integrity via inhibition of snail family transcriptional repressor 2; this pathway was disrupted in AD and influenced by hypoxia, indicating a link between LXRα dysfunction and BBB breakdown in the disease. Analysis of lipid mediator profiles in AD brains revealed distinct inflammatory profiles across brain regions: the occipital cortex exhibited elevated COX-related mediators, associated with neuronal activity, while the temporal cortex showed increased LOX-related mediators, linked to microglial activation around amyloid plaques, highlighting the 5-LOX/FLAP pathway as a potential therapeutic target. Initial evidence also suggested a disrupted lipid mediator profile in the occipital cortex of subjects with capillary cerebral amyloid angiopathy. In summary, this thesis underscores the complex, multifactorial nature of AD, emphasizing the critical involvement of cerebrovascular dysfunction and neuroinflammation alongside classical hallmarks, and necessitates further research into their mechanisms for the development of effective treatments.