Alzheimer Hastalığı’nın Beyin Anjiyotensin Reseptörleri ile İlişkisi ve Anjiyotensin Reseptör Blokörlerinin Bu İlişkiye Etkisi

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease, that is characterized by a decline in cognitive function, and whose etiology is not yet fully understood. Recently, it has been shown that the incidence of AD is lower in individuals with a history of Angiotensin Receptor Blockers (ARBs) use. However, the mechanistic relationship between the brain renin-angiotensin system (RAS) and AD remains unknown. The brain RAS mainly acts through three receptor subtypes: AT1R, AT2R, and AT4R. AT1R promotes inflammation and oxidative stress. AT2R increases nitric oxide. AT4R is essential for dopamine and acetylcholine release and mediates memory consolidation. The first part of this thesis aims to dissect the brain RAS differences associated with AD and assess how brain RAS levels correlate with brain oxidative stress, and inflammation, as well as amyloid-beta and tangle pathologies. The second part of the thesis aims to analyze the effects of ARBs on brain RAS, oxidative stress, inflammation, as well as amyloid-beta and tangle pathologies in postmortem frontal-cortex brain samples of cognitively intact and AD individuals. To this end, gene and protein expressions of brain RAS receptors, protein carbonyl levels as a marker of oxidative stress, and levels of inflammatory markers such as IL-6, TNF-α, IFN-γ, and IL-1β were measured. Our results showed higher protein levels of the AT1R in the brains of AD participants. Brain AT1R levels were correlated with higher oxidative stress and amyloid-beta scores. ARB use was associated with higher protein levels of AT4R and lower oxidative stress and amyloid-beta scores in cognitively normal participants. No significant changes were observed in oxidative stress, inflammation, or tangle and amyloid-beta load in AD brains treated with ARBs. This study offers insight into the role of brain RAS in AD-related brain pathology and suggests a possible role for AT4R in ARBs-mediated protective effects in cognitively intact individuals.