Unraveling the role of brain renin angiotensin system in vascular dementia: mechanisms and therapeutic perspectives.

Abstract

Dementia is a heterogeneous syndrome characterized by the progressive deterioration of various brain functions, severely impacting cognitive, emotional, and social abilities. According to a World Health Organization (WHO) report, dementia represents a pressing global health concern, with the number of affected individuals projected to triple by 2050. Among its various subtypes, vascular dementia (VD) stands as the second most common form, following Alzheimer's disease (AD). Despite ongoing efforts in drug development, no pharmaceutical entity has yet received approval from the U.S. Food and Drug Administration (FDA) for the treatment of VD. Emerging evidence underscores the critical involvement of the brain's Renin-Angiotensin System (RAS) in the pathogenesis of multiple neurodegenerative disorders, including VD. The intricate roles of RAS components include regulating vascular tone, neuronal growth and survival, regulating cerebral blood flow and endothelial dysfunction, increasing neuroinflammation (by increasing release of IL-1, IL-6, TNF-α, microglial activation), oxidative stress and destruction of BBB integrity, mainly through Angiotensin II type 1 (AT1) and type 2 (AT2) receptors, are of significant interest in the pathophysiology of VD. However, disruptions in these signaling pathways are believed to contribute substantially to the progression of VD. This review addresses the limitations of current therapeutic approaches for VD while emphasizing the untapped potential of RAS-targeted interventions. We systematically explore the neurophysiological mechanisms of brain RAS, their role in promoting neuronal health, and the factors that compromise these pathways, ultimately leading to cognitive decline. By elucidating these mechanisms and challenges, the review offers novel insights into designing innovative RAS-based therapeutic strategies, paving the way for effective clinical management of VD. This work aspires to stimulate further research and development in this underexplored yet promising domain.