A Role for the Brain RAS in Alzheimer’s and Parkinson’s Diseases

Abstract

The brain renin-angiotensin system (RAS) has available the necessary functional components to produce the active ligands angiotensins II (AngII), angiotensin III, angiotensins (IV), angiotensin (1–7), and angiotensin (3–7). These ligands interact with several receptor proteins including AT1, AT2, AT4, and Mas distributed within the central and peripheral nervous systems as well as local RASs in several organs. This review first describes the enzymatic pathways in place to synthesize these ligands and the binding characteristics of these angiotensin receptor subtypes. We next discuss current hypotheses to explain the disorders of Alzheimer’s disease (AD) and Parkinson’s disease (PD), as well as research efforts focused on the use of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), in their treatment. ACE inhibitors and ARBs are showing promise in the treatment of several neurodegenerative pathologies; however, there is a need for the development of analogs capable of penetrating the blood-brain barrier and acting as agonists or antagonists at these receptor sites. AngII and AngIV have been shown to play opposing roles regarding memory acquisition and consolidation in animal models. We discuss the development of efficacious AngIV analogs in the treatment of animal models of AD and PD. These AngIV analogs act via the AT4 receptor subtype which may coincide with the hepatocyte growth factor/c-Met receptor system. Finally, future research directions are described concerning new approaches to the treatment of these two neurological diseases.

Potential of protease inhibitor in 3-nitropropionic acid induced Huntington's disease like symptoms: Mitochondrial dysfunction and neurodegeneration

“…Changes in AT1 receptor levels have been observed in Huntington's disease in which AT1 receptor levels are decreased by approximately 30% in the putamen (Lopez-Real et al, 2005). The use of ACE inhibitors and AT1 and/or AT2 receptor blockers have shown preliminary experimental promise in the treatment of stress, depression, alcohol consumption, seizure, AD and PD (Wright et al, 2013). Trandolapril is a centrally acting ACE inhibitor.…”

Intracerebroventricular Infusion of Angiotensin-(1–7) Ameliorates Cognitive Impairment and Memory Dysfunction in a Mouse Model of Alzheimer’s Disease

“…involved in the pathophysiology of Alzheimer's disease (AD) and dementia [1][2][3]. Interestingly, treatment with RAS blockers of hypertensive patients is associated with slowing of cognitive impairment and AD progression [1,[4][5][6][7][8].…”

“…Apart from the classical RAS, evolving concept of the RAS is that there exits protective arms of the RAS which exert protective effects against brain disease [3,[9][10][11]. Angiotensin-(1-7) is regarded as the major bioactive peptide of protective arms of the RAS [3,[9][10][11].…”

Angiotensin-III is Increased in Alzheimer’s Disease in Association with Amyloid-β and Tau Pathology

“…Emerging data has identified a number of regulatory pathways within brain RAS that are involved in the metabolism of Ang-II and counter-regulate the activity of the 'classical' RAS axis (reviewed in [4]). ACE-2 converts Ang-II to Ang 1-7, which via the MAS receptor counter-regulates the actions of the classical axis, known as the ACE2/Ang(1-7)/MASR pathway (reviewed in [42,43]).…”

“…It is now well established that there is a local-acting renin-angiotensin-system (RAS) within the brain that functions independently from the systemic RAS [1][2][3][4] and that hyperactivity of brain RAS is associated with the pathogenesis of Alzheimer's disease (AD) [5]. Most of the deleterious effects of the brain RAS in AD are believed to be associated with elevated Ang-II levels and its subsequent over-activation of angiotensin receptor type-1 (AT1R), commonly referred to as the classical axis of RAS (reviewed in [5]).…”