The brain angiotensin IV/AT₄ receptor system as a new target for the treatment of Alzheimer's disease

The brain renin‐angiotensin system (RAS) regulates several physiologies including blood pressure, body sodium and water balance, cyclicity of reproductive hormones and related sexual behaviors, and the release of pituitary gland hormones. These physiologies are under the control of the angiotensin II (AngII)/AT 1 receptor subtype system. The AngII/AT 2 receptor subtype system is expressed during fetal development and is less abundant in the adult. This system appears to oppose growth responses facilitated by activation of the AT 1 receptor. There is a growing list of nontraditional physiologies mediated by the most recently discovered angiotensin IV (AngIV)/AT 4 receptor subtype system that include the regulation of blood flow, modulation of exploratory behaviors, involvement in stress responses and seizure, and a role in learning and memory acquisition. There is evidence to support an inhibitory influence by AngII, and a facilitory role by AngIV, on neuronal firing rate, long‐term potentiation, and associative and spatial learning and memory. These findings suggest an important role for the RAS, and the AT 4 receptor in particular, in normal cognitive processing and provide the stimulus for developing drugs that penetrate the blood‐brain barrier to interact with this brain receptor in the treatment of dysfunctional memory. Drug Dev Res 70: 472–480, 2009.