• angiotensin II;
  • angiotensin II type 2 receptor;
  • cerebral blood flow;
  • cerebrospinal fluid;
  • cognitive impairment;
  • stroke

Here, we briefly review the role of the renin–angiotensin system (RAS) in cognitive impairment and neurodegenerative disease, mainly discussing our experimental studies on the angiotensin II type 2 (AT2) receptor. Ischemic brain damage is enhanced in mice with overexpression of angiotensin II, with reduced cerebral blood flow in the penumbra and an increase in oxidative stress in the ischemic area. Angiotensin II binds two types of receptors, type 1 (AT1) and type 2 (AT2). Our previous experiments showed that AT1 receptor signaling has a harmful effect, and AT2 receptor signaling has a protective effect on the brain after stroke. AT2 receptor signaling in bone marrow stromal cells or hematopoietic cells was shown to prevent ischemic brain damage after middle cerebral artery occlusion. In contrast, AT2 receptor signaling also affects cognitive function. We showed that direct stimulation of the AT2 receptor by a newly generated direct AT2 receptor agonist, Compound 21 (C21), enhanced cognitive function in wild-type (C57BL6) mice and an Alzheimer's disease mouse model with intracerebroventricular injection of amyloid β (1–40). Finally, we carried out clinical research by investigating the levels of RAS components in patients with neurodegenerative diseases. We observed a reduction of angiotensin II and angiotensin converting enzyme (ACE) 2 levels, and an increase in ACE level in cerebrospinal fluid from patients with multiple sclerosis. These results suggest that RAS is also involved in neurodegenerative disease. Therefore, regulation of RAS might be a new therapeutic target to protect neurons from neural diseases. Geriatr Gerontol Int 2012; ••: ••–••.