This work was performed to test our hypothesis that angiotensin-(1–7) can ameliorate cognitive impairment and cerebrovascular reactivity in 5XFAD mice, a useful model of Alzheimer’s disease. 5XFAD mice received intracerebroventricular infusion of (1) vehicle, (2) angiotensin-(1–7), or (3) angiotensin-(1–7)+A779, a specific Mas receptor antagonist, for 4 weeks. Angiotensin-(1–7), through Mas receptor, significantly ameliorated cognitive impairment in 5XFAD mice. As estimated by acetazolamide-induced increase in cerebral blood flow, angiotensin-(1–7), through Mas receptor, enhanced cerebrovascular reactivity in 5XFAD mice. In conclusion, angiotensin-(1–7)/Mas receptor axis improves cognitive function and cerebrovascular function in a mouse model of Alzheimer’s disease.
KehoePG, WilcockGK (2007) Is inhibition of the renin-angiotensin system a new treatment option for Alzheimer’s disease?Lancet Neurol6, 373–378.
2.
WrightJW, HardingJW (2010) The brain RAS and Alzheimer’s disease. Exp Neurol223, 326–333.
3.
WrightJW, KawasLH, HardingJW (2013) A role for the brain RAS in Alzheimer’s and Parkinson’s diseases. Front Endocrinol (Lausanne)4, 158.
4.
DaviesNM, KehoePG, Ben-ShlomoY, MartinRM (2011) Associations of anti-hypertensive treatments with Alzheimer’s disease, vascular dementia, and other dementias. J Alzheimers Dis26, 699–708.
5.
LiNC, LeeA, WhitmerRA, KivipeltoM, LawlerE, KazisLE, WolozinB (2010) Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: Prospective cohort analysis. BMJ340, b5465.
6.
OhruiT, TomitaN, Sato-NakagawaT, MatsuiT, MaruyamaM, NiwaK, AraiH, SasakiH (2004) Effects of brain-penetrating ACE inhibitors on Alzheimer disease progression. Neurology63, 1324–1325.
7.
SinkKM, LengX, WilliamsonJ, KritchevskySB, YaffeK, KullerL, YasarS, AtkinsonH, RobbinsM, PsatyB, GoffDCJr (2009) Angiotensin-converting enzyme inhibitors and cognitive decline in older adults with hypertension: Results from the Cardiovascular Health Study. Arch Intern Med169, 1195–1202.
8.
TzourioC, AndersonC, ChapmanN, WoodwardM, NealB, MacMahonS, ChalmersJ (2003) Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med163, 1069–1075.
9.
MeccaAP, RegenhardtRW, O’ConnorTE, JosephJP, RaizadaMK, KatovichMJ, SumnersC (2011) Cerebroprotection by angiotensin-(1-7) in endothelin-1-induced ischaemic stroke. Exp Physiol96, 1084–1096.
10.
SantosRA, FerreiraAJ, Verano-BragaT, BaderM (2013) Angiotensin-converting enzyme 2, angiotensin-(1-7) and Mas: New players of the renin-angiotensin system. J Endocrinol216, R1–R17.
11.
XuP, SriramulaS, LazartiguesE (2011) ACE2/ANG-(1-7)/Mas pathway in the brain: The axis of good. Am J Physiol Regul Integr Comp Physiol300, R804–817.
12.
OakleyH, ColeSL, LoganS, MausE, ShaoP, CraftJ, Guillozet-BongaartsA, OhnoM, DisterhoftJ, Van EldikL, BerryR, VassarR (2006) Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: Potential factors in amyloid plaque formation. J Neurosci26, 10129–10140.
13.
SantosRA, Campagnole-SantosMJ, BarachoNC, FontesMA, SilvaLC, NevesLA, OliveiraDR, CaligiorneSM, RodriguesAR, GropenCJr, CarvalhoWS, Simoes E SilvaAC, KhoslaMC (1994) Characterization of a new angiotensin antagonist selective for angiotensin-(1-7): Evidence that the actions of angiotensin-(1-7) are mediated by specific angiotensin receptors. Brain Res Bull35, 293–298.
14.
LuJ, ZhangY, ShiJ (2008) Effects of intracerebroventricular infusion of angiotensin-(1-7) on bradykinin formation and the kinin receptor expression after focal cerebral ischemia-reperfusion in rats. Brain Res1219, 127–135.
15.
ZhangY, LuJ, ShiJ, LinX, DongJ, ZhangS, LiuY, TongQ (2008) Central administration of angiotensin-(1-7) stimulates nitric oxide release and upregulates the endothelial nitric oxide synthase expression following focal cerebral ischemia/reperfusion in rats. Neuropeptides42, 593–600.
16.
DeVosSL, MillerTM (2013) Direct intraventricular delivery of drugs to the rodent central nervous system. J Vis Expe50326.
17.
ToyamaK, KoibuchiN, UekawaK, HasegawaY, KataokaK, KatayamaT, SuetaD, MaMJ, NakagawaT, YasudaO, TomimotoH, IchijoH, OgawaH, Kim-MitsuyamaS (2014) Apoptosis signal-regulating kinase 1 is a novel target molecule for cognitive impairment induced by chronic cerebral hypoperfusion. Arterioscler Thromb Vasc Biol34, 616–625.
18.
HechtN, HeJ, KremenetskaiaI, NieminenM, VajkoczyP, WoitzikJ (2012) Cerebral hemodynamic reserve and vascular remodeling in C57/BL6 mice are influenced by age. Stroke43, 3052–3062.
FreundM, WaltherT, von Bohlen und HalbachO (2012) Immunohistochemical localization of the angiotensin-(1-7) receptor Mas in the murine forebrain. Cell Tissue Res348, 29–35.
21.
JiangT, GaoL, GuoJ, LuJ, WangY, ZhangY (2012) Suppressing inflammation by inhibiting the NF-kappaB pathway contributes to the neuroprotective effect of angiotensin-(1-7) in rats with permanent cerebral ischaemia. Br J Pharmacol167, 1520–1532.
22.
RegenhardtRW, DeslandF, MeccaAP, PioquintoDJ, AfzalA, MoccoJ, SumnersC (2013) Anti-inflammatory effects of angiotensin-(1-7) in ischemic stroke. Neuropharmacology71, 154–163.
23.
KlohsJ, RudinM, ShimshekDR, BeckmannN (2014) Imaging of cerebrovascular pathology in animal models of Alzheimer’s disease. Front Aging Neurosci6, 32.
24.
ZhuD, ShiJ, ZhangY, WangB, LiuW, ChenZ, TongQ (2011) Central angiotensin II stimulation promotes beta amyloid production in Sprague Dawley rats. PLoS One6, e16037.
25.
de la TorreJC (2004) Is Alzheimer’s disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. Lancet Neurol3, 184–190.
26.
IadecolaC (2004) Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci5, 347–360.
RuitenbergA, den HeijerT, BakkerSL, van SwietenJC, KoudstaalPJ, HofmanA, BretelerMM (2005) Cerebral hypoperfusion and clinical onset of dementia: The Rotterdam Study. Ann Neurol57, 789–794.
29.
SilvestriniM, PasqualettiP, BaruffaldiR, BartoliniM, HandoukY, MatteisM, MoffaF, ProvincialiL, VernieriF (2006) Cerebrovascular reactivity and cognitive decline in patients with Alzheimer disease. Stroke37, 1010–1015.
30.
SamurakiM, MatsunariI, YoshitaM, ShimaK, Noguchi-ShinoharaM, HamaguchiT, OnoK, YamadaM (2015) Cerebral amyloid angiopathy-related microbleeds correlate with glucose metabolism and brain volume in Alzheimer’s disease. J Alzheimers Dis48, 517–528.
