Angiotensin II, hypertension and angiotensin II receptor antagonism: Roles in the behavioural and brain pathology of a mouse model of Alzheimer's disease.
Elevated angiotensin II causes hypertension and contributes to Alzheimer's disease by affecting cerebral blood flow. Angiotensin II receptor blockers may provide candidates to reduce (vascular) risk factors for Alzheimer's disease. We studied effects of two months of angiotensin II-induced hypertension on systolic blood pressure, and treatment with the angiotensin II receptor blockers, eprosartan mesylate, after one month of induced hypertension in wild-type C57bl/6j and AβPPswe/PS1ΔE9 (AβPP/PS1/Alzheimer's disease) mice. AβPP/PS1 showed higher systolic blood pressure than wild-type. Subsequent eprosartan mesylate treatment restored this elevated systolic blood pressure in all mice. Functional connectivity was decreased in angiotensin II-infused Alzheimer's disease and wild-type mice, and only 12 months of Alzheimer's disease mice showed impaired cerebral blood flow. Only angiotensin II-infused Alzheimer's disease mice exhibited decreased spatial learning in the Morris water maze. Altogether, angiotensin II-induced hypertension not only exacerbated Alzheimer's disease-like pathological changes such as impairment of cerebral blood flow, functional connectivity, and cognition only in Alzheimer's disease model mice, but it also induced decreased functional connectivity in wild-type mice. However, we could not detect hypertension-induced overexpression of Aβ nor increased neuroinflammation. Our findings suggest a link between midlife hypertension, decreased cerebral hemodynamics and connectivity in an Alzheimer's disease mouse model. Eprosartan mesylate treatment restored and beneficially affected cerebral blood flow and connectivity. This model could be used to investigate prevention/treatment strategies in early Alzheimer's disease.
1 Department of Anatomy, Radboud Alzheimer Center, Donders Institute for Brain, Cognition & Behaviour, Radboud university medical center, Nijmegen, The Netherlands.|2 Department of Geriatric Medicine, Radboud Alzheimer Center, Donders Institute for Brain, Cognition & Behaviour, Radboud university medical center, Nijmegen, The Netherlands.
Maximilian
M
Wiesmann
1 Department of Anatomy, Radboud Alzheimer Center, Donders Institute for Brain, Cognition & Behaviour, Radboud university medical center, Nijmegen, The Netherlands.
Monica
M
Roelofs
1 Department of Anatomy, Radboud Alzheimer Center, Donders Institute for Brain, Cognition & Behaviour, Radboud university medical center, Nijmegen, The Netherlands.
Robert
R
van der Lugt
3 Department of Radiology & Nuclear Medicine, Radboud university medical center, Nijmegen, The Netherlands.
Arend
A
Heerschap
1 Department of Anatomy, Radboud Alzheimer Center, Donders Institute for Brain, Cognition & Behaviour, Radboud university medical center, Nijmegen, The Netherlands.
Amanda J
AJ
Kiliaan
2 Department of Geriatric Medicine, Radboud Alzheimer Center, Donders Institute for Brain, Cognition & Behaviour, Radboud university medical center, Nijmegen, The Netherlands.
Jurgen Ahr
JA
Claassen
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics; D000804:Angiotensin II / Q000008:administration & dosage*; D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018782:Maze Learning / Q000187:drug effects; D008822:Mice, Transgenic; D065853:Spatial Learning / Q000187:drug effects; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D016229:Amyloid beta-Peptides; D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D013876:Thiophenes; D000804:Angiotensin II; C401803:eprosartan mesylate dihydrate
Alzheimer’s; brain imaging; cerebral blood flow; cognitive impairment; hypertension