Angiotensin II-inhibiting drugs have no effect on intraneuronal aβ or oligomeric aβ levels in a triple transgenic mouse model of alzheimer's disease

Linda Ferrington, J. Scott Miners, Laura E. Palmer, Susan M. Bond, Joanne E. Povey, Paul A T Kelly, Seth Love, Karen J. Horsburgh, Patrick G. Kehoe

Research output: Contribution to journalArticle (Academic Journal)peer-review

30 Citations (Scopus)

Abstract

Background: Reducing the excessive accumulation of amyloid β-protein (Aβ) in Alzheimer's disease (AD) is a key objective of most AD therapies. Several studies suggest that pharmacological inhibition of angiotensin-converting enzyme (ACE) or its by-product angiotensin II may delay onset or progression of dementia and it has been suggested that this occurs via regulation of Aβ. Intraneuronal oligomeric accumulation of Aβ is postulated to be one of the earliest pathological events. Thus this study investigated the effect of an ACE-inhibitor, captopril, and two angiotensin II receptor blockers (ARBs), eprosartan and valsartan, on intraneuronal Aβ pathology and oligomeric Aβ levels in a triple transgenic (3×TGAD) mouse model of AD. Methods: Male, adult (3-4 month old) 3×TgAD mice (n=39) were randomly assigned to 4 treatment groups: valsartan (0.17g/l), eprosartan (0.8g/l), captopril (5g/l) or normal drinking water and the drugs given ad libitum for 2 months. Mean arterial blood pressure (MABP) was measured at baseline, at 2 weeks and at 2 months when the mice were sacrificed and the brains hemisected for analysis. One hemisphere was processed for Aβ and amyloid precursor protein (APP) immunohistochemistry and the other for biochemical measurement of oligomeric Aβ and APP. ACE activity was measured in the brain and kidney. Results: MABP was significantly reduced at 2 weeks and 2 months in the ACE-I group (p=0.0006) but was unaltered in the ARB groups compared to vehicle. Neither ACE-I nor ARB treatment altered Aβ and APP immunolabelling or the level of Aβ or APP in brain tissue homogenates. Similarly neither ACE-I nor ARB treatment altered ACE activity in either brain or kidney compared to control tissue. Conclusions: ACE-I or ARB administration over 2 months did not affect APP levels or either intraneuronal Aβ or oligomeric Aβ levels in 3×TGAD mice. While ARBs did not alter MABP, captopril did mediate reductions in MABP in the 3×TGAD mice which appeared to be independent of ACE activity. Further studies are needed to examine the effects of these drugs over a longer term and in older mice (i.e. when AD-like changes are more pronounced).

Translated title of the contributionAngiotensin II-inhibiting drugs have no effect on intraneuronal Aβ or oligomeric Aβ levels in a triple transgenic mouse model of Alzheimer's disease
Original languageEnglish
Pages (from-to)197-208
Number of pages12
JournalAmerican Journal of Translational Research
Volume3
Issue number2
Publication statusPublished - 28 Mar 2011

Keywords

  • Alzheimer's disease
  • Amyloid-beta (Aβ)
  • Angiotensin converting enzyme inhibitor
  • Angiotensin-II receptor blocker
  • Triple transgenic mouse model

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