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Am J Translational Res 2011;3(2):197-208
Original Article
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 AT Kelly,
Seth Love, Karen J. Horsburgh, Patrick G. Kehoe
Cerebral Pharmacology Laboratory, Centre for Cognitive and Neural Systems, University of Edinburgh, George
Square, Edinburgh, EH8 9JZ, UK; Dementia Research Group, John James Laboratories, University of Bristol,
Frenchay Hospital, Bristol, BS16 1LE, UK; Department of Neuropathology, Institute of Clinical Neurosciences,
University of Bristol, Frenchay Hospital, Bristol, BS16 1LE, UK; Centre for Cognitive Aging and Cognitive
Epidemiology, Centre for Cognitive and Neural Systems, University of Edinburgh, 1 George Square, Edinburgh
EH8 9JZ, UK; Dept of Anatomy & Structural Biology, University of Otago, Dunedin, New Zealand.
Received January 26, 2011; Accepted February 4, 2011; Epub February 5, 2011; Published February 15, 2011
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 A levels in a triple transgenic (3xTGAD) mouse model of AD. Methods: Male, adult (3-
4month old) 3xTgAD 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 2months. 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 2months 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
3xTGAD mice. While ARBs did not alter MABP, captopril did mediate reductions in MABP in the 3xTGAD 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). (AJTR1101003).
Keywords: Angiotensin converting enzyme inhibitor, angiotensin-II receptor blocker, triple transgenic mouse
model, Alzheimer’s disease, amyloid-beta (Aβ)
Full Text PDF
Address all correspondence to:
Dr. Patrick G Kehoe,
Dementia Research Group, The John James Building,
Frenchay Day Hospital, Frenchay Hospital, Bristol,
BS16 1LE, UK
Tel: 0117 340 6607, Fax: 0117 340 3070
E-mail: Patrick.Kehoe@bristol.ac.uk
Original Article
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 AT Kelly,
Seth Love, Karen J. Horsburgh, Patrick G. Kehoe
Cerebral Pharmacology Laboratory, Centre for Cognitive and Neural Systems, University of Edinburgh, George
Square, Edinburgh, EH8 9JZ, UK; Dementia Research Group, John James Laboratories, University of Bristol,
Frenchay Hospital, Bristol, BS16 1LE, UK; Department of Neuropathology, Institute of Clinical Neurosciences,
University of Bristol, Frenchay Hospital, Bristol, BS16 1LE, UK; Centre for Cognitive Aging and Cognitive
Epidemiology, Centre for Cognitive and Neural Systems, University of Edinburgh, 1 George Square, Edinburgh
EH8 9JZ, UK; Dept of Anatomy & Structural Biology, University of Otago, Dunedin, New Zealand.
Received January 26, 2011; Accepted February 4, 2011; Epub February 5, 2011; Published February 15, 2011
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 A levels in a triple transgenic (3xTGAD) mouse model of AD. Methods: Male, adult (3-
4month old) 3xTgAD 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 2months. 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 2months 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
3xTGAD mice. While ARBs did not alter MABP, captopril did mediate reductions in MABP in the 3xTGAD 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). (AJTR1101003).
Keywords: Angiotensin converting enzyme inhibitor, angiotensin-II receptor blocker, triple transgenic mouse
model, Alzheimer’s disease, amyloid-beta (Aβ)
Full Text PDF
Address all correspondence to:
Dr. Patrick G Kehoe,
Dementia Research Group, The John James Building,
Frenchay Day Hospital, Frenchay Hospital, Bristol,
BS16 1LE, UK
Tel: 0117 340 6607, Fax: 0117 340 3070
E-mail: Patrick.Kehoe@bristol.ac.uk
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