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Background
Hyperactivity of the classical axis of the
renin-angiotensin system (RAS), mediated by angiotensin II (Ang II)
activation of the angiotensin II type 1 receptor (AT1R), is implicated in the
pathogenesis of Alzheimer’s disease (AD). Angiotensin-converting enzyme-2
(ACE-2) degrades Ang II to angiotensin 1–7 (Ang (1-7)) and
counter-regulates the classical axis of RAS. We have investigated the
expression and distribution of ACE-2 in post-mortem human brain tissue in
relation to AD pathology and classical RAS axis activity.
Methods
We measured ACE-2 activity by fluorogenic peptide
substrate assay in mid-frontal cortex (Brodmann area 9) in a cohort of AD
(n = 90) and age-matched non-demented controls (n = 59) for which we have
previous data on ACE-1 activity, amyloid β (Aβ) level and tau pathology, as
well as known ACE1 (rs1799752) indel polymorphism,
apolipoprotein E (APOE) genotype, and cerebral amyloid angiopathy severity
scores.
Results
ACE-2 activity was significantly reduced in AD
compared with age-matched controls (P < 0.0001) and correlated inversely
with levels of Aβ (r = −0.267, P < 0.001) and phosphorylated tau
(p-tau) pathology (r = −0.327, P < 0.01). ACE-2 was reduced in
individuals possessing an APOE ε4 allele (P < 0.05) and was
associated with ACE1 indel polymorphism (P < 0.05), with lower
ACE-2 activity in individuals homozygous for the ACE1 insertion AD
risk allele. ACE-2 activity correlated inversely with ACE-1 activity
(r = −0.453, P < 0.0001), and the ratio of ACE-1 to ACE-2 was significantly
elevated in AD (P < 0.0001). Finally, we show that the ratio of Ang II to
Ang (1–7) (a proxy measure of ACE-2 activity indicating conversion
of Ang II to Ang (1–7)) is reduced in AD.
Conclusions
Together, our findings indicate that ACE-2 activity
is reduced in AD and is an important regulator of the central classical
ACE-1/Ang II/AT1R axis of RAS, and also that dysregulation of this pathway
likely plays a significant role in the pathogenesis of AD.
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موجز عن البحث:
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Angiotensin II converting enzyme-1 (ACE1) now has a
recognised role in the pathogenesis of Alzheimer’s disease (AD). ACE1
converts angiotensin-I (Ang-I) to angiotensin-II (Ang-II) and is the
rate-limiting enzyme of the classical RAS axis that is commonly known for
regulating blood pressure. ACE1 is overactive within the brain in AD and is
associated with cognitive decline and disease pathology [16] via
overproduction of Ang-II (a potent vasoconstrictor) and its downstream
effects mediated by angiotensin-II type 1 receptor (AT1R) sig- nalling. The
angiotensin hypothesis of AD describes how Ang-II signalling contributes both
directly and indirectly to the development of disease pathology in AD [9],
which is supported by clinical observational and pharmaco-epidemiological
studies indicating that com- monly prescribed ACE1 inhibitors (ACE1 Is), used
to treat hypertension, lower the incidence and rate of cog- nitive decline in
AD [2, 10, 15] and are associated with reduced Aβ and Tau pathology [5, 6].
Yet, the role of ACE1 in AD is complicated by seemingly paradoxical
associations whereby polymorphisms in ACE1, associ- ated with lower levels of
enzyme production (akin to a net result of ACEIs), are risk factors for AD
[4, 12, 14]. This divergent role of ACE1 may be partly explained by studies
in cell and mouse models of AD showing that ACE1 has both endopeptidase and
carboxypeptidase activity and is capable of degrading Aβ in vitro [7, 8, 18,
19] and in vivo [21] although not all studies are support- ive [3]. These
dual properties of ACE1 seem somewhat contradictory and make understanding
the role of ACE1 in AD challenging, particularly as ACE1 activity in brain
tissue in AD correlated with, rather than inversely corre- lated with,
measures of Aβ pathology [16].
We studied brain tissue from 72 AD and 48 controls
obtained from South West Dementia brain bank tissue bank, University of
Bristol, UK with ethics committee approval. Cohorts were approximately
matched for age-at-death (AD Mean = 78.04, SD = 10.41; controls Mean = 79.42,
SD = 9.89), post-mortem delay (PM) (AD Mean = 45.86, SD = 25.8; controls Mean
= 48.25, SD = 37.96) and gender (AD = 27 M: 45 F; controls = 29 M: 19 F). AD
cases were diagnosed according to international neuropathological guidelines
[17]. Controls were cogni- tively normal and had few or absent
neurofibrillary tan- gles, a Braak stage less than 3, and no other
neuropathological abnormalities. ACE1 C-domain and N-domain activity was
measured by immunocapture -based FRET assays. Our findings show that ACE1
catalytic domain activity is significantly altered in AD. ACE1 C-domain
activity, largely responsible for Ang-II production is significantly
increased in AD by ~ 25%, whereas N-domain activity, likely contributing to
Aβ cleavage and clearance, is reduced by ~ 50% in AD.
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ملخص المشاركة:
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Background:
The classical brain RAS axis (ACE-1/Ang-II/AT1R) exerts damaging effects in
the brain in both animal and human studies. Hyperactivity of this axis contributes
to the pathogenesis of Alzheimer’s disease (AD). Alternative RAS pathways
((ACE-2/Ang(1-7)/MasR) and (APN/Ang-IV/IRAP)) have recently been discovered
that counter-regulate the damaging effects of classical RAS signalling whilst
are also implicated in boosting learning and memory. However, the involvement
of these alternative RAS pathways in relation to AD pathogenesis remains
unclear. We have measured brain angiotensins and their receptors involved in
the alternative RAS signalling in relation to AD in a well-characterised
cohort of post-mortem brains.
Methods:
Human post-mortem brain tissue was obtained from the South West Dementia
Brain Bank, University of Bristol, with local Research Ethics Committee
approval. The AD cases (n=72) and the age-matched controls (n=48) were
matched closely for age-at-death and post-mortem delay. The levels of
Ang(1-7) and Ang-IV were measured in the mid-frontal cortex (Brodmann area
8/9) by ELISA. The expression and distribution of MasR, and insulin-regulated
aminopeptidase (IRAP) (Ang-IV receptor), were determined by ELISA and
immunohistochemistry. Pre-existing data on Ang-II level, and amyloid (Aβ)
level (by ELISA) and Tau load (field fraction analysis), Braak staging
information was also available for analyses.
Results:
MasR level was significantly reduced in AD however Ang-(1-7) remained
unchanged. Also, Ang-IV level was also reduced in AD with no changes in IRAP
level in AD group.
Conclusions:
Our recent studies show that dysregulation of alternative brain regulatory
RAS components, that are modifiable pharmacologically, are associated with
the pathogenesis of AD.
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ملخص المشاركة:
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Background: The classical brain RAS axis
(ACE-1/Ang-II/AT1R) exerts damaging effects in the brain in both animal and
human studies. Hyperactivity of this axis contributes to the pathogenesis of
Alzheimer’s disease (AD)1. Alternative RAS pathways
((ACE-2/Ang(1-7)/MasR) and (APN/Ang-IV/IRAP)) have recently been discovered
that counter-regulate the damaging effects of classical RAS signalling whilst
are also implicated in boosting learning and memory2,3. However,
the involvement of these alternative RAS pathways in relation to AD pathogenesis
remains unclear. We previously showed that ACE-2 activity was reduced in AD
in association with disease pathology4. In this study, we have
measured brain angiotensins and their receptors involved in the alternative
RAS signalling in relation to AD and vascular markers in a well-characterised
cohort of post-mortem brains.
Methods: Human post-mortem brain tissue was obtained from
the South West Dementia Brain Bank, University of Bristol, with local
Research Ethics Committee approval. The AD cases (n=72) and the age-matched
controls (n=48) were matched closely for age-at-death and post-mortem delay. The
levels of Ang(1-7) and Ang-IV were measured in the mid-frontal cortex
(Brodmann area 8/9) by ELISA. The expression and distribution of MasR, and insulin-regulated aminopeptidase (IRAP)
(Ang-IV receptor) were determined by ELISA and immunohistochemistry. The
activity of IRAP was measured by catalytic activity assay. Pre-existing data
on Braak staging information, ischemic markers (VEGF level and MAG:PLP ratio)
was also available for analysis.
Results: Mas
receptor level was significantly reduced in AD but Ang(1-7) remained
unchanged. Ang-IV level was also reduced in AD with no changes in IRAP level
and activity in the AD group. MasR and Ang(1-7) level, and AngIV and IRAP level, were all inversely correlated
with VEGF level.
Conclusions: Our
studies show dysregulation of alternative brain regulatory RAS pathways in AD
are associated with vascular dysfunction, indicated by a strong association
with VEGF and MAG:PLP.
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