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1 Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; 2 Mayo Clinic, Jacksonville, Florida 32224; and 3 McLaughlin Research Institute, Great Falls, Montana 59405
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The amyloid-
(A) peptide, which is derived from the amyloid precursor protein
(APP), is involved in the pathogenesis of Alzheimer's dementia and
impairs endothelium-dependent vasodilation in cerebral vessels. We
investigated whether cerebrovascular autoregulation, i.e., the ability
of the cerebral circulation to maintain flow in the face of changes in
mean arterial pressure (MAP), is impaired in transgenic mice that
overexpress APP and A. Neocortical cerebral blood flow (CBF) was
monitored by laser-Doppler flowmetry in anesthetized APP(+) and APP(
)
mice. MAP was elevated by intravenous infusion of phenylephrine and
reduced by controlled exsanguination. In APP() mice, autoregulation
was preserved. However, in APP(+) mice, autoregulation was markedly
disrupted. The magnitude of the disruption was linearly related to
brain A concentration. The failure of autoregulation was paralleled
by impairment of the CBF response to endothelium-dependent
vasodilators. Thus A disrupts a critical homeostatic mechanism of
the cerebral circulation and renders CBF highly dependent on MAP. The
resulting alterations in cerebral perfusion may play a role in the
brain dysfunction and periventricular white-matter changes associated
with Alzheimer's dementia.
Alzheimer's disease; cerebral blood flow; endothelium-dependent vasodilation
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ALZHEIMER'S DISEASE
(AD) is a highly prevalent form of dementia characterized
neuropathologically by amyloid deposition in neuropil (amyloid plaques)
and cerebral blood vessels (amyloid angiopathy) and by alterations in
phosphorylated neurofilament, which is termed neurofibrillary tangles
(see Refs. 33 and 39 for a review). Recent
advances in the molecular pathology of AD have provided evidence that
implicates the amyloid precursor protein (APP), a transmembrane
glycoprotein, in the mechanisms of the disease (33).
Peptides produced by proteolytic processing of APP, the A peptides,
are major constituents of vascular (A1-40) and parenchymal
(A1-42) amyloid (5, 17), whereas mutations in the
APP gene are linked to familial forms of AD (33).
Transgenic mice that overexpress APP exhibit elevated brain levels of
A and develop neuropathological, cognitive, and cerebral metabolic alterations which resemble those of AD (e.g., see Refs. 9, 29). Therefore, a widely held hypothesis concerning the
pathogenesis of AD is that abnormal processing of APP results in
accumulation of A in the brain, which in turn leads to neuronal
dysfunction and neurodegeneration (33).
The mechanisms by which A leads to brain dysfunction have not been
elucidated in full (see Ref. 35 for a review). Although there is evidence that A alters neuronal function (23),
recent data suggests that this peptide can also produce cerebrovascular dysfunction. Thus synthetic A impairs endothelium-dependent
relaxation and enhances vasoconstriction both in vivo and in vitro
(27, 30, 38). Furthermore, elevations of brain A levels
in APP mice are associated with a reduction in resting cerebral blood flow (CBF) and an impairment of selected vasodilatatory responses of
the cerebral circulation (13, 29, 31). The functional implications of these cerebrovascular alterations have not been fully
elucidated, and their impact on the mechanisms regulating the cerebral
circulation remains to be defined.
Cerebrovascular autoregulation is one of the fundamental properties of
the cerebral circulation through which CBF is maintained relatively
constant despite variations in mean arterial pressure (MAP) within a
certain range (7). This property of cerebral blood vessels
acts as a critical homeostatic mechanism that assures stable brain
perfusion during the fluctuations in MAP that occur during normal
activities (14) and in pathological states associated with
hypotension or hypertension (32). Considering that the brain is critically dependent on a stable blood supply, alterations in
autoregulation can have deleterious effects on the structural and
functional integrity of the brain (22). We report here
that mice that overexpress APP have a profound disruption of
cerebrovascular autoregulation that is more pronounced in transgenic
lines with higher levels of brain A. The loss of autoregulation is
paralleled by alterations in endothelium-dependent cerebrovascular
responses. Although the findings unveil a previously unrecognized
effect of APP and A overexpression on cerebrovascular function, they also raise the possibility that failure of autoregulation may contribute to brain dysfunction in diseases such as AD in which brain
A is elevated.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Transgenic Mice
The transgenic lines used in these studies have been described previously (31). All mice were studied at age 2-3 mo. All APP transgenes consist of the human APP695 isoform expressed using the cosTet hamster prion protein (PrP)-derived cosmid (10). Tg6209 is wild-type APP whereas Tg2123 has the "Swedish" K670N, M671L changes; both of these arrays have a 3'-myc epitope tag. The Tg6209 and Tg2123 transgene arrays are expressed on the inbred FVB/N background (10). Tg2576 mice express Swedish mutant APP without a myc tag on a mixed C57BL/6J-SJL/J background (9, 10). Results from Tg2123 male (M) and female (F) mice are presented separately because the transgene array in this line is located on the X chromosome. Owing to random X inactivation, only half of the somatic cells in female mice will express the transgene; therefore, males express approximately twice the amount of APP as females. Amyloid plaques and vascular amyloid are not present in Tg6209, Tg2123F, or Tg2123M mice (10). The line Tg2576 does not exhibit amyloid deposition at the age at which the mice were studied (2-3 mo) (9). For all lines studied, APP(+) mice were compared with corresponding APP() age-matched littermates.
CBF Study by Laser-Doppler Flowmetry
Techniques used for studying CBF in mice by laser-Doppler flowmetry (LDF) were similar to those previously described (13, 30). Mice were anesthetized with urethane (750 mg/kg ip) and chloralose (50 mg/kg ip). The trachea was intubated and mice were artificially ventilated with an oxygen-nitrogen mixture. One femoral artery was cannulated for arterial pressure recording and blood sampling. Rectal temperature was maintained at 37°C using a thermostatically controlled rectal probe connected to a heating lamp. End-tidal CO2 was monitored by a CO2 analyzer (Capstar-100, CWI) (13). A small craniotomy (2 × 2 mm) was performed to expose the whisker-barrel area of the somatosensory cortex, the dura was removed, and the site was superfused with Ringer solution; temperature was 37°C and pH was 7.3-7.4 (30). The LDF probe (tip diameter 0.8 mm, Vasamedic; St. Paul, MN) was mounted on a micromanipulator (Kopf) and positioned 0.5 mm above the pial surface. Zero values for CBF were obtained after the heart was stopped by an overdose of halothane at the end of the experiment.Determination of A
measurement by ELISA has been described in detail
previously (37). At the end of the experiments, the
hemisphere contralateral to the craniotomy was sonicated in formic acid
and centrifuged. The formic acid extract was neutralized and assayed by
ELISA using BAN50 as capture for human transgene-specific A and
detection with BA27 for A1-40 and BC05 for A1-42.
Femtomoles per milliliter were calculated by comparing the sample
absorbance to the absorbance of a standard curve. Values were corrected
with the wet weight of the original homogenate and are finally
expressed as picomoles per gram of wet weight.
Experimental Protocols
Cerebrovascular autoregulation.
Techniques used for studying cerebrovascular autoregulation in
rodents were similar to those previously described (11,
16). Mice were anesthetized and prepared for CBF measurement by
LDF. After stabilization of MAP and blood gases (Table
1), MAP was elevated or decreased in
10-mmHg steps by intravenous infusion of phenylephrine (1-2
µg · kg
1 · min1) or via
controlled exsanguination (100-400 µl of arterial blood), respectively (16). The range of MAP studied was
20-160 mmHg. CBF values were recorded 5 min after MAP was
changed. Lower and upper limits of autoregulation were tested in
separate animals (16) because of potential pathological
effects of changes in MAP above or below the autoregulated range. At
the end of the experiments, brains were removed and frozen in liquid
nitrogen for subsequent measurement of A.
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Endothelium-dependent and -independent responses.
After stabilization of MAP and blood gases (Table 1), ACh (10 µM,
Sigma), bradykinin (BK, 50 µM, Sigma), the calcium ionophore A-23187
(3 µM, Sigma), S-nitroso-N-acetylpenicillamine
(SNAP, 100 or 500 µM, RBI), or the thromboxane analog U-46619 (0.1 or 1 µM, Sigma) were superfused on the cerebral cortex until the evoked
change in CBF reached a steady state (usually 3-5 min). The
concentrations of ACh, BK, and A-23187 were chosen to produce 50% of
maximal responses as determined by dose-response curves (13). In the mouse microcirculation, the CBF response to
ACh is mediated by endothelial nitric oxide (NO), whereas responses to
BK and A-23184 are mediated by cyclooxygenase-1 through reactive oxygen
species (ROS; see Refs. 28, 36). To study the
changes in CBF produced by systemic hypercapnia, CO2 was
introduced in the circuit of the ventilator until arterial
PCO2 (PaCO2) reached 50-60 mmHg (see Table 1). The response to hypercapnia is not dependent on the endothelium, and NO is thought to play a
"permissive" role in the vasodilation (12, 40).
Hypocapnia (PaCO2 = 19-22 mmHg) was produced
by increasing the ventilatory rate of the respirator. At the end of the
experiments, brains were removed and frozen in liquid nitrogen for
subsequent measurement of A.
Data Analysis
Data in text and figures are expressed as means ± SE. Two-group comparisons were analyzed by the two-tailed t-test for independent samples. Multiple comparisons were evaluated by ANOVA and Tukey's test. Probability values <0.05 were considered statistically significant.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Cerebrovascular Autoregulation in APP Transgenics
In these experiments, we studied cerebrovascular autoregulation in four lines of APP transgenic mice that expressed different levels of A in brain. Lowest A levels were observed in the Tg6209 line, and
highest levels were identified in the Tg2576 line (Fig. 1A). In APP() mice, CBF was
independent of MAP in the range of 60-120 mmHg, which indicates
that autoregulation was present (Fig. 2A). No differences in
autoregulation were observed among APP() mice of different
genetic backgrounds (Fig. 2A). In APP(+) mice, however,
the relationships between CBF and MAP were substantially altered (Fig.
2B). There was a progressive reduction in the autoregulated range, which was more marked in transgenic lines with higher levels of
A (Fig. 2B). In Tg2576 mice, the relationship between MAP and CBF was essentially linear, which indicates total dependence of CBF
on MAP and loss of autoregulation (Fig. 2B).
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To quantify the impairment of autoregulation and to correlate it with
brain A levels, we devised an autoregulation dysfunction index
(ADI). For any given transgenic line, ADI is defined as the sum of the
absolute difference between CBF in APP() mice and APP(+) mice at each
level of MAP (Fig. 2). We used the ADI instead of the autoregulation
index (e.g., Ref. 2) to quantify disruption in both the
upper and lower ranges of the curve. ADI was lowest in Tg6209 mice and
highest in Tg2576 mice, which indicates a relationship between A
levels and dysfunction of autoregulation (see Fig. 1B). We
then correlated the ADI with the level of brain A measured
postmortem in each mouse. The relationship between A1-40 or
A1-42 and ADI was linear and highly correlated
(r2 = 0.904 for A1-40;
P < 0.001; Fig. 3).
These findings indicate that the autoregulatory dysfunction in APP mice
is proportional to brain A levels.
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Vasodilatatory and Vasoconstrictor Responses in APP Transgenics
Autoregulation depends on the ability of cerebral resistance vessels to dilate when MAP falls and to constrict when MAP rises (7). To determine whether the dysfunction in autoregulation of APP mice was related to alterations in cerebrovasodilation, we studied cerebrovascular reactivity to endothelial-dependent and -independent vasodilators. The increase in CBF produced by the endothelium-dependent vasodilators ACh, BK, and A-23187 were attenuated in APP mice. The effect was greater in mice with higher levels of brain A (Fig.
4). In contrast, responses to the
endothelium-independent vasodilator SNAP and to hypercapnia did not
differ between APP() and APP(+) mice except in the Tg2576 line, in
which a reduction was observed (Figs. 4D and
5).
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To determine whether the dysfunction of autoregulation was related to
an impairment of vasoconstriction, we studied cerebrovascular reactivity to interventions that reduce CBF. The thromboxane analog U-46619 reduced CBF more in APP(+) mice, and the effect was greater in
transgenic lines with higher A levels (Fig.
6A). On the other hand,
hypocapnia (PaCO2 = 18-22 mmHg) reduced CBF
comparably in APP(+) and APP() mice (Fig. 6B). Therefore,
the reactivity of CBF to vasoconstrictor stimuli is not impaired in APP
mice.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We have demonstrated that mice overexpressing APP exhibit a marked
disruption in cerebrovascular autoregulation. The effect is greatest in
Tg2576 mice in which autoregulation is essentially lost. To determine
whether the mechanisms of the disruption were related to brain A
levels, we devised the ADI, and we correlated this index with brain
A measured in each mouse in which autoregulation was studied. It was
found that there is a linear correlation between ADI and brain
A1-40 and A1-42. Thus APP mice with higher A levels
exhibit greater disruption in autoregulation. This effect occurs in the
absence of A deposition in the brain and blood vessels. The data
indicate that A induces an alteration in the relationship between
cerebral perfusion pressure and CBF that renders the brain more
vulnerable to the deleterious effects of arterial hypertension and
hypotension. This is a previously unrecognized biological effect of
A that has critical implications for the structural and functional
integrity of the brain.
The disruption of autoregulation cannot be the result of alterations in
body temperature or arterial blood gases, because these variables were
monitored and carefully controlled. Certain anesthetics such as
halothane abolish autoregulation (34). To avoid this
problem, we used urethane-chloralose anesthesia, and autoregulation was
present in nontransgenic mice. Therefore, anesthesia-related effects
are not involved in the dysfunction of autoregulation. In addition, the
disruption of the upper limit of autoregulation cannot be the result of
pharmacological effects of the agent used to elevate MAP, because
phenylephrine does not have confounding cerebrovascular effects
(24), and for this reason it is often used to study the
effects of hypertension on CBF (e.g., Ref. 8). It is
unlikely that the cerebrovascular abnormalities in APP mice are the
nonspecific result of varying degrees of global brain dysfunction for
several reasons. First, although cerebrovascular autoregulation,
functional hyperemia (31), and endothelium-dependent responses are altered in Tg6209, Tg2123M, and Tg2123F mice, responses to hypercapnia, hypocapnia, and to the NO-donor SNAP are preserved. Therefore, these mice do not exhibit failure of all cerebrovascular responses, which is what might occur if the alterations reflected global brain dysfunction. Second, in Tg2123M mice, which have higher
levels of brain A than Tg6209 and Tg2123F mice, the disruption in
autoregulation is not associated with alterations in brain energy
metabolism as was assessed by the 2-deoxyglucose method (29). Third, Tg6209, Tg2123F, and Tg2123M are lines that
do not develop amyloid deposition in brain and blood vessels. Although Tg2576 mice develop amyloid plaques and other neuropathological abnormalities, we studied them at an age (2-3 mo) when these
alterations are not present (15). Therefore, the
cerebrovascular dysfunction cannot be attributed to gross
neuropathological abnormalities. Fourth, the selective alterations in
endothelium-dependent relaxation and functional hyperemia observed in
APP mice can be reproduced in normal mice by topical application of
synthetic A (27, 30). Collectively, these observations
indicate that the disruption in autoregulation that is observed in APP
mice is not related to flaws in the experimental preparation or to
factors that affect cerebrovascular reactivity nonspecifically.
To maintain flow in the autoregulated range of MAP, cerebral resistance
vessels undergo vasoconstriction during hypertension and vasodilatation
during hypotension (7). Therefore, failure of
vasoconstriction and vasodilation may result in disruption of
autoregulation. To determine whether such a mechanism was involved in
the alteration of autoregulation in APP mice, we investigated the
reactivity of the cerebral circulation to agents that increase or
decrease CBF. We found that, in agreement with previous observations (13), the increase in CBF produced by the
endothelium-dependent vasodilators ACh, BK, and A-23187 are markedly
attenuated in APP mice. A new finding, however, was that the effect is
more pronounced in transgenic lines with higher A levels. This new
observation provides a link between brain A concentration and
disruption of endothelium-dependent vascular responses. The alteration
in endothelium-dependent vasodilation could contribute to the loss of
the lower limit of autoregulation by reducing the ability of the
vessels to dilate when MAP is lowered. In support of this hypothesis,
the endothelium is involved in the response of smooth muscle cells to
pressure (6). Furthermore, inhibition of the synthesis of
the endothelium-dependent vasodilator NO impairs the lower limit of
autoregulation (20), and mice lacking endothelial NO
synthase have altered autoregulation (11). However, we
cannot rule out the participation of other factors as well. For
example, ATP-activated potassium channels are involved in the
vasodilation that occurs at low MAP (see Ref. 3 for a
review) and may also play a role in the dysfunction that is observed in
APP mice.
As for the upper range of autoregulation, a failure of vasoconstriction
should be responsible for the alterations in CBF at high MAP. To
determine whether there was a global impairment in vasoconstriction in
APP mice, we tested the effect of interventions that decrease CBF. We
found that the reduction in CBF produced by hypocapnia is not affected
in APP mice, and that the CBF reduction produced by the thromboxane
analog U-46619 is enhanced, an effect that is more marked in transgenic
lines with higher levels of A. Therefore, the failure of APP mice to
autoregulate at high MAP cannot be attributed to a nonspecific defect
of cerebral vessels to constrict. The vasoconstriction produced by
hypertension is related to a "myogenic" constrictor response evoked
by increased intravascular pressure (18). Although the
loss of autoregulation during hypertension could be related to an
impairment of the myogenic response, this possibility needs to be
tested experimentally.
We have previously demonstrated that the cerebrovascular alterations
induced by A are mediated by ROS. This conclusion is based on
several pieces of evidence. First, the alterations of endothelium-dependent relaxation produced by synthetic A applied to
the cerebral cortex of normal mice or to isolated blood vessels are
abrogated by ROS scavengers (27, 30, 38). Second, the alterations of endothelium-dependent relaxation in APP mice are counteracted by topical application of the ROS scavenger superoxide dismutase (13). Third, overexpression of Cu,Zn-SOD in APP
mice prevents the cerebrovascular effects of A (13).
Fourth, substitution of methionine in position 35 with isoleucine, a
mutation that prevents A from producing ROS, eliminates the
cerebrovascular effects of the peptide (27, 30). Our
working hypothesis is that A leads to vascular ROS production that
is similar in cellular source and magnitude to that evoked by
homocysteine, diabetes, or hypertension, which are conditions that
produce ROS-mediated cerebrovascular alterations (3).
Although there is no direct experimental evidence that ROS contribute
to the alteration in autoregulation, the fact that the other vascular
effects of A are mediated by ROS strongly suggests that these agents
are also involved in the impairment of autoregulation.
Another new finding of the present study is that in Tg2676 mice, which
is the transgenic line in which A levels and ADI are greatest, CBF
responses to both endothelium-dependent and -independent vasodilators
are attenuated. This observation suggests that in Tg2576, unlike the
other lines, the loss of autoregulation at low MAP is due to a global
impairment of cerebrovascular reactivity. The reasons for the greater
impairment in cerebrovascular dilatation in Tg2576 are unknown. Amyloid
deposition in blood vessels can be ruled out because mice were studied
at 2-3 mo of age when brain A levels are elevated but there is
no amyloid deposition in the tissue (9). We doubt that
structural alterations of the endothelium play a role, because
endothelial cells do not exhibit ultrastructural abnormalities in APP
mice (13). Therefore, one possibility is that the higher
levels of A attained in Tg2576 mice have direct effects on
cerebrovascular smooth muscle cells impairing the ability to relax.
Ongoing studies are addressing this issue.
The present findings provide an explanation for the observation that middle cerebral artery (MCA) occlusion produces more severe ischemia and larger infarcts in APP mice (41). Loss of autoregulation impairs the ability of cerebral resistance vessels to dilate in response to the reduction in transmural pressure produced by MCA occlusion and leads to more severe ischemia. In addition, it must be kept in mind that resting neocortical flow is reduced by 20-40% in APP mice (Tg2123 and Tg2576; Ref. 29). Therefore, absolute CBF values at low intravascular pressure are even lower than anticipated on the basis of the relative flow measurement by LDF. However, it is unlikely that the disruption in autoregulation in APP mice results from the reduction in resting CBF, because reductions in CBF of 50% do not affect autoregulation (2).
It has long been speculated that cerebrovascular dysfunction
contributes to AD (see Ref. 21 for a review). Pathological studies of AD brains have reported rarefaction, thickening, and coiling
of cerebral blood vessels and white-matter ischemic changes (4, 21), whereas studies using functional brain imaging
have shown that AD patients have reduced CBF and glucose utilization (19). The response to hypercapnia is preserved in AD
patients (26). However, the pathogenic significance of
these cerebrovascular changes has remained unclear because the
possibility that these changes were a consequence of the neuronal
dysfunction, gliosis, and atrophy occurring in AD was not ruled out.
The findings of the present study demonstrate that in APP mice,
cerebrovascular dysfunction precedes the neuropathological alterations.
Inasmuch as the pathology in APP mice reflects that of AD, the results support the view that the cerebrovascular effects of A are an early
event in AD and as such may play a pathogenic role in the mechanisms of
the disease. Although to our knowledge the full range of
cerebrovascular autoregulation has not been studied in AD, alterations
in cerebrovascular autoregulation have important implications for the
functional and structural integrity of the brain. Loss of
autoregulation renders the brain more susceptible to fluctuations in
MAP, such as those occurring during sleep (14). Thus
reductions in MAP that would not alter cerebral perfusion in the normal
brain may lead to cerebral ischemia in the presence of A.
Hypoperfusion-related ischemia would be most marked in the
periventricular white matter, an area supplied by terminal arterioles
with limited collateral flow (22, 25). These observations raise the possibility that an impairment in autoregulation contributes to the periventricular white-matter lesions that are frequently observed in patients with AD (1).
We conclude that overexpression of APP in mice produces a profound
disruption in cerebrovascular autoregulation that is more pronounced in
transgenic lines with high levels of brain A. The A-related
failure of autoregulation is paralleled by a disruption of
endothelium-dependent vasodilatation that is also greater in lines with
high brain A levels. Thus A renders the brain more vulnerable to
the variations in MAP that occur during normal activities. The data
unveil a novel aspect of the vascular biology of A and support the
view that cerebrovascular alterations may play a role in the mechanisms
of AD and related conditions.
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ACKNOWLEDGEMENTS |
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The editorial assistance of Karen MacEwan is gratefully acknowledged.
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FOOTNOTES |
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This work is supported by grants from the National Institutes of Health (NS-37853 and NS-38252 to C. Iadecola and AG-15453 to G. A. Carlson) and the Fraternal Order of Eagles (to G. A. Carlson). C. Iadecola is the recipient of a Javits Award from the National Institute of Neurological Disorders and Stroke.
Address for reprint requests and other correspondence: C. Iadecola, Dept. of Neurology, Univ. of Minnesota, MMC 295, 516 Delaware St. SE, Minneapolis, MN 55455 (E-mail: iadec001{at}tc.umn.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published March 7, 2002;10.1152/ajpheart.00022.2002
Received 14 January 2002; accepted in final form 4 March 2002.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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