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The Journal of Neuroscience, December 10, 2008, 28(50):13542-13550; doi:10.1523/JNEUROSCI.4686-08.2008
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Neurobiology of Disease
Cerebrovascular Dysfunction in Amyloid Precursor Protein Transgenic Mice: Contribution of Soluble and Insoluble Amyloid-β Peptide, Partial Restoration via-Secretase Inhibition
Byung Hee Han,1 Meng-liang Zhou,1 Fadi Abousaleh,1 Robert P. Brendza,2 Hans H. Dietrich,1 Jessica Koenigsknecht-Talboo,2 John R. Cirrito,2,4 Eric Milner,1 David M. Holtzman,2,3,4 andGregory J. Zipfel1,2,4 Departments of 1Neurological Surgery, 2Neurology, and 3Developmental Biology, and the 4Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110
Abstract
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Abstract
Introduction
The contributing effect of cerebrovascular pathology in Alzheimer's disease (AD) has become increasingly appreciated. Recent evidence suggests that amyloid-β peptide (Aβ), the same peptide found in neuritic plaques of AD, may play a role via its vasoactive properties. Several studies have examined young Tg2576 mice expressing mutant amyloid precursor protein (APP) and having elevated levels of soluble Aβ but no cerebral amyloid angiopathy (CAA). These studies suggest but do not prove that soluble Aβ can significantly impair the cerebral circulation. Other studies examining older Tg2576 mice having extensive CAA found even greater cerebrovascular dysfunction, suggesting that CAA is likely to further impair vascular function. Herein, we examined vasodilatory responses in young and older Tg2576 mice to further assess the roles of soluble and insoluble Aβ on vessel function. We found that (1) vascular impairment was present in both young and older Tg2576 mice; (2) a strong correlation between CAA severity and vessel reactivity exists; (3) a surprisingly small amount of CAA led to marked reduction or complete loss of vessel function; 4) CAA-induced vasomotor impairment resulted from dysfunction rather than loss or disruption of vascular smooth muscle cells; and 5) acute depletion of Aβ improved vessel function in young and to a lesser degree older Tg2576 mice. These results strongly suggest that both soluble and insoluble Aβ cause cerebrovascular dysfunction, that mechanisms other than Aβ-induced alteration in vessel integrity are responsible, and that anti-Aβ therapy may have beneficial vascular effects in addition to positive effects on parenchymal amyloid.
Key words: cerebral amyloid angiopathy; amyloid-β; vascular function;
-secretase; hypercapnia; Alzheimer's disease
Introduction
There is compelling evidence that the amyloid-β peptide (Aβ), a cleavage product of amyloid precursor protein (APP), is a key factor in the pathogenesis of Alzheimer's disease (AD) (Sisodia, 1999; Selkoe, 2001
Another link between cerebrovascular disease and AD is cerebral amyloid angiopathy (CAA). CAA is characterized by Aβ deposition within walls of leptomeningeal and cortical arterioles. It is almost universally found in AD patients (Mandybur, 1975
To further assess the contribution of soluble and insoluble Aβ on cerebrovascular function, we examined vasomotor responses and structural integrity of individual cerebral vessels in young (6 month; pre-CAA) and older (12–15 month; extensive CAA) Tg2576 mice that overexpress mutant APP. In young Tg2576 mice, we found that responses to vasodilatory stimuli were impaired, that vascular smooth muscle cell (VSMC) dysfunction contributed to this impairment, and that
Materials and Methods
Animals and surgical procedure. All experimental protocols were approved by the animal studies committee at Washington University. The production, genotyping, and background strain (B6/SJL) of Tg2576 mice used in this study have been described previously (Hsiao et al., 1996Cerebral vasodilatory responses. Fifteen hours later, mice were anesthetized with isoflorane and
-chloralose (80 mg/kg, i.p.) and ventilated at a stroke volume of 5 ml/kg body weight and ventilation rate of 150 strokes/min with a rodent ventilator (Harvard Apparatus). Core body temperature was maintained at 37°C by a thermo-regulated heating pad (Cell MicroControls). An arterial catheter was placed into the femoral artery for measuring mean arterial blood pressure and blood gases. The mouse was then placed in a custom-built stereotaxic device to secure its head on the microscope stage. The leptomeningeal vessels were visualized using a Nikon Eclipse 600ME digital video microscopy system and MetaMorph imaging software (Molecular Devices). Vessel diameter response to hypercapnia or topical vasodilators was then assessed. To induce hypercapnia, mice were ventilated with 5% CO2/30% O2-containing air for 5 min followed by ventilation with 30% O2-containing air. Blood gases were analyzed before, 4 min after hypercapnia, and 4 min after recovery. For vasodilator experiments, the endothelium-dependent vasodilator acetylcholine (ACh; 100 µM; Sigma) or the VSMC-dependent vasodilator S-nitroso-N-acetyl-penicillamine (SNAP; 500 µM; Sigma) was infused into the cranial window at a rate of 20 µl/min for 5 min. The cranial window was then infused with aCSF for 20–30 min or until the vessel diameter returned to its baseline value. The order of vasodilatory agents was randomly assigned. To examine the effect of
Vessel diameter measurement. Vessel diameters were determined with Diamtrak software (Tim Neild, Monash University, Melbourne, Australia). Averaged vessel diameter across a 25 µm longitudinal segment (8 consecutive segments per mouse) of the dorsal middle cerebral arteries were analyzed before (baseline) and 3–5 min after treatment with vasodilatory stimuli (see Fig. 2A). Data were calculated as % vasodilation vs baseline vessel diameter
CAA quantification. To label amyloid deposits in the brain, mice were i.p. injected with a Congo red derivative, Methoxy-X04 (10 mg/kg) 15 h before vascular imaging as described previously (Klunk et al., 2002
VSMC staining and two-photon microscopy. After live brain imaging described above, mice were perfused with PBS. Brains were removed, fixed in 4% paraformaldehyde, and preserved in 30% glucose-PBS solution at 4°C. To label VSMCs, fixed whole brains were permeabilized with PBS containing 0.25% Triton X-100 for 20 min at room temperature, blocked with 2% bovine serum albumin (BSA) in PBS for 30 min, followed by incubation with phalloidin-Alexa-488 (Invitrogen) in 1% BSA-PBS. Methoxy-X04 and phalloidin staining was simultaneously imaged using a Zeiss LSM 510 META LNO two-photon microscope.
Determination of Aβ levels in interstitial fluid and plasma. In vivo microdialysis to assess brain interstitial fluid (ISF) Aβ1-x in the hippocampus of awake, freely moving Tg2576 mice was performed as previously described (Cirrito et al., 2003
Statistical analyses. Data were expressed as means ± SEM. Comparison among multiple groups were performed with a one-way ANOVA followed by Dunnett's multiple comparison method. P value <0.05 was considered significant.
Results
CAA deposits increased with age in Tg2576 mice
To assess progression of CAA deposits in the leptomeningial arteries, Aβ that was deposited in a β-pleated sheet structure was visualized using a congo red derivative fluorescent dye, methoxy-X04 (Fig. 1). Consistent with previous reports (Hsiao et al., 1996
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Figure 1. Progression of CAA in Tg2576 mice. Fluorescent microscopic images were taken 24 h after intraperitoneal injection of methoxy-X04 through a closed cranial window in 6- (A), 12- (B, D), and 15- (C) month-old Tg2576 mice. Neither CAA deposits nor parenchymal Aβ plaques was noted in 6-month-old mice (A). At 12 months of age, methoxy-X04-positive Aβ deposition (bright blue) in the pial arterioles was prominent but patchy (B, D). By 15 months of age, CAA deposits were further progressed to almost the entire pial arteriole system without interruption (C). Scale bars: A–C, 200 µm, D, 50 µm.
Vessel dysfunction in young Tg2576 mice lacking CAA
Vasodilatory response to hypercapnia was decreased by 48% in young Tg2576 mice (pre-CAA) compared with age-matched, littermate wild type (WT) mice (Tg2576 mice: 14.5 ± 2.5% vs WT mice: 27.7 ± 5.1%; p = 0.0233) (Fig. 2B). The attenuated vasodilatory response could not be attributed to differences between groups in extent of pCO2 change after induced hypercapnia (Table 1), other physiological parameters (Table 1), or baseline vascular diameters (Fig. 2C). A similar reduction in vessel response to topical ACh and SNAP was also noted in young Tg2576 mice compared with age-matched, littermate WT mice (ACh–Tg2576 mice: 11.4 ± 2.2% vs WT mice: 20.5 ± 2.6%; p = 0.009; SNAP–Tg2576 mice: 20.0 ± 3.7% vs WT mice: 33.9 ± 2.6%; p = 0.003) (Fig. 2D). These data confirm that young Tg2576 mice have significant impairment in vascular reactivity and indicate that under our experimental conditions this is primarily the consequence of VSMC dysfunction.
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Figure 2. Cerebrovascular dysfunction in Tg2576 mice. Vascular responses to vasodilatory stimuli in the leptomeningeal arterioles through a closed cranial window were visualized and monitored via video microscopy in 6-month-old and 12- to 15-month-old Tg2576 mice. A, To determine vessel diameter, an average vessel diameter in 25-µm-long vessel segments (8 consecutive segments per animal) was measured using a Diamtrak software. B, Vasodilatory response to hypercapnia. Percentage changes in vessel diameter were calculated and represented as mean ± SEM. C, Baseline vessel diameters were similar between groups before exposure to hypercapnia. D, Vascular responses to ACh and SNAP were attenuated in 6-month-old Tg2576 mice lacking CAA.
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Table 1. Physiological parameters pre-hypercapnia and post-hypercapnia
Further vessel dysfunction in older Tg2576 mice having extensive CAA
Hypercapnia-induced vasodilation was even further reduced by 85% in older Tg2576 mice having extensive CAA (Tg2576 mice: 4.1 ± 2.0% vs WT mice: 25.3 ± 3.0%; p < 0.0001) (Fig. 2B). To more specifically examine the relationship between CAA deposits and vessel function, we compared amyloid load across individual 25 µm vessel segments (reported as % CAA) to the vasodilatory function across the given vessel segment. In those segments having no or minimal CAA (i.e., 0–10% CAA), we noted significant reduction in hypercapnia-induced vasodilation compared with vessel segments from age-matched, littermate WT mice (Fig. 3B). Cerebrovascular function was further compromised in vessel segments having 11–20% CAA, and vascular response was completely abolished in vessel segments have >20% CAA (Fig. 3B). These alterations in vasodilatory response could not be attributed to extent of pCO2 change after induced hypercapnia or to other physiological parameters between groups (Table 1). These data strongly implicate CAA as a causal factor in the cerebrovascular dysfunction of older Tg2576 mice.
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Figure 3. Vascular function was severely reduced in CAA-affected vessels. A, Live images of the leptomeningeal arterioles of 12- to 15-month-old WT and Tg2576 mouse brains were taken before (baseline) and 4 min after the onset of hypercapnia. Methoxy-X04-positive CAA deposits were imaged in the same vessels. In WT mice, vasodilatory response to hypercapnia was evident across the entire vessel segments (arrowheads). In Tg2576 mice, however, hypercapnia-induced vasodilation was noted in vessels without CAA (arrowheads), whereas there was little to no vascular response within the CAA-affected vessels (arrows). Scale bar, 100 µm. B, Relationship between vasodilatory function and CAA coverage. Percentage CAA coverage within 25 µm longitudinal vessels (8 consecutive segments per brain) were assessed as described in the Materials and Methods. CAA coverage was plotted against vasodilatory response to hypercapnia. Data indicate mean ± SEM. *p < 0.05 compared with WT mice analyzed by one-way ANOVA followed by Dunnett's test.
Relationship between CAA and cerebral vessel structural integrity
To explore whether alterations in VSMC architecture and/or density accounted for the observed cerebrovascular dysfunction, we sought to rigorously characterize vessel wall changes in Tg2576 mice. In young mice, no CAA was found and VSMCs were arranged closely in parallel in all examined pial arterioles (Fig. 4B,Ca). At 12 months of age, CAA deposits were found between VSMCs (Fig. 4D–F). In vessels having small amounts of CAA (<20%), no or minimal disruption of VSMC topography was noted and circumferential amyloid deposition was distinctly rare (Fig. 4D–Fb). However, when greater amounts of CAA were present (>20%), architectural VSMC changes became increasingly frequent and more severe, particularly when extent of CAA reached very high levels (>40%) (Fig. 4D–Fc,d). At 15 months of age, VSMCs were extensively dismantled throughout the pial vessels, as CAA deposition had progressed to the point of near-continuous involvement of the arteriole system (Fig. 4G–Ie). These architectural changes were not apparent in age-matched WT mice (data not shown).
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Figure 4. Disruption of vascular smooth muscle cells was noted in CAA-affected vessels. Amyloid deposition and vascular smooth muscle cells (VSMCs) in the leptomeningeal vessels were stained with methoxy-X04 (blue) and phalloidin-Alexa 488 (green), respectively, and imaged with a two-photon microscope. In 6-month-old Tg2576 mice having no CAA deposits, VSMCs were arranged closely in parallel to each other in the leptomeningeal vessels (A–Ca). At 12 months of age, the VSMC architecture had no or minimal disruption in the pial arterioles having small amounts of CAA (D–Fb, c), whereas severe disruption of VSMC arrangement in the vessel segments had greater amounts of CAA (D–Fd). Structural VSMC changes became more evident and severe in 15-month-old mice (G–Ie). Scale bars: A–I, 50 µm, a–e, 20 µm.
We also examined VSMC density. In WT mice of all examined ages, we found20 VSMCs per 100 µm vessel segment (Fig. 5A). In young Tg2576 mice, VSMC density did not differ from age-matched WT mice. In older Tg2576 mice, however, decreased overall VSMC density was noted (Tg2576 mice: 15.5 ± 0.5 cells/100 µm vs WT mice: 20.6 ± 1.3 cells/100 µm; p < 0.05). A correlative analysis between CAA load and VSMC density was performed, and a strong correlation between CAA severity (measured as % CAA) and VSMC density was noted (R2 = 0.506; p < 0.001) (Fig. 5B). Specifically, unaffected or mildly affected vessels (i.e., 0–20% CAA) had no VSMC loss, moderately affected vessels (i.e., 21–40% CAA) had a nonsignificant trend for VSMC loss, and severely affected vessels (i.e., >40% CAA) had substantial and significant VSMC loss (Fig. 5C). Finally, a positive correlation between vessel caliber and severity of CAA deposits was noted (R2 = 0.3588, p < 0.001) (Fig. 5D). These data suggest that mild amounts of CAA have no or minimal effect on vessel wall integrity, but as increasing amounts of CAA develop significant disruptions of vessel wall integrity including frank loss of VSMCs occur.
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Figure 5. Correlation between CAA coverage and VSMC loss. A number of VSMCs and CAA coverage were assessed as described in the Materials and Methods. A, A number of VSMCs were decreased in the leptomeningeal vessels of 12- to 15-month-old, but not 6-month-old Tg2576 mice compared with age-matched WT mice (p < 0.05). B, At 12–15 months of age, VSMC loss was markedly noted in the leptomeningeal vessel segments having >40% CAA coverage. C, Correlation between CAA severity and VSMC loss. D, Correlation between vessel caliber versus severity of CAA deposits in the leptomeningeal vessels (R2 = 0.3588, p < 0.001).
Our results and those of others (Zhang et al., 1997
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Figure 6. Blockade of Aβ production restored vascular function in Tg2576 mice. A, The blood–brain barrier permeable 20% versus >20% CAA coverage (G). Note that LY411,575 restored vascular function in cerebral arterioles with little or no CAA (
We next examined whether
Discussion
Our principal findings are as follows: (1) soluble and insoluble forms of Aβ contribute to age-dependent cerebrovascular dysfunction in Tg2576 mice; (2) CAA-induced cerebrovascular impairment develops via dysfunction rather than frank loss or disruption of VSMCs; and (3) acute depletion of soluble Aβ viaVascular dysfunction in young Tg2576 mice
Our results indicate that soluble Aβ induces significant cerebrovascular dysfunction. First, we demonstrated that young Tg2576 mice having elevated soluble Aβ levels (but no CAA) had markedly reduced cerebrovascular responses to vasodilatory stimuli. This is consistent with the majority of previous reports (Iadecola et al., 1999Vascular dysfunction in older Tg2576 mice
Results from our study also implicate insoluble vascular Aβ (i.e., CAA) in causing significant and often severe cerebrovascular dysfunction. We documented a differential impairment in vasomotor function in young (pre-CAA) vs older (extensive CAA) Tg2576 mice, with the former having 50% impairment and the latter having 85% impairment in hypercapnia-induced vasodilation. This result, along with that of other investigators who have also documented marked cerebrovascular dysfunction in older Tg2576 mice (Christie et al., 2001One surprising finding from this analysis was that relatively small amounts of CAA were associated with either substantial vessel dysfunction (11–20% CAA) or complete vasomotor paralysis (>20% CAA). Although previous studies (Christie et al., 2001
Finally, we examined whether
Mechanisms of Aβ-induced vasomotor impairment
Our results suggest that both soluble and insoluble forms of Aβ cause vasomotor impairment at least in part via VSMC dysfunction. For example, we noted impaired vascular responses to hypercapnia and SNAP in young Tg2576 mice, both of which suggest abnormal VSMC function. Although some studies have noted similar results using VSMC-dependent vasodilators such as SNAP (Park et al., 2005Our study noted even greater impairment of hypercapnia-induced vasodilation in CAA-ladened vessels of older Tg2576 mice. When coupled with the findings of Christie et al. (2001)
In regards to the underlying molecular pathways leading to Aβ-induced cerebrovascular dysfunction, much is known for soluble Aβ. Both reactive oxygen species (ROS) (Iadecola, 2004
Conclusion
Our work supports the findings of previous investigators who documented age-dependent impairment of cerebrovascular function in APP transgenic mice. In addition, our observations extend on these studies on several fronts. One, we demonstrated for the first time that both young and older Tg2576 mice can display significant cerebrovascular dysfunction under uniform experimental conditions. Two, we more directly implicated CAA as a causal factor in cerebrovascular dysfunction by demonstrating a dose–response to CAA severity and by controlling for confounds such as prolonged exposure to soluble Aβ and mutant APP. Three, we provided robust evidence that CAA-related vessel dysfunction begins before significant alterations in vessel wall integrity, indicating that downstream molecular effectors likely exist and are the true mediators of CAA-induced cerebrovascular dysfunction. Four, we identified VSMC dysfunction as a likely key cellular event underlying CAA-induced cerebrovascular impairment. And five, we provided evidence supporting the concept that Aβ-directed therapy may prove a viable strategy toward attenuating Aβ-induced cerebrovascular dysfunction. Whether restoration of vasoreactivity via
Footnotes
Received Sept. 30, 2008; accepted Oct. 29, 2008.This work was supported by National Institutes of Health (NIH) Grants NS053899 (G.J.Z.) and NS032636 (D.M.H.), grants from the American Association of Neurological Surgeons/Congress of Neurological Surgeons (G.J.Z.) and American Health Assistance Foundation (G.J.Z. and R.P.B.), NIH Neuroscience Blueprint Core Grant NS057105 to Washington University, and Eli Lilly and Co. We thank Robert Mach for providing Methoxy-X04 for these studies.
Correspondence should be addressed to Dr. Gregory J. Zipfel, Department of Neurological Surgery, Campus Box 8057, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. Email: zipfelg{at}nsurg.wustl.edu
Copyright © 2008 Society for Neuroscience 0270-6474/08/2813542-09$15.00/0
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