Cerebrovascular dysfunction in amyloid precursor protein transgenic mice: contribution of soluble and insoluble amyloid-beta peptide, partial restoration via gamma-secretase inhibition - PubMed (original) (raw)
Cerebrovascular dysfunction in amyloid precursor protein transgenic mice: contribution of soluble and insoluble amyloid-beta peptide, partial restoration via gamma-secretase inhibition
Byung Hee Han et al. J Neurosci. 2008.
Abstract
The contributing effect of cerebrovascular pathology in Alzheimer's disease (AD) has become increasingly appreciated. Recent evidence suggests that amyloid-beta peptide (Abeta), 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 Abeta but no cerebral amyloid angiopathy (CAA). These studies suggest but do not prove that soluble Abeta 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 Abeta 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 Abeta improved vessel function in young and to a lesser degree older Tg2576 mice. These results strongly suggest that both soluble and insoluble Abeta cause cerebrovascular dysfunction, that mechanisms other than Abeta-induced alteration in vessel integrity are responsible, and that anti-Abeta therapy may have beneficial vascular effects in addition to positive effects on parenchymal amyloid.
Figures
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.
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.
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.
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.
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 (_R_2 = 0.3588, p < 0.001).
Figure 6.
Blockade of Aβ production restored vascular function in Tg2576 mice. A, The blood–brain barrier permeable γ–secretase inhibitor, LY411,575 depleted soluble Aβ1-x levels in the interstitial fluid (ISF) in 6-month-old Tg2576 mice. LY411,575 (3 mg/kg) was subcutaneously administered and human Aβ1-x levels in the ISF were assayed as described in the Materials and Methods. Data represent mean ± SEM (n = 5). B, Baseline vessel diameters were analyzed in the leptomeningeal arterioles before and 3 h after LY411,575 treatment in 6-month-old Tg2576 and WT mice. C, D, Six-month-old WT or Tg2576 mice treated with vehicle (Veh), LY411,575 (LY), or the inactive form LY424,196 (inactive LY) were subjected to vascular function tests in response to hypercapnia (C), ACh (100 μ
m
) (D), or SNAP (500 μ
m
) (D) (n = 7–9). E, In 12- to 15-month-old Tg2576 mice, CAA deposits were fluorescently labeled with methoxy-X04 and photographically imaged before (green) and 15 h after (red) the LY411,575 treatment. Scale bar, 20 μm. F, G, Vascular reactivity was examined in 12- to 15-month-old Tg2576 mice 15 h after treatment with vehicle or LY411,575 (n = 5). Vascular reactivity was analyzed in all vessel segments (F) and further compared in vessels having ≤20% versus >20% CAA coverage (G). Note that LY411,575 restored vascular function in cerebral arterioles with little or no CAA (≤20% coverage), but had no effect in vessels with extensive CAA (>20% coverage). *p < 0.05 as analyzed by ANOVA followed by Dunnett's multiple comparison test.
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