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Tau pathology-dependent remodelling of cerebral arteries precedes Alzheimer's disease-related microvascular cerebral amyloid angiopathy.

Merlini M, Wanner D, Nitsch RM - Acta Neuropathol. (2016)

Bottom Line: Whether this occurs already before disease onset, as may be indicated by early Braak tau-related cerebral hypoperfusion and blood-brain barrier (BBB) impairment found in previous studies, remains unknown.Collagen content was only significantly changed in small arteries.Our data indicate that vessel wall remodelling of leptomeningeal arteries is an early-onset, Braak tau pathology-dependent process unrelated to CAA and AD, which potentially may contribute to downstream CAA-dependent microvascular pathology in AD.

View Article: PubMed Central - PubMed

Affiliation: Institute for Regenerative Medicine - IREM, University of Zurich, Schlieren Campus, Wagistrasse 12, 8952, Schlieren, Switzerland. mario.merlini@uzh.ch.

ABSTRACT
Alzheimer's disease (AD) is characterised by pathologic cerebrovascular remodelling. Whether this occurs already before disease onset, as may be indicated by early Braak tau-related cerebral hypoperfusion and blood-brain barrier (BBB) impairment found in previous studies, remains unknown. Therefore, we systematically quantified Braak tau stage- and cerebral amyloid angiopathy (CAA)-dependent alterations in the alpha-smooth muscle actin (α-SMA), collagen, and elastin content of leptomeningeal arterioles, small arteries, and medium-sized arteries surrounding the gyrus frontalis medialis (GFM) and hippocampus (HIPP), including the sulci, of 17 clinically and pathologically diagnosed AD subjects (Braak stage IV-VI) and 28 non-demented control subjects (Braak stage I-IV). GFM and HIPP paraffin sections were stained for general collagen and elastin with the Verhoeff-van Gieson stain; α-SMA and CAA/amyloid β (Aβ) were detected using immunohistochemistry. Significant arterial elastin degradation was observed from Braak stage III onward and correlated with Braak tau pathology (ρ = 0.909, 95% CI 0.370 to 0.990, p < 0.05). This was accompanied by an increase in neutrophil elastase expression by α-SMA-positive cells in the vessel wall. Small and medium-sized arteries exhibited significant CAA-independent α-SMA loss starting between Braak stage I and II-III, along with accumulation of phosphorylated paired helical filament (PHF) tau in the perivascular space of intraparenchymal vessels. α-SMA remained at the decreased level throughout the later Braak stages. In contrast, arterioles exhibited significant α-SMA loss only at Braak stage V and VI/in AD subjects, which was CAA-dependent/correlated with CAA burden (ρ = -0.422, 95% CI -0.557 to -0.265, p < 0.0001). Collagen content was only significantly changed in small arteries. Our data indicate that vessel wall remodelling of leptomeningeal arteries is an early-onset, Braak tau pathology-dependent process unrelated to CAA and AD, which potentially may contribute to downstream CAA-dependent microvascular pathology in AD.

No MeSH data available.


Related in: MedlinePlus

Identification of leptomeningeal arterioles and arteries and elastin degradation. Identification of the vessel types shown was based on vessel diameters as measured in alpha-smooth muscle actin (α-SMA)-stained gyrus frontalis medialis (GFM) and hippocampus (HIPP) sections (a). The degradation of the internal elastic lamina (barrow indicates the internal elastic lamina/elastin) was assessed in Verhoeff–van Gieson (VVG)-stained small and medium-sized arteries according to the scoring system shown. Elastin degradation due to cerebral amyloid angiopathy (CAA) is only observed in the rare, not significant number of small and medium-sized arteries with CAA fractions >1.0 and in which CAA is present in the media [c, c1: VVG stain for elastin (arrow indicates focal loss of elastin) and collagen (brightred); asterisk denotes medial layer, arrowhead indicates double barrel formation as commonly observed for vessels with severe CAA as shown in c2 (image of adjacent section): immunohistochemical stain for amyloid β (Aβ)/CAA (green) and α-SMA (red)]. Elastin appears not to be affected by CAA in small and medium-sized arteries with adventitial CAA burden only [c, c3: VVG stain for elastin (arrow indicates preservation of elastin integrity) and collagen; asterisk denotes medial layer; c4 (image of adjacent section): immunohistochemical stain for Aβ/CAA and α-SMA]. Scale bar 100 μm
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Fig1: Identification of leptomeningeal arterioles and arteries and elastin degradation. Identification of the vessel types shown was based on vessel diameters as measured in alpha-smooth muscle actin (α-SMA)-stained gyrus frontalis medialis (GFM) and hippocampus (HIPP) sections (a). The degradation of the internal elastic lamina (barrow indicates the internal elastic lamina/elastin) was assessed in Verhoeff–van Gieson (VVG)-stained small and medium-sized arteries according to the scoring system shown. Elastin degradation due to cerebral amyloid angiopathy (CAA) is only observed in the rare, not significant number of small and medium-sized arteries with CAA fractions >1.0 and in which CAA is present in the media [c, c1: VVG stain for elastin (arrow indicates focal loss of elastin) and collagen (brightred); asterisk denotes medial layer, arrowhead indicates double barrel formation as commonly observed for vessels with severe CAA as shown in c2 (image of adjacent section): immunohistochemical stain for amyloid β (Aβ)/CAA (green) and α-SMA (red)]. Elastin appears not to be affected by CAA in small and medium-sized arteries with adventitial CAA burden only [c, c3: VVG stain for elastin (arrow indicates preservation of elastin integrity) and collagen; asterisk denotes medial layer; c4 (image of adjacent section): immunohistochemical stain for Aβ/CAA and α-SMA]. Scale bar 100 μm

Mentions: Detailed image acquisition procedures can be found in the Supplementary Materials and Methods. Microscopic images were acquired from leptomeningeal arterioles, small arteries, and medium-sized arteries surrounding the GFM and HIPP, including the sulci. Images of 10 to 15 vessels of each vessel type/brain region/subject from the VVG and immunostained HIPP and GFM sections were acquired. Differentiation between the three vessel types was made according to vessel diameter, ranging from 50 to 100 µm (arterioles), 100 to 300 µm (small arteries), and 300 to 700 µm (medium-sized arteries) (Fig. 1a). Veins and venules were not imaged and were identified by their relatively small α-SMA-to-lumen ratio. Images were acquired using the image acquisition tool of the Visiopharm software (Visiopharm, Hørsholm, Denmark). All images were acquired in a random manner blinded to subject/Braak stage.Fig. 1


Tau pathology-dependent remodelling of cerebral arteries precedes Alzheimer's disease-related microvascular cerebral amyloid angiopathy.

Merlini M, Wanner D, Nitsch RM - Acta Neuropathol. (2016)

Identification of leptomeningeal arterioles and arteries and elastin degradation. Identification of the vessel types shown was based on vessel diameters as measured in alpha-smooth muscle actin (α-SMA)-stained gyrus frontalis medialis (GFM) and hippocampus (HIPP) sections (a). The degradation of the internal elastic lamina (barrow indicates the internal elastic lamina/elastin) was assessed in Verhoeff–van Gieson (VVG)-stained small and medium-sized arteries according to the scoring system shown. Elastin degradation due to cerebral amyloid angiopathy (CAA) is only observed in the rare, not significant number of small and medium-sized arteries with CAA fractions >1.0 and in which CAA is present in the media [c, c1: VVG stain for elastin (arrow indicates focal loss of elastin) and collagen (brightred); asterisk denotes medial layer, arrowhead indicates double barrel formation as commonly observed for vessels with severe CAA as shown in c2 (image of adjacent section): immunohistochemical stain for amyloid β (Aβ)/CAA (green) and α-SMA (red)]. Elastin appears not to be affected by CAA in small and medium-sized arteries with adventitial CAA burden only [c, c3: VVG stain for elastin (arrow indicates preservation of elastin integrity) and collagen; asterisk denotes medial layer; c4 (image of adjacent section): immunohistochemical stain for Aβ/CAA and α-SMA]. Scale bar 100 μm
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Fig1: Identification of leptomeningeal arterioles and arteries and elastin degradation. Identification of the vessel types shown was based on vessel diameters as measured in alpha-smooth muscle actin (α-SMA)-stained gyrus frontalis medialis (GFM) and hippocampus (HIPP) sections (a). The degradation of the internal elastic lamina (barrow indicates the internal elastic lamina/elastin) was assessed in Verhoeff–van Gieson (VVG)-stained small and medium-sized arteries according to the scoring system shown. Elastin degradation due to cerebral amyloid angiopathy (CAA) is only observed in the rare, not significant number of small and medium-sized arteries with CAA fractions >1.0 and in which CAA is present in the media [c, c1: VVG stain for elastin (arrow indicates focal loss of elastin) and collagen (brightred); asterisk denotes medial layer, arrowhead indicates double barrel formation as commonly observed for vessels with severe CAA as shown in c2 (image of adjacent section): immunohistochemical stain for amyloid β (Aβ)/CAA (green) and α-SMA (red)]. Elastin appears not to be affected by CAA in small and medium-sized arteries with adventitial CAA burden only [c, c3: VVG stain for elastin (arrow indicates preservation of elastin integrity) and collagen; asterisk denotes medial layer; c4 (image of adjacent section): immunohistochemical stain for Aβ/CAA and α-SMA]. Scale bar 100 μm
Mentions: Detailed image acquisition procedures can be found in the Supplementary Materials and Methods. Microscopic images were acquired from leptomeningeal arterioles, small arteries, and medium-sized arteries surrounding the GFM and HIPP, including the sulci. Images of 10 to 15 vessels of each vessel type/brain region/subject from the VVG and immunostained HIPP and GFM sections were acquired. Differentiation between the three vessel types was made according to vessel diameter, ranging from 50 to 100 µm (arterioles), 100 to 300 µm (small arteries), and 300 to 700 µm (medium-sized arteries) (Fig. 1a). Veins and venules were not imaged and were identified by their relatively small α-SMA-to-lumen ratio. Images were acquired using the image acquisition tool of the Visiopharm software (Visiopharm, Hørsholm, Denmark). All images were acquired in a random manner blinded to subject/Braak stage.Fig. 1

Bottom Line: Whether this occurs already before disease onset, as may be indicated by early Braak tau-related cerebral hypoperfusion and blood-brain barrier (BBB) impairment found in previous studies, remains unknown.Collagen content was only significantly changed in small arteries.Our data indicate that vessel wall remodelling of leptomeningeal arteries is an early-onset, Braak tau pathology-dependent process unrelated to CAA and AD, which potentially may contribute to downstream CAA-dependent microvascular pathology in AD.

View Article: PubMed Central - PubMed

Affiliation: Institute for Regenerative Medicine - IREM, University of Zurich, Schlieren Campus, Wagistrasse 12, 8952, Schlieren, Switzerland. mario.merlini@uzh.ch.

ABSTRACT
Alzheimer's disease (AD) is characterised by pathologic cerebrovascular remodelling. Whether this occurs already before disease onset, as may be indicated by early Braak tau-related cerebral hypoperfusion and blood-brain barrier (BBB) impairment found in previous studies, remains unknown. Therefore, we systematically quantified Braak tau stage- and cerebral amyloid angiopathy (CAA)-dependent alterations in the alpha-smooth muscle actin (α-SMA), collagen, and elastin content of leptomeningeal arterioles, small arteries, and medium-sized arteries surrounding the gyrus frontalis medialis (GFM) and hippocampus (HIPP), including the sulci, of 17 clinically and pathologically diagnosed AD subjects (Braak stage IV-VI) and 28 non-demented control subjects (Braak stage I-IV). GFM and HIPP paraffin sections were stained for general collagen and elastin with the Verhoeff-van Gieson stain; α-SMA and CAA/amyloid β (Aβ) were detected using immunohistochemistry. Significant arterial elastin degradation was observed from Braak stage III onward and correlated with Braak tau pathology (ρ = 0.909, 95% CI 0.370 to 0.990, p < 0.05). This was accompanied by an increase in neutrophil elastase expression by α-SMA-positive cells in the vessel wall. Small and medium-sized arteries exhibited significant CAA-independent α-SMA loss starting between Braak stage I and II-III, along with accumulation of phosphorylated paired helical filament (PHF) tau in the perivascular space of intraparenchymal vessels. α-SMA remained at the decreased level throughout the later Braak stages. In contrast, arterioles exhibited significant α-SMA loss only at Braak stage V and VI/in AD subjects, which was CAA-dependent/correlated with CAA burden (ρ = -0.422, 95% CI -0.557 to -0.265, p < 0.0001). Collagen content was only significantly changed in small arteries. Our data indicate that vessel wall remodelling of leptomeningeal arteries is an early-onset, Braak tau pathology-dependent process unrelated to CAA and AD, which potentially may contribute to downstream CAA-dependent microvascular pathology in AD.

No MeSH data available.


Related in: MedlinePlus