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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

Quantification of collagen and alpha smooth muscle actin in leptomeningeal arterioles and arteries of Alzheimer’s disease and non-demented control subjects. Leptomeningeal vessels surrounding the hippocampus (HIPP) of Alzheimer’s disease (AD) subjects show a significant decrease in alpha smooth muscle actin (α-SMA) compared to vessels of non-demented control (NDCTRL) subjects (a). The α-SMA fraction of small and medium-sized leptomeningeal AD arteries surrounding the gyrus frontalis medials (GFM) is also significantly decreased; the α-SMA fraction of leptomeningeal AD arterioles surrounding the GFM tends to be decreased (a). The collagen fraction of HIPP and GFM AD vessels is not significantly different from that of their NDCTRL counterparts (b). Cerebral amyloid angiopathy-affected (CAA+) arterioles show exacerbation of the α-SMA loss, which is not observed for CAA+ small and medium-sized arteries (c). NDCTRL, AD CAA−, and AD CAA+ vessels have similar collagen fractions (c). The graphs represent the mean ± SE of 10 vessels/vessel category/subject of a total of 45 subjects; *p < 0.05, **p < 0.01, and ***p < 0.001 as determined by a two-tailed unpaired Student’s t test corrected for multiple comparisons (Holm–Sidak test, α = 0.05)
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Fig2: Quantification of collagen and alpha smooth muscle actin in leptomeningeal arterioles and arteries of Alzheimer’s disease and non-demented control subjects. Leptomeningeal vessels surrounding the hippocampus (HIPP) of Alzheimer’s disease (AD) subjects show a significant decrease in alpha smooth muscle actin (α-SMA) compared to vessels of non-demented control (NDCTRL) subjects (a). The α-SMA fraction of small and medium-sized leptomeningeal AD arteries surrounding the gyrus frontalis medials (GFM) is also significantly decreased; the α-SMA fraction of leptomeningeal AD arterioles surrounding the GFM tends to be decreased (a). The collagen fraction of HIPP and GFM AD vessels is not significantly different from that of their NDCTRL counterparts (b). Cerebral amyloid angiopathy-affected (CAA+) arterioles show exacerbation of the α-SMA loss, which is not observed for CAA+ small and medium-sized arteries (c). NDCTRL, AD CAA−, and AD CAA+ vessels have similar collagen fractions (c). The graphs represent the mean ± SE of 10 vessels/vessel category/subject of a total of 45 subjects; *p < 0.05, **p < 0.01, and ***p < 0.001 as determined by a two-tailed unpaired Student’s t test corrected for multiple comparisons (Holm–Sidak test, α = 0.05)

Mentions: All data were expressed as the mean ± SE and were analysed using MATLAB™ (The MathWorks, Inc., Natick, MA, USA) and GraphPad Prism (GraphPad, Inc., La Jolla, CA, USA). CAA+ and CAA− blood vessels were analysed separately, except for the analyses shown in Fig. 2a, b. Blood vessels of the same type (i.e. arterioles, small arteries, or medium-sized arteries) were pooled per antemortem cognitive status of the subjects (AD or NDCTRL), CAA fraction, or Braak stage, depending on the analysis. The significance of the differences between each vessel type and the respective parameter of interest was determined using a two-tailed unpaired Student’s t test corrected for multiple comparisons (Holm–Sidak test, α = 0.05). Correlations were determined using Spearman’s correlation ρs (α = 0.05, CI 95 %, two tailed), except for the analyses of Braak pathology vs. arterial elastin degradation for which Pearson’s correlation ρp was used (α = 0.05, CI 95 %, two tailed) according to a d’Agostino–Pearson omnibus normality test.Fig. 2


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)

Quantification of collagen and alpha smooth muscle actin in leptomeningeal arterioles and arteries of Alzheimer’s disease and non-demented control subjects. Leptomeningeal vessels surrounding the hippocampus (HIPP) of Alzheimer’s disease (AD) subjects show a significant decrease in alpha smooth muscle actin (α-SMA) compared to vessels of non-demented control (NDCTRL) subjects (a). The α-SMA fraction of small and medium-sized leptomeningeal AD arteries surrounding the gyrus frontalis medials (GFM) is also significantly decreased; the α-SMA fraction of leptomeningeal AD arterioles surrounding the GFM tends to be decreased (a). The collagen fraction of HIPP and GFM AD vessels is not significantly different from that of their NDCTRL counterparts (b). Cerebral amyloid angiopathy-affected (CAA+) arterioles show exacerbation of the α-SMA loss, which is not observed for CAA+ small and medium-sized arteries (c). NDCTRL, AD CAA−, and AD CAA+ vessels have similar collagen fractions (c). The graphs represent the mean ± SE of 10 vessels/vessel category/subject of a total of 45 subjects; *p < 0.05, **p < 0.01, and ***p < 0.001 as determined by a two-tailed unpaired Student’s t test corrected for multiple comparisons (Holm–Sidak test, α = 0.05)
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Fig2: Quantification of collagen and alpha smooth muscle actin in leptomeningeal arterioles and arteries of Alzheimer’s disease and non-demented control subjects. Leptomeningeal vessels surrounding the hippocampus (HIPP) of Alzheimer’s disease (AD) subjects show a significant decrease in alpha smooth muscle actin (α-SMA) compared to vessels of non-demented control (NDCTRL) subjects (a). The α-SMA fraction of small and medium-sized leptomeningeal AD arteries surrounding the gyrus frontalis medials (GFM) is also significantly decreased; the α-SMA fraction of leptomeningeal AD arterioles surrounding the GFM tends to be decreased (a). The collagen fraction of HIPP and GFM AD vessels is not significantly different from that of their NDCTRL counterparts (b). Cerebral amyloid angiopathy-affected (CAA+) arterioles show exacerbation of the α-SMA loss, which is not observed for CAA+ small and medium-sized arteries (c). NDCTRL, AD CAA−, and AD CAA+ vessels have similar collagen fractions (c). The graphs represent the mean ± SE of 10 vessels/vessel category/subject of a total of 45 subjects; *p < 0.05, **p < 0.01, and ***p < 0.001 as determined by a two-tailed unpaired Student’s t test corrected for multiple comparisons (Holm–Sidak test, α = 0.05)
Mentions: All data were expressed as the mean ± SE and were analysed using MATLAB™ (The MathWorks, Inc., Natick, MA, USA) and GraphPad Prism (GraphPad, Inc., La Jolla, CA, USA). CAA+ and CAA− blood vessels were analysed separately, except for the analyses shown in Fig. 2a, b. Blood vessels of the same type (i.e. arterioles, small arteries, or medium-sized arteries) were pooled per antemortem cognitive status of the subjects (AD or NDCTRL), CAA fraction, or Braak stage, depending on the analysis. The significance of the differences between each vessel type and the respective parameter of interest was determined using a two-tailed unpaired Student’s t test corrected for multiple comparisons (Holm–Sidak test, α = 0.05). Correlations were determined using Spearman’s correlation ρs (α = 0.05, CI 95 %, two tailed), except for the analyses of Braak pathology vs. arterial elastin degradation for which Pearson’s correlation ρp was used (α = 0.05, CI 95 %, two tailed) according to a d’Agostino–Pearson omnibus normality test.Fig. 2

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