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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.


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Relationship between cerebral amyloid angiopathy burden and the collagen and alpha-smooth muscle actin fraction of leptomeningeal arterioles and arteries. Leptomeningeal arterioles with the highest cerebral amyloid angiopathy (CAA) burden (“CAA fraction”) surrounding the gyrus frontalis medialis (GFM) and hippocampus (HIPP) show a significant decrease in the alpha-smooth muscle actin (α-SMA) fraction (a), whereas CAA burden does not affect these fractions in the leptomeningeal small arteries (b) and medium-sized arteries (c). None of the vessels show an effect of CAA burden on the collagen fraction (a–c). Mean ± SE of ~30–70 vessels/vessel category; **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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Fig3: Relationship between cerebral amyloid angiopathy burden and the collagen and alpha-smooth muscle actin fraction of leptomeningeal arterioles and arteries. Leptomeningeal arterioles with the highest cerebral amyloid angiopathy (CAA) burden (“CAA fraction”) surrounding the gyrus frontalis medialis (GFM) and hippocampus (HIPP) show a significant decrease in the alpha-smooth muscle actin (α-SMA) fraction (a), whereas CAA burden does not affect these fractions in the leptomeningeal small arteries (b) and medium-sized arteries (c). None of the vessels show an effect of CAA burden on the collagen fraction (a–c). Mean ± SE of ~30–70 vessels/vessel category; **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: To further analyse the CAA-independent decrease in the α-SMA fraction of the small- and medium-sized arteries in AD, and to determine whether the apparent effect of CAA on the α-SMA fraction of the arterioles in AD correlated with the degree of CAA burden, we analysed the α-SMA fraction at the different CAA fractions (Fig. 3). The vessels were categorised according to their calculated vessel CAA fraction. As shown in Fig. 3a, the α-SMA fraction was significantly decreased in arterioles with the highest CAA fraction/burden (CAA fraction 0.5–1.5 vs. 0–0.05: 63 % decreased, p < 0.001; CAA fraction 0.5–1.5 vs. 0.05–0.5: 51 % decreased, p < 0.05), and tended to be decreased in arterioles with a CAA fraction between 0.05 and 0.5 compared to those with a CAA fraction between 0 and 0.05. A Spearman’s correlation analysis revealed that arteriolar CAA burden and α-SMA loss were correlated (CAA and α-SMA: ρs = −0.422, 95 % CI −0.557 to −0.265, p < 0.0001). In line with the results found for small and medium-sized arteries of AD subjects with and without CAA (Fig. 2c, “CAA+” and “CAA−”), no significant CAA-dependent change in the α-SMA fraction was observed in either of these artery types (Fig. 3b). Further analysis revealed again that none of the vessels showed significant changes in their collagen fraction (Fig. 3, right graphs).Fig. 3


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)

Relationship between cerebral amyloid angiopathy burden and the collagen and alpha-smooth muscle actin fraction of leptomeningeal arterioles and arteries. Leptomeningeal arterioles with the highest cerebral amyloid angiopathy (CAA) burden (“CAA fraction”) surrounding the gyrus frontalis medialis (GFM) and hippocampus (HIPP) show a significant decrease in the alpha-smooth muscle actin (α-SMA) fraction (a), whereas CAA burden does not affect these fractions in the leptomeningeal small arteries (b) and medium-sized arteries (c). None of the vessels show an effect of CAA burden on the collagen fraction (a–c). Mean ± SE of ~30–70 vessels/vessel category; **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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Fig3: Relationship between cerebral amyloid angiopathy burden and the collagen and alpha-smooth muscle actin fraction of leptomeningeal arterioles and arteries. Leptomeningeal arterioles with the highest cerebral amyloid angiopathy (CAA) burden (“CAA fraction”) surrounding the gyrus frontalis medialis (GFM) and hippocampus (HIPP) show a significant decrease in the alpha-smooth muscle actin (α-SMA) fraction (a), whereas CAA burden does not affect these fractions in the leptomeningeal small arteries (b) and medium-sized arteries (c). None of the vessels show an effect of CAA burden on the collagen fraction (a–c). Mean ± SE of ~30–70 vessels/vessel category; **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: To further analyse the CAA-independent decrease in the α-SMA fraction of the small- and medium-sized arteries in AD, and to determine whether the apparent effect of CAA on the α-SMA fraction of the arterioles in AD correlated with the degree of CAA burden, we analysed the α-SMA fraction at the different CAA fractions (Fig. 3). The vessels were categorised according to their calculated vessel CAA fraction. As shown in Fig. 3a, the α-SMA fraction was significantly decreased in arterioles with the highest CAA fraction/burden (CAA fraction 0.5–1.5 vs. 0–0.05: 63 % decreased, p < 0.001; CAA fraction 0.5–1.5 vs. 0.05–0.5: 51 % decreased, p < 0.05), and tended to be decreased in arterioles with a CAA fraction between 0.05 and 0.5 compared to those with a CAA fraction between 0 and 0.05. A Spearman’s correlation analysis revealed that arteriolar CAA burden and α-SMA loss were correlated (CAA and α-SMA: ρs = −0.422, 95 % CI −0.557 to −0.265, p < 0.0001). In line with the results found for small and medium-sized arteries of AD subjects with and without CAA (Fig. 2c, “CAA+” and “CAA−”), no significant CAA-dependent change in the α-SMA fraction was observed in either of these artery types (Fig. 3b). Further analysis revealed again that none of the vessels showed significant changes in their collagen fraction (Fig. 3, right graphs).Fig. 3

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