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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

Relationship between Braak pathology, the collagen and alpha-smooth muscle actin fraction of leptomeningeal arterioles and arteries, and perivascular accumulation of phosphorylated paired helical filament tau. Small and medium-sized leptomeningeal arteries surrounding the gyrus frontalis medialis (GFM) and hippocampus (HIPP) show a significant reduction in the alpha-smooth muscle actin (α-SMA) fraction between Braak stage I and II–III, which remains reduced throughout the later Braak stages; leptomeningeal arterioles show a significant α-SMA loss only at Braak stage V and VI (a). The collagen fraction of only small arteries is significantly changed (i.e. reduced) with increasing Braak stage (b). 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). Intraparenchymal perivascular accumulation of phosphorylated paired helical filament tau (PHF-tau) (cupper panel PHF-tau staining: area indicated by arrowheads is shown enlarged in inset; asterisks indicate intraneuronal PHF-tau) is accompanied by α-SMA loss (cupper panel α-SMA staining: arrowheads point to discontinuous α-SMA staining; enlarged in inset). Compare with the largely continuous, uniform α-SMA staining of a small intraparenchymal artery without perivascular PHF-tau accumulation (clower two panels; PHF-tau staining: arrowhead points to absence of perivascular PHF-tau; area indicated by arrowhead is shown enlarged in inset; asterisks indicate intraneuronal PHF-tau). The proportion of subjects per Braak stage with parenchymal perivascular PHF-tau accumulation is increased with increasing Braak tau pathology (d). All images were acquired from consecutive HIPP sections of a Braak stage II subject. Scale bar 50 μm
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Fig4: Relationship between Braak pathology, the collagen and alpha-smooth muscle actin fraction of leptomeningeal arterioles and arteries, and perivascular accumulation of phosphorylated paired helical filament tau. Small and medium-sized leptomeningeal arteries surrounding the gyrus frontalis medialis (GFM) and hippocampus (HIPP) show a significant reduction in the alpha-smooth muscle actin (α-SMA) fraction between Braak stage I and II–III, which remains reduced throughout the later Braak stages; leptomeningeal arterioles show a significant α-SMA loss only at Braak stage V and VI (a). The collagen fraction of only small arteries is significantly changed (i.e. reduced) with increasing Braak stage (b). 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). Intraparenchymal perivascular accumulation of phosphorylated paired helical filament tau (PHF-tau) (cupper panel PHF-tau staining: area indicated by arrowheads is shown enlarged in inset; asterisks indicate intraneuronal PHF-tau) is accompanied by α-SMA loss (cupper panel α-SMA staining: arrowheads point to discontinuous α-SMA staining; enlarged in inset). Compare with the largely continuous, uniform α-SMA staining of a small intraparenchymal artery without perivascular PHF-tau accumulation (clower two panels; PHF-tau staining: arrowhead points to absence of perivascular PHF-tau; area indicated by arrowhead is shown enlarged in inset; asterisks indicate intraneuronal PHF-tau). The proportion of subjects per Braak stage with parenchymal perivascular PHF-tau accumulation is increased with increasing Braak tau pathology (d). All images were acquired from consecutive HIPP sections of a Braak stage II subject. Scale bar 50 μm

Mentions: The difference in CAA dependence of α-SMA loss between the arterioles and the arteries (Figs. 2, 3), and the similarities in collagen content between AD, NDCTRL, CAA-, and non-CAA-affected vessels prompted us to study whether Braak tau pathology, independent of CAA and cognitive status of the subjects, might affect the cerebrovascular α-SMA and collagen content in our study population, and whether this might also be vessel type dependent. To this end, the α-SMA and collagen fractions of arterioles, small arteries, and medium-sized arteries without CAA (“CAA−”) were categorised according to Braak stage, rather than to antemortem clinical AD or NDCTRL diagnosis (Fig. 4). A significant decrease in the α-SMA fraction was observed for small and medium-sized arteries between Braak stage I and II–III (small arteries: ~25 % decrease, p < 0.05; medium-sized arteries: ~50 % decrease, p < 0.01). Although the α-SMA fraction of both artery types was not significantly different between Braak stage II and VI (Fig. 4a), comparison of the α-SMA fraction between Braak stage I and IV, I and V, and I and VI showed a further significant decrease in the α-SMA fraction of both artery types (p < 0.01–0.001). Separate correlation analysis considering all Braak stages and the respective α-SMA fraction showed that these two parameters were weakly correlated in the small arteries and moderately correlated in the medium-sized arteries (ρs small arteries = −0.216, 95 % CI −0.317 to −0.110, p < 0.001; ρs medium-sized arteries = −0.433, 95 % CI −0.640 to −0.167, p < 0.001). Similar to what was found by others [54], arteriolar α-SMA loss was not Braak stage dependent, and a significant decrease in the arteriolar α-SMA fraction was observed only at Braak stage V and VI (~40–45 % decrease, p < 0.05–0.01) (Fig. 4a).Fig. 4


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 Braak pathology, the collagen and alpha-smooth muscle actin fraction of leptomeningeal arterioles and arteries, and perivascular accumulation of phosphorylated paired helical filament tau. Small and medium-sized leptomeningeal arteries surrounding the gyrus frontalis medialis (GFM) and hippocampus (HIPP) show a significant reduction in the alpha-smooth muscle actin (α-SMA) fraction between Braak stage I and II–III, which remains reduced throughout the later Braak stages; leptomeningeal arterioles show a significant α-SMA loss only at Braak stage V and VI (a). The collagen fraction of only small arteries is significantly changed (i.e. reduced) with increasing Braak stage (b). 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). Intraparenchymal perivascular accumulation of phosphorylated paired helical filament tau (PHF-tau) (cupper panel PHF-tau staining: area indicated by arrowheads is shown enlarged in inset; asterisks indicate intraneuronal PHF-tau) is accompanied by α-SMA loss (cupper panel α-SMA staining: arrowheads point to discontinuous α-SMA staining; enlarged in inset). Compare with the largely continuous, uniform α-SMA staining of a small intraparenchymal artery without perivascular PHF-tau accumulation (clower two panels; PHF-tau staining: arrowhead points to absence of perivascular PHF-tau; area indicated by arrowhead is shown enlarged in inset; asterisks indicate intraneuronal PHF-tau). The proportion of subjects per Braak stage with parenchymal perivascular PHF-tau accumulation is increased with increasing Braak tau pathology (d). All images were acquired from consecutive HIPP sections of a Braak stage II subject. Scale bar 50 μm
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Fig4: Relationship between Braak pathology, the collagen and alpha-smooth muscle actin fraction of leptomeningeal arterioles and arteries, and perivascular accumulation of phosphorylated paired helical filament tau. Small and medium-sized leptomeningeal arteries surrounding the gyrus frontalis medialis (GFM) and hippocampus (HIPP) show a significant reduction in the alpha-smooth muscle actin (α-SMA) fraction between Braak stage I and II–III, which remains reduced throughout the later Braak stages; leptomeningeal arterioles show a significant α-SMA loss only at Braak stage V and VI (a). The collagen fraction of only small arteries is significantly changed (i.e. reduced) with increasing Braak stage (b). 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). Intraparenchymal perivascular accumulation of phosphorylated paired helical filament tau (PHF-tau) (cupper panel PHF-tau staining: area indicated by arrowheads is shown enlarged in inset; asterisks indicate intraneuronal PHF-tau) is accompanied by α-SMA loss (cupper panel α-SMA staining: arrowheads point to discontinuous α-SMA staining; enlarged in inset). Compare with the largely continuous, uniform α-SMA staining of a small intraparenchymal artery without perivascular PHF-tau accumulation (clower two panels; PHF-tau staining: arrowhead points to absence of perivascular PHF-tau; area indicated by arrowhead is shown enlarged in inset; asterisks indicate intraneuronal PHF-tau). The proportion of subjects per Braak stage with parenchymal perivascular PHF-tau accumulation is increased with increasing Braak tau pathology (d). All images were acquired from consecutive HIPP sections of a Braak stage II subject. Scale bar 50 μm
Mentions: The difference in CAA dependence of α-SMA loss between the arterioles and the arteries (Figs. 2, 3), and the similarities in collagen content between AD, NDCTRL, CAA-, and non-CAA-affected vessels prompted us to study whether Braak tau pathology, independent of CAA and cognitive status of the subjects, might affect the cerebrovascular α-SMA and collagen content in our study population, and whether this might also be vessel type dependent. To this end, the α-SMA and collagen fractions of arterioles, small arteries, and medium-sized arteries without CAA (“CAA−”) were categorised according to Braak stage, rather than to antemortem clinical AD or NDCTRL diagnosis (Fig. 4). A significant decrease in the α-SMA fraction was observed for small and medium-sized arteries between Braak stage I and II–III (small arteries: ~25 % decrease, p < 0.05; medium-sized arteries: ~50 % decrease, p < 0.01). Although the α-SMA fraction of both artery types was not significantly different between Braak stage II and VI (Fig. 4a), comparison of the α-SMA fraction between Braak stage I and IV, I and V, and I and VI showed a further significant decrease in the α-SMA fraction of both artery types (p < 0.01–0.001). Separate correlation analysis considering all Braak stages and the respective α-SMA fraction showed that these two parameters were weakly correlated in the small arteries and moderately correlated in the medium-sized arteries (ρs small arteries = −0.216, 95 % CI −0.317 to −0.110, p < 0.001; ρs medium-sized arteries = −0.433, 95 % CI −0.640 to −0.167, p < 0.001). Similar to what was found by others [54], arteriolar α-SMA loss was not Braak stage dependent, and a significant decrease in the arteriolar α-SMA fraction was observed only at Braak stage V and VI (~40–45 % decrease, p < 0.05–0.01) (Fig. 4a).Fig. 4

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