Limits...
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 Braak stage-dependent elastin degradation and neutrophil elastase presence in the wall of leptomeningeal arteries. Elastin in leptomeningeal arteries is degraded in a Braak stage-dependent manner, which differs between small and medium-sized leptomeningeal arteries (a). The percentage of small arteries with moderate (score 2) elastin degradation is increased between Braak stage II and VI; the percentage of small arteries with severe elastin degradation sharply increases between Braak stage II and III and remains at this level between Braak stage III and VI (aleft). The percentage of medium-sized leptomeningeal arteries with moderate elastin degradation (score 2) is increased between Braak stage II and III and remains at this level between Braak stage III and VI (aright). The overall percentage of medium-sized arteries with severe elastin degradation is not increased between Braak stage I and VI (a). Severe arterial elastin degradation [b Verhoeff–van Gieson (VVG) stain: arrow in inset indicates focal elastin loss] tends to be accompanied by increased vessel wall neutrophil elastase fractions (b Ntrelast: arrow; cbar graph). Confocal microscopy of Ntrelast in the arterial wall reveals Ntrelast expression by α-SMA-positive cells/smooth muscle cells [dright panel co-localisation (yellow) and arrows]. Ntrelast-positive cells attached to the luminal side of the intimal layer (darrowheads and asterisk) and present between the leptomeningeal layer and the adventitia (dnumber sign) are identified as neutrophils (Ntrelast is also a neutrophil-specific marker), and are not α-SMA-positive cells [dmiddle panel absence of α-SMA staining around DAPI-stained nuclei at the luminal side of the intimal layer (arrowheads and asterisk) and between the leptomeningeal layer and the adventitia (number sign)]. Some neutrophils have a flattened morphology (dleft and right panel: arrowheads), suggestive of diapedesis. Scale bar 20 μm
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4835519&req=5

Fig5: Quantification of Braak stage-dependent elastin degradation and neutrophil elastase presence in the wall of leptomeningeal arteries. Elastin in leptomeningeal arteries is degraded in a Braak stage-dependent manner, which differs between small and medium-sized leptomeningeal arteries (a). The percentage of small arteries with moderate (score 2) elastin degradation is increased between Braak stage II and VI; the percentage of small arteries with severe elastin degradation sharply increases between Braak stage II and III and remains at this level between Braak stage III and VI (aleft). The percentage of medium-sized leptomeningeal arteries with moderate elastin degradation (score 2) is increased between Braak stage II and III and remains at this level between Braak stage III and VI (aright). The overall percentage of medium-sized arteries with severe elastin degradation is not increased between Braak stage I and VI (a). Severe arterial elastin degradation [b Verhoeff–van Gieson (VVG) stain: arrow in inset indicates focal elastin loss] tends to be accompanied by increased vessel wall neutrophil elastase fractions (b Ntrelast: arrow; cbar graph). Confocal microscopy of Ntrelast in the arterial wall reveals Ntrelast expression by α-SMA-positive cells/smooth muscle cells [dright panel co-localisation (yellow) and arrows]. Ntrelast-positive cells attached to the luminal side of the intimal layer (darrowheads and asterisk) and present between the leptomeningeal layer and the adventitia (dnumber sign) are identified as neutrophils (Ntrelast is also a neutrophil-specific marker), and are not α-SMA-positive cells [dmiddle panel absence of α-SMA staining around DAPI-stained nuclei at the luminal side of the intimal layer (arrowheads and asterisk) and between the leptomeningeal layer and the adventitia (number sign)]. Some neutrophils have a flattened morphology (dleft and right panel: arrowheads), suggestive of diapedesis. Scale bar 20 μm

Mentions: The arterial internal elastic lamina is formed by vascular smooth muscle-derived elastin and plays an important role in vessel wall distension and recoil at normally elevated blood pressure levels [44, 58]. Elastin can be degraded enzymatically, chiefly by neutrophil- and/or vascular smooth muscle-derived neutrophil elastase, and by chronic hypertensive vessel wall stress [31, 34, 42, 43]. Importantly, vessel wall collagen governs vessel wall distension during high-pressure vessel wall stress [44, 58]. Given the significant Braak stage-dependent α-SMA loss in both the small and medium-sized arteries and collagen loss in the small arteries (Fig. 4), we hypothesised that arterial elastin might also be affected by Braak tau pathology. Indeed, quantification of arterial elastin degradation revealed a Braak stage-dependent increase in the percentage of small arteries with moderate elastin degradation (score 2, 26 % increase) between Braak stage II and VI, which was accompanied by a decrease in the percentage of small arteries without (score 0, 42 % decrease) and with mild (score 1, 32 % decrease) elastin degradation (Fig. 5a, left). However, between Braak stage I and II, the percentage of small arteries in all three elastin degradation categories was decreased, which was reflected by an increase in the percentage of vessels without elastin degradation (score 0, ~40 % increase). The percentage of small arteries with severe elastin degradation was sharply increased between Braak stage II and III (score 3, 33 % increase), and largely remained at this level at the later Braak stages. The elastin degradation in the medium-sized arteries was less severe than that observed in the small arteries, and followed a different pattern (Fig. 5a, right). The percentage of medium-sized arteries with mild and moderate elastin degradation was increased between Braak stage II and IV (score 1, 33 % increase; score 2, 16 % increase). However, the percentage of medium-sized arteries with mild elastin degradation was sharply decreased between Braak stage IV and VI (score 1, 26 % decrease), and this was accompanied by an increase in the medium-sized arteries without elastin degradation (score 0, 33 % increase) (Fig. 5a). The percentage of medium-sized arteries with moderate elastin degradation, however, remained largely stable between Braak stage III and VI (score 2, 25 and 23 %, respectively) (Fig. 5a). The percentage of medium-sized arteries with severe elastin degradation was not changed considerably between all Braak stages analysed (score 3, ~6–9 %), except at Braak stage III (score 3, 19 %) and V (score 3, 13 %) (Fig. 5a). CAA appeared to affect elastin integrity only in the rare number of small and medium-sized arteries affected heavily by CAA in which CAA was present in the media (Fig. 1c: c1 and c2), but not in the small and medium-sized arteries with adventitial CAA burden only (Fig. 1c: c3 and c4).Fig. 5


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 Braak stage-dependent elastin degradation and neutrophil elastase presence in the wall of leptomeningeal arteries. Elastin in leptomeningeal arteries is degraded in a Braak stage-dependent manner, which differs between small and medium-sized leptomeningeal arteries (a). The percentage of small arteries with moderate (score 2) elastin degradation is increased between Braak stage II and VI; the percentage of small arteries with severe elastin degradation sharply increases between Braak stage II and III and remains at this level between Braak stage III and VI (aleft). The percentage of medium-sized leptomeningeal arteries with moderate elastin degradation (score 2) is increased between Braak stage II and III and remains at this level between Braak stage III and VI (aright). The overall percentage of medium-sized arteries with severe elastin degradation is not increased between Braak stage I and VI (a). Severe arterial elastin degradation [b Verhoeff–van Gieson (VVG) stain: arrow in inset indicates focal elastin loss] tends to be accompanied by increased vessel wall neutrophil elastase fractions (b Ntrelast: arrow; cbar graph). Confocal microscopy of Ntrelast in the arterial wall reveals Ntrelast expression by α-SMA-positive cells/smooth muscle cells [dright panel co-localisation (yellow) and arrows]. Ntrelast-positive cells attached to the luminal side of the intimal layer (darrowheads and asterisk) and present between the leptomeningeal layer and the adventitia (dnumber sign) are identified as neutrophils (Ntrelast is also a neutrophil-specific marker), and are not α-SMA-positive cells [dmiddle panel absence of α-SMA staining around DAPI-stained nuclei at the luminal side of the intimal layer (arrowheads and asterisk) and between the leptomeningeal layer and the adventitia (number sign)]. Some neutrophils have a flattened morphology (dleft and right panel: arrowheads), suggestive of diapedesis. Scale bar 20 μm
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835519&req=5

Fig5: Quantification of Braak stage-dependent elastin degradation and neutrophil elastase presence in the wall of leptomeningeal arteries. Elastin in leptomeningeal arteries is degraded in a Braak stage-dependent manner, which differs between small and medium-sized leptomeningeal arteries (a). The percentage of small arteries with moderate (score 2) elastin degradation is increased between Braak stage II and VI; the percentage of small arteries with severe elastin degradation sharply increases between Braak stage II and III and remains at this level between Braak stage III and VI (aleft). The percentage of medium-sized leptomeningeal arteries with moderate elastin degradation (score 2) is increased between Braak stage II and III and remains at this level between Braak stage III and VI (aright). The overall percentage of medium-sized arteries with severe elastin degradation is not increased between Braak stage I and VI (a). Severe arterial elastin degradation [b Verhoeff–van Gieson (VVG) stain: arrow in inset indicates focal elastin loss] tends to be accompanied by increased vessel wall neutrophil elastase fractions (b Ntrelast: arrow; cbar graph). Confocal microscopy of Ntrelast in the arterial wall reveals Ntrelast expression by α-SMA-positive cells/smooth muscle cells [dright panel co-localisation (yellow) and arrows]. Ntrelast-positive cells attached to the luminal side of the intimal layer (darrowheads and asterisk) and present between the leptomeningeal layer and the adventitia (dnumber sign) are identified as neutrophils (Ntrelast is also a neutrophil-specific marker), and are not α-SMA-positive cells [dmiddle panel absence of α-SMA staining around DAPI-stained nuclei at the luminal side of the intimal layer (arrowheads and asterisk) and between the leptomeningeal layer and the adventitia (number sign)]. Some neutrophils have a flattened morphology (dleft and right panel: arrowheads), suggestive of diapedesis. Scale bar 20 μm
Mentions: The arterial internal elastic lamina is formed by vascular smooth muscle-derived elastin and plays an important role in vessel wall distension and recoil at normally elevated blood pressure levels [44, 58]. Elastin can be degraded enzymatically, chiefly by neutrophil- and/or vascular smooth muscle-derived neutrophil elastase, and by chronic hypertensive vessel wall stress [31, 34, 42, 43]. Importantly, vessel wall collagen governs vessel wall distension during high-pressure vessel wall stress [44, 58]. Given the significant Braak stage-dependent α-SMA loss in both the small and medium-sized arteries and collagen loss in the small arteries (Fig. 4), we hypothesised that arterial elastin might also be affected by Braak tau pathology. Indeed, quantification of arterial elastin degradation revealed a Braak stage-dependent increase in the percentage of small arteries with moderate elastin degradation (score 2, 26 % increase) between Braak stage II and VI, which was accompanied by a decrease in the percentage of small arteries without (score 0, 42 % decrease) and with mild (score 1, 32 % decrease) elastin degradation (Fig. 5a, left). However, between Braak stage I and II, the percentage of small arteries in all three elastin degradation categories was decreased, which was reflected by an increase in the percentage of vessels without elastin degradation (score 0, ~40 % increase). The percentage of small arteries with severe elastin degradation was sharply increased between Braak stage II and III (score 3, 33 % increase), and largely remained at this level at the later Braak stages. The elastin degradation in the medium-sized arteries was less severe than that observed in the small arteries, and followed a different pattern (Fig. 5a, right). The percentage of medium-sized arteries with mild and moderate elastin degradation was increased between Braak stage II and IV (score 1, 33 % increase; score 2, 16 % increase). However, the percentage of medium-sized arteries with mild elastin degradation was sharply decreased between Braak stage IV and VI (score 1, 26 % decrease), and this was accompanied by an increase in the medium-sized arteries without elastin degradation (score 0, 33 % increase) (Fig. 5a). The percentage of medium-sized arteries with moderate elastin degradation, however, remained largely stable between Braak stage III and VI (score 2, 25 and 23 %, respectively) (Fig. 5a). The percentage of medium-sized arteries with severe elastin degradation was not changed considerably between all Braak stages analysed (score 3, ~6–9 %), except at Braak stage III (score 3, 19 %) and V (score 3, 13 %) (Fig. 5a). CAA appeared to affect elastin integrity only in the rare number of small and medium-sized arteries affected heavily by CAA in which CAA was present in the media (Fig. 1c: c1 and c2), but not in the small and medium-sized arteries with adventitial CAA burden only (Fig. 1c: c3 and c4).Fig. 5

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