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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

Proposed model of early Braak stage, tau pathology-dependent remodelling of cerebral arteries instigating cerebral amyloid angiopathy-related microvascular pathology. In the vascular system under healthy, physiological conditions (a), arteries cushion the blood propulsion wave amplitudes originating from aortic blood propulsions by distension of their vessel wall. This mechanism ensures that the blood propulsion wave amplitudes are decreased such that the ones experienced by the downstream, relatively fragile arterioles and capillaries are proportional to their small vessel wall distension capacity. Arterial elastin degradation and vascular smooth muscle loss start at early Braak tau stages (b), coincide with increasing (perivascular) tau pathology, and reduce the arterial wall distension, compliance, and overall arterial blood flow-regulating capacity. Consequently, arterial cushioning of aortic blood propulsion waves is diminished, increasing the distension and shear stress experienced by the arterioles and capillaries. With time, this pathologic, artery-driven mechanism contributes to remodelling of cerebral microvessels and the development of cerebral amyloid angiopathy (CAA)-related microvascular pathology characteristic in Alzheimer’s disease (AD)
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Fig6: Proposed model of early Braak stage, tau pathology-dependent remodelling of cerebral arteries instigating cerebral amyloid angiopathy-related microvascular pathology. In the vascular system under healthy, physiological conditions (a), arteries cushion the blood propulsion wave amplitudes originating from aortic blood propulsions by distension of their vessel wall. This mechanism ensures that the blood propulsion wave amplitudes are decreased such that the ones experienced by the downstream, relatively fragile arterioles and capillaries are proportional to their small vessel wall distension capacity. Arterial elastin degradation and vascular smooth muscle loss start at early Braak tau stages (b), coincide with increasing (perivascular) tau pathology, and reduce the arterial wall distension, compliance, and overall arterial blood flow-regulating capacity. Consequently, arterial cushioning of aortic blood propulsion waves is diminished, increasing the distension and shear stress experienced by the arterioles and capillaries. With time, this pathologic, artery-driven mechanism contributes to remodelling of cerebral microvessels and the development of cerebral amyloid angiopathy (CAA)-related microvascular pathology characteristic in Alzheimer’s disease (AD)

Mentions: We propose a disease model in which the loss of arterial vascular smooth muscle and degradation of arterial elastin are related to early Braak tau pathology (“Arterial Pathology Stage”) (Fig. 6). This arterial remodelling impairs the arterial wall distension dynamics that drive perivascular clearance and decreases the arteries’ aortic blood propulsion wave cushioning capacity, which increases the distension and shear stress on the downstream, relatively fragile arteriolar and capillary walls [51]. With time, this microvessel wall stress leads to pathologic arteriolar and capillary remodelling and, ultimately, contributes to CAA- and AD-related microvascular pathology (Fig. 6, “Microvascular Pathology Stage”). Thus, a combination of vessel-specific therapeutics that protect and improve cerebral vessel wall dynamics and, hence, cerebral perfusion/clearance, and therapeutics directed against neuronal or aggregated protein targets may hold more promise than AD monotherapy.Fig. 6


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)

Proposed model of early Braak stage, tau pathology-dependent remodelling of cerebral arteries instigating cerebral amyloid angiopathy-related microvascular pathology. In the vascular system under healthy, physiological conditions (a), arteries cushion the blood propulsion wave amplitudes originating from aortic blood propulsions by distension of their vessel wall. This mechanism ensures that the blood propulsion wave amplitudes are decreased such that the ones experienced by the downstream, relatively fragile arterioles and capillaries are proportional to their small vessel wall distension capacity. Arterial elastin degradation and vascular smooth muscle loss start at early Braak tau stages (b), coincide with increasing (perivascular) tau pathology, and reduce the arterial wall distension, compliance, and overall arterial blood flow-regulating capacity. Consequently, arterial cushioning of aortic blood propulsion waves is diminished, increasing the distension and shear stress experienced by the arterioles and capillaries. With time, this pathologic, artery-driven mechanism contributes to remodelling of cerebral microvessels and the development of cerebral amyloid angiopathy (CAA)-related microvascular pathology characteristic in Alzheimer’s disease (AD)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig6: Proposed model of early Braak stage, tau pathology-dependent remodelling of cerebral arteries instigating cerebral amyloid angiopathy-related microvascular pathology. In the vascular system under healthy, physiological conditions (a), arteries cushion the blood propulsion wave amplitudes originating from aortic blood propulsions by distension of their vessel wall. This mechanism ensures that the blood propulsion wave amplitudes are decreased such that the ones experienced by the downstream, relatively fragile arterioles and capillaries are proportional to their small vessel wall distension capacity. Arterial elastin degradation and vascular smooth muscle loss start at early Braak tau stages (b), coincide with increasing (perivascular) tau pathology, and reduce the arterial wall distension, compliance, and overall arterial blood flow-regulating capacity. Consequently, arterial cushioning of aortic blood propulsion waves is diminished, increasing the distension and shear stress experienced by the arterioles and capillaries. With time, this pathologic, artery-driven mechanism contributes to remodelling of cerebral microvessels and the development of cerebral amyloid angiopathy (CAA)-related microvascular pathology characteristic in Alzheimer’s disease (AD)
Mentions: We propose a disease model in which the loss of arterial vascular smooth muscle and degradation of arterial elastin are related to early Braak tau pathology (“Arterial Pathology Stage”) (Fig. 6). This arterial remodelling impairs the arterial wall distension dynamics that drive perivascular clearance and decreases the arteries’ aortic blood propulsion wave cushioning capacity, which increases the distension and shear stress on the downstream, relatively fragile arteriolar and capillary walls [51]. With time, this microvessel wall stress leads to pathologic arteriolar and capillary remodelling and, ultimately, contributes to CAA- and AD-related microvascular pathology (Fig. 6, “Microvascular Pathology Stage”). Thus, a combination of vessel-specific therapeutics that protect and improve cerebral vessel wall dynamics and, hence, cerebral perfusion/clearance, and therapeutics directed against neuronal or aggregated protein targets may hold more promise than AD monotherapy.Fig. 6

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