title: Tau pathology-dependent remodelling of cerebral arteries precedes Alzheimer's disease-related microvascular cerebral amyloid angiopathy.
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.
authors.affiliation: Institute for Regenerative Medicine - IREM, University of Zurich, Schlieren Campus, Wagistrasse 12, 8952, Schlieren, Switzerland. mario.merlini@uzh.ch.|Center for Molecular Cardiology - Vascular Aging and Stroke, University of Zurich, Schlieren Campus, Wagistrasse 12, 8952, Schlieren, Switzerland. mario.merlini@uzh.ch.
authors.forename: Mario
authors.initials: M
authors.lastname: Merlini
authors.affiliation: Faculty of Science, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
authors.forename: Debora
authors.initials: D
authors.lastname: Wanner
authors.affiliation: Institute for Regenerative Medicine - IREM, University of Zurich, Schlieren Campus, Wagistrasse 12, 8952, Schlieren, Switzerland.
authors.forename: Roger M
authors.initials: RM
authors.lastname: Nitsch
mesh_terms: D000199:Actins / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000473:pathology*; D000704:Analysis of Variance; D001812:Blood-Brain Barrier / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D016657:Cerebral Amyloid Angiopathy / Q000000981:diagnostic imaging / Q000473:pathology*; D003094:Collagen / Q000378:metabolism; D018450:Disease Progression; D004549:Elastin / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D055806:Microvessels / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D009426:Netherlands; D059906:Neuroimaging; D011569:Psychiatric Status Rating Scales; D012189:Retrospective Studies; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D016875:tau Proteins; D003094:Collagen; D004549:Elastin
keywords: Cerebrovascular pathology; Collagen; Hyperphosphorylated tau; Internal elastic lamina; Neutrophil elastase; Vascular smooth muscle