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Tytuł:
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Early Aβ reduction prevents progression of cerebral amyloid angiopathy.
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Autorzy:
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Schelle, Juliane
Wegenast‐Braun, Bettina M.
Fritschi, Sarah K.
Kaeser, Stephan A.
Jährling, Nina
Eicke, Daniel
Skodras, Angelos
Beschorner, Natalie
Obermueller, Ulrike
Häsler, Lisa M.
Wolfer, David P.
Mueggler, Thomas
Shimshek, Derya R.
Neumann, Ulf
Dodt, Hans‐Ulrich
Staufenbiel, Matthias
Jucker, Mathias
Wegenast-Braun, Bettina M
Dodt, Hans-Ulrich
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Temat:
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CEREBRAL amyloid angiopathy
AMYLOID beta-protein precursor
CEREBRAL hemorrhage
CEREBROSPINAL fluid
AMYLOID
BRAIN metabolism
DISEASE progression
BRAIN
RESEARCH
ANIMAL experimentation
RESEARCH methodology
EVALUATION research
MEDICAL cooperation
COMPARATIVE studies
RESEARCH funding
PEPTIDES
MICE
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Źródło:
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Annals of Neurology; Oct2019, Vol. 86 Issue 4, p561-571, 11p
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Objective: Clinical trials targeting β-amyloid peptides (Aβ) for Alzheimer disease (AD) failed for arguable reasons that include selecting the wrong stages of AD pathophysiology or Aβ being the wrong target. Targeting Aβ to prevent cerebral amyloid angiopathy (CAA) has not been rigorously followed, although the causal role of Aβ for CAA and related hemorrhages is undisputed. CAA occurs with normal aging and to various degrees in AD, where its impact and treatment is confounded by the presence of parenchymal Aβ deposition.Methods: APPDutch mice develop CAA in the absence of parenchymal amyloid, mimicking hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D). Mice were treated with a β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor. We used 3-dimensional ultramicroscopy and immunoassays for visualizing CAA and assessing Aβ in cerebrospinal fluid (CSF) and brain.Results: CAA onset in mice was at 22 to 24 months, first in frontal leptomeningeal and superficial cortical vessels followed by vessels penetrating the cortical layers. CSF Aβ increased with aging followed by a decrease of both Aβ40 and Aβ42 upon CAA onset, supporting the idea that combined reduction of CSF Aβ40 and Aβ42 is a specific biomarker for vascular amyloid. BACE1 inhibitor treatment starting at CAA onset and continuing for 4 months revealed a 90% Aβ reduction in CSF and largely prevented CAA progression and associated pathologies.Interpretation: This is the first study showing that Aβ reduction at early disease time points largely prevents CAA in the absence of parenchymal amyloid. Our observation provides a preclinical basis for Aβ-reducing treatments in patients at risk of CAA and in presymptomatic HCHWA-D. ANN NEUROL 2019;86:561-571. [ABSTRACT FROM AUTHOR]
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