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Ann Neurol. 2019 Oct;86(4):561-571. doi: 10.1002/ana.25562. Epub 2019 Aug 19.

Early Aβ reduction prevents progression of cerebral amyloid angiopathy.

Author information

1
German Center for Neurodegenerative Diseases, Tübingen, Germany.
2
Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
3
TU Wien, Vienna, Austria.
4
Center for Brain Research, Medical University of Vienna, Vienna, Austria.
5
Institute of Anatomy, University of Zürich, Zürich, Switzerland.
6
Institute for Biomedical Engineering, University and Swiss Federal Institute for Technology, Zürich, Switzerland.
7
Novartis Institutes for Biomedical Research, Basel, Switzerland.

Abstract

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.

PMID:
31359452
DOI:
10.1002/ana.25562

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