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Early Aβ reduction prevents progression of cerebral amyloid angiopathy


Abstract

OBJECTIVE:
Clinical trials targeting Aβ for Alzheimer's disease (AD) failed for arguable reasons that include selecting the wrong stages of AD pathophysiology or Aβ being the wrong target at all. 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 degree 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 (HCHWA-D). Mice were treated with a BACE1 inhibitor. 3D-ultramicroscopy and immunoassays were used for visualizing CAA and assessing Aβ in CSF and brain.

RESULTS:
CAA onset in mice was at 22-24 mo of age, 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 that combined reduction of CSF Aβ40 and 42 is a specific biomarker for vascular amyloid. BACE1 inhibitor treatment starting at CAA onset and continued for 4 mo 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. This article is protected by copyright. All rights reserved.

Abstract

OBJECTIVE:
Clinical trials targeting Aβ for Alzheimer's disease (AD) failed for arguable reasons that include selecting the wrong stages of AD pathophysiology or Aβ being the wrong target at all. 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 degree 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 (HCHWA-D). Mice were treated with a BACE1 inhibitor. 3D-ultramicroscopy and immunoassays were used for visualizing CAA and assessing Aβ in CSF and brain.

RESULTS:
CAA onset in mice was at 22-24 mo of age, 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 that combined reduction of CSF Aβ40 and 42 is a specific biomarker for vascular amyloid. BACE1 inhibitor treatment starting at CAA onset and continued for 4 mo 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. This article is protected by copyright. All rights reserved.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Anatomy
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Neurology, Clinical Neurology
Language:English
Date:1 October 2019
Deposited On:21 Aug 2019 11:11
Last Modified:17 Sep 2019 20:30
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0364-5134
OA Status:Green
Publisher DOI:https://doi.org/10.1002/ana.25562

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