Abstract
Amyloid-β (Aβ) is produced through the enzymatic cleavage of amyloid precursor protein (APP) by β (Bace1) and γ-secretases. The accumulation and aggregation of Aβ as amyloid plaques is the hallmark pathology of Alzheimer׳s disease and has been found in other neurological disorders, such as traumatic brain injury and multiple sclerosis. Although the role of Aβ after injury is not well understood, several studies have reported a negative correlation between Aβ formation and functional outcome. In this study we show that levels of APP, the enzymes cleaving APP (Bace1 and γ-secretase), and Aβ are significantly increased from 1 to 3 days after impact spinal cord injury (SCI) in mice. To determine the role of Aβ after SCI, we reduced or inhibited Aβ in vivo through pharmacological (using DAPT) or genetic (Bace1 knockout mice) approaches. We found that these interventions significantly impaired functional recovery as evaluated by white matter sparing and behavioral testing. These data are consistent with a beneficial role for Aβ after SCI.
Keywords:
Amyloid precursor protein; Amyloid-β; Bace1; Spinal cord injury; γ-Secretase.
Copyright © 2014 Elsevier B.V. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid Precursor Protein Secretases / antagonists & inhibitors
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Amyloid Precursor Protein Secretases / genetics
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Amyloid Precursor Protein Secretases / metabolism*
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Amyloid beta-Protein Precursor / metabolism*
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Animals
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Aspartic Acid Endopeptidases / genetics
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Aspartic Acid Endopeptidases / metabolism*
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Blotting, Western
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Enzyme Inhibitors / pharmacology
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Enzyme-Linked Immunosorbent Assay
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Fluorescent Antibody Technique
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Mice, Inbred C57BL
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Mice, Knockout
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Microglia / physiology
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Motor Activity / drug effects
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Motor Activity / physiology
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Nerve Fibers, Myelinated / drug effects
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Nerve Fibers, Myelinated / metabolism
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Nerve Fibers, Myelinated / pathology
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Presenilin-1 / antagonists & inhibitors
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Presenilin-1 / metabolism*
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Recovery of Function / drug effects
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Recovery of Function / physiology*
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Spinal Cord / drug effects
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Spinal Cord / metabolism*
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Spinal Cord / pathology
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Spinal Cord Injuries / drug therapy
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Spinal Cord Injuries / metabolism*
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Spinal Cord Injuries / pathology
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Time Factors
Substances
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Amyloid beta-Protein Precursor
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Enzyme Inhibitors
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Presenilin-1
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presenilin 1, mouse
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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Bace1 protein, mouse