Caspase-3-Mediated Cleavage of Amyloid Precursor Protein and Formation of AmyloidβPeptide in Traumatic Axonal Injury
- 1 May 2002
- journal article
- research article
- Published by Mary Ann Liebert Inc in Journal of Neurotrauma
- Vol. 19 (5), 601-614
- https://doi.org/10.1089/089771502753754073
Abstract
Immunohistochemical studies demonstrate accumulation of the β-amyloid precursor protein (APP) within injured axons following traumatic brain injury (TBI). Despite such descriptions, little is known about the ultimate fate of accumulating APP at sites of traumatic axonal injury (TAI). Recently, caspase-3-mediated cleavage of APP and subsequent Aβ deposition was linked to apoptotic neuronal death pathways in hippocampal neurons following ischemic and excitotoxic brain injury. Given that (1) APP is known to accumulate within traumatically injured axons, (2) caspase-3 activation has been demonstrated in traumatic axonal injury (TAI), and (3) recent studies have identified a caspase-3 cleavage site within APP, we initiated the current investigation to determine whether caspase-3-mediated cleavage of APP occurs in TAI. We further assessed whether these events were found in relation to Aβ peptide formation. To this end, we employed antibodies targeting APP, the caspase-3-mediated breakdown product of APP proteolysis, and the Aβ peptide. Rats were subjected to impact acceleration TBI (6 h to 10 days survival), and their brains were processed for single-label bright field and multiple double-label immunofluorescent paradigms using the above antibodies. By 12 h postinjury, caspase-3-mediated APP proteolysis (CMAP) was demonstrated within the medial lemniscus (ML) and medial longitudinal fasciculus (MLF) in axons undergoing TAI, identified by their concomitant APP accumulation. Immunoreactivity for CMAP persisted up to 48 h postinjury in the ML and MLF, but was notably reduced by 10 days following injury. Further, CMAP was colocalized with Aβ formation in foci of TAI. The current study demonstrates that caspase-3 cleavage of APP occurs in TAI and is associated with formation of Aβ peptide. These findings are of interest given recent epidemiological studies supporting an association between TBI and later risk for AD development.Keywords
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