title: Caspase inhibition therapy abolishes brain trauma-induced increases in Abeta peptide: implications for clinical outcome.
abstract: The detrimental effects of traumatic brain injury (TBI) on brain tissue integrity involve progressive axonal damage, necrotic cell loss, and both acute and delayed apoptotic neuronal death due to activation of caspases. Post-injury accumulation of amyloid precursor protein (APP) and its toxic metabolite amyloid-beta peptide (Abeta) has been implicated in apoptosis as well as in increasing the risk for developing Alzheimer's disease (AD) after TBI. Activated caspases proteolyze APP and are associated with increased Abeta production after neuronal injury. Conversely, Abeta and related APP/Abeta fragments stimulate caspase activation, creating a potential vicious cycle of secondary injury after TBI. Blockade of caspase activation after brain injury suppresses apoptosis and improves neurological outcome, but it is not known whether such intervention also prevents increases in Abeta levels in vivo. The present study examined the effect of caspase inhibition on post-injury levels of soluble Abeta, APP, activated caspase-3, and caspase-cleaved APP in the hippocampus of nontransgenic mice expressing human Abeta, subjected to controlled cortical injury (CCI). CCI produced brain tissue damage with cell loss and elevated levels of activated caspase-3, Abeta(1-42) and Abeta(1-40), APP, and caspase-cleaved APP fragments in hippocampal neurons and axons. Post-CCI intervention with intracerebroventricular injection of 100 nM Boc-Asp(OMe)-CH(2)F (BAF, a pan-caspase inhibitor) significantly reduced caspase-3 activation and improved histological outcome, suppressed increases in Abeta and caspase-cleaved APP, but showed no significant effect on overall APP levels in the hippocampus after CCI. These data demonstrate that after TBI, caspase inhibition can suppress elevations in Abeta. The extent to which Abeta suppression contributes to improved outcome following inhibition of caspases after TBI is unclear, but such intervention may be a valuable therapeutic strategy for preventing the long-term evolution of Abeta-mediated pathology in TBI patients who are at risk for developing AD later in life.
authors.affiliation: Department of Neurology, University of Pittsburgh School of Medicine, 3471 Fifth Avenue, Suite 811, 15213, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Abrahamson
authors.forename: Milos D
authors.initials: MD
authors.lastname: Ikonomovic
authors.forename: John R
authors.initials: JR
authors.lastname: Ciallella
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Hope
authors.forename: William R
authors.initials: WR
authors.lastname: Paljug
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Isanski
authors.forename: Dorothy G
authors.initials: DG
authors.lastname: Flood
authors.forename: Robert S B
authors.initials: RS
authors.lastname: Clark
authors.forename: Steven T
authors.initials: ST
authors.lastname: DeKosky
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D001930:Brain Injuries / Q000139:chemically induced / Q000378:metabolism*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D007839:Functional Laterality; D006624:Hippocampus / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism*; D013266:Stilbamidines / Q000378:metabolism; D013997:Time Factors
chemical_list: C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D061945:Caspase Inhibitors; D010446:Peptide Fragments; D013266:Stilbamidines; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C413643:benzyloxycarbonyl-aspartyl(O-methyl)fluoromethane; D001224:Aspartic Acid; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases