title: Inhibition of amyloid precursor protein secretases reduces recovery after spinal cord injury.
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.
authors.affiliation: The George Washington University, Washington, DC, United States. Electronic address: ahdeah@gwu.edu.
authors.forename: Ahdeah
authors.initials: A
authors.lastname: Pajoohesh-Ganji
authors.affiliation: Georgetown University, Washington, DC, United States.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Burns
authors.affiliation: The George Washington University, Washington, DC, United States.
authors.forename: Sonali
authors.initials: S
authors.lastname: Pal-Ghosh
authors.affiliation: The George Washington University, Washington, DC, United States.
authors.forename: Gauri
authors.initials: G
authors.lastname: Tadvalkar
authors.affiliation: The George Washington University, Washington, DC, United States; Georgetown University, Washington, DC, United States; University of Maryland, Baltimore, United States.
authors.forename: Nicole G
authors.initials: NG
authors.lastname: Hokenbury
authors.affiliation: The George Washington University, Washington, DC, United States.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Stepp
authors.affiliation: University of Maryland, Baltimore, United States.
authors.forename: Alan I
authors.initials: AI
authors.lastname: Faden
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors
chemical_list: D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D053764:Presenilin-1; C580804:presenilin 1, mouse; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
keywords: Amyloid precursor protein; Amyloid-β; Bace1; Spinal cord injury; γ-Secretase