title: Twofold overexpression of human beta-amyloid precursor proteins in transgenic mice does not affect the neuromotor, cognitive, or neurodegenerative sequelae following experimental brain injury.
abstract: By using transgenic mice that overexpress human beta-amyloid precursor proteins (APPs) at levels twofold higher than endogenous APPs, following introduction of the human APP gene in a yeast artificial chromosome (YAC), we examined the effects of controlled cortical impact (CCI) brain injury on neuromotor/cognitive dysfunction and the development of Alzheimer's disease (AD)-like neuropathology. Neuropathological analyses included Nissl-staining and immunohistochemistry to detect APPs, beta-amyloid (Abeta), neurofilament proteins, and glial fibrillary acidic protein, whereas Abeta levels were measured in brain homogenates from mice subjected to CCI and control mice by using a sensitive sandwich enzyme-linked immunosorbent assay. Twenty APP-YAC transgenic mice and 17 wild type (WT) littermate controls were anesthetized and subjected to CCI (velocity, 5 m/second; deformation depth, 1 mm). Sham (anesthetized but uninjured) controls (n = 10 APP-YAC; n = 8 WT) also were studied. Motor function was evaluated by using rotarod, inclined-plane, and forelimb/hindlimb flexion tests. The Morris water maze was used to assess memory. Although CCI induced significant motor dysfunction and cognitive deficits, no differences were observed between brain-injured APP-YAC mice and WT mice at 24 hours and 1 week postinjury. By 1 week postinjury, both cortical and hippocampal CA3 neuron loss as well as extensive astrogliosis were observed in all injured animals, suggesting that overexpression of human APPs exhibited no neuroprotective effects. Although AD-like pathology (including amyloid plaques) was not observed in either sham or brain-inj ured animals, a significant decrease in brain concentrations of only Abeta terminating at amino acid 40 (Abeta x-40) was observed following brain injury in APP-YAC mice (P < 0.05 compared with sham control levels). Our data show that the APP-YAC mice do not develop AD-like neuropathology following traumatic brain injury. This may be because this injury does not induce elevated levels of the more amyloidogenic forms of human Abeta (i.e., Abeta x-42/43) in these mice.
authors.affiliation: Department of Neurosurgery, University of Pennsylvania, Philadelphia 19104, USA.
authors.forename: H
authors.initials: H
authors.lastname: Murai
authors.forename: J E
authors.initials: JE
authors.lastname: Pierce
authors.forename: R
authors.initials: R
authors.lastname: Raghupathi
authors.forename: D H
authors.initials: DH
authors.lastname: Smith
authors.forename: K E
authors.initials: KE
authors.lastname: Saatman
authors.forename: J Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: V M
authors.initials: VM
authors.lastname: Lee
authors.forename: J F
authors.initials: JF
authors.lastname: Loring
authors.forename: C
authors.initials: C
authors.lastname: Eckman
authors.forename: S
authors.initials: S
authors.lastname: Younkin
authors.forename: T K
authors.initials: TK
authors.lastname: McIntosh
mesh_terms: D016229:Amyloid beta-Peptides / Q000032:analysis / Q000235:genetics*; D000818:Animals; D001522:Behavior, Animal; D001930:Brain Injuries / Q000378:metabolism / Q000503:physiopathology*; D003071:Cognition / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D007074:Immunoglobulin G / Q000032:analysis / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000502:physiology*; D009046:Motor Neurons / Q000737:chemistry / Q000502:physiology*; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology; D016900:Neurofilament Proteins / Q000032:analysis; D014048:Tolonium Chloride
chemical_list: D016229:Amyloid beta-Peptides; D005904:Glial Fibrillary Acidic Protein; D007074:Immunoglobulin G; D016900:Neurofilament Proteins; C044882:neurofilament protein L; D014048:Tolonium Chloride