TWOFOLD OVEREXPRESSION OF HUMAN BETA-AMYLOID PRECURSOR PROTEINS IN TRANSGENIC MICE DOES NOT AFFECT THE NEUROMOTOR, COGNITIVE, OR NEURODEGENERATIVE SEQUELAE FOLLOWING EXPERIMENTAL BRAIN INJURY

By using transgenic mice that overexpress human beta-amyloid precursor proteins (APPs) at levels twofold higher than endogenous APPs, follow ing introduction of the human APP gene in a yeast artificial chromosom e (YAC), we examined the effects of controlled cortical impact (CCI) b rain injury on neuromotor/cognitive dysfunction and the development of Alzheimer's disease (AD)-like neuropathology. Neuropathological analy ses included Nissl-staining and immunohistochemistry to detect APPs, b eta-amyloid (A beta), neurofilament proteins, and glial fibrillary aci dic protein, whereas A beta levels were measured in brain homogenates from mice subjected to CCI and control mice by using a sensitive sandw ich enzyme-linked immunosorbent assay. Twenty APP-YAC transgenic mice and 17 wild type (WT) littermate controls were anesthetized and subjec ted to CCI (velocity, 5 m/second; deformation depth, 1 mm). Sham (anes thetized 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 a nd cognitive deficits, no differences were observed between brain-inju red APP-YAC mice and WT mice at 24 hours and 1 week postinjury. By 1 w eek postinjury, both cortical and hippocampal CA3 neuron loss as well as extensive astrogliosis were observed in all injured animals, sugges ting that overexpression of human APPs exhibited no neuroprotective ef fects. Although AD-like pathology (including amyloid plaques) was not observed in either sham or brain-injured animals, a significant decrea se in brain concentrations of only A beta terminating at amino acid 40 (APx-40) was observed following brain injury in APP-YAC mice (P < 0.0 5 compared with sham control levels). Our data show that the APP-YAC m ice do. not develop AD-like neuropathology following traumatic brain i njury. This may be because this injury does not induce elevated levels of the more amyloidogenic forms of human A beta (i.e., A beta x-42/43 ) in these mice. (C) 1998 Wiley-Liss, Inc.