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Twofold overexpression of human β‐amyloid precursor proteins in transgenic mice does not affect the neuromotor, cognitive, or neurodegenerative sequelae following experimental brain injury
Author(s) -
Murai Hisayuki,
Pierce Jean E.S.,
Raghupathi Ramesh,
Smith Douglas H.,
Saatman Kathryn E.,
Trojanowski John Q.,
Lee Virginia M.Y.,
Loring Jeanne F.,
Eckman Chris,
Younkin Steven,
McIntosh Tracy K.
Publication year - 1998
Publication title -
journal of comparative neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.855
H-Index - 209
eISSN - 1096-9861
pISSN - 0021-9967
DOI - 10.1002/(sici)1096-9861(19980323)392:4<428::aid-cne2>3.0.co;2-2
Subject(s) - affect (linguistics) , biology , genetically modified mouse , neuroscience , transgene , cognition , amyloid precursor protein , amyloid (mycology) , amyloid β , disease , alzheimer's disease , pathology , psychology , gene , biochemistry , medicine , communication , botany
By using transgenic mice that overexpress human β‐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, β‐amyloid (Aβ), neurofilament proteins, and glial fibrillary acidic protein, whereas Aβ 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‐injured animals, a significant decrease in brain concentrations of only Aβ terminating at amino acid 40 (Aβx‐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 Aβ (i.e., Aβx‐42/43) in these mice. J. Comp. Neurol. 392:428–438, 1998. © 1998 Wiley‐Liss, Inc.

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