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Int J Clin Exp Pathol 2010;3(1):56-68
Original Article
MPEP Reduces Seizure Severity in Fmr-1 KO Mice Over Expressing Human Aβ
Cara J. Westmark, Pamela R. Westmark, James S. Malter
Department of Pathology & Laboratory Medicine and Waisman Center for Developmental Disabilities, University of Wisconsin, Madison, WI
53705, USA
Received July 17, 2009; accepted September 20, 2009; Available online October 10, 2009
Abstract: Metabotropic glutamate receptor 5 (mGluR5) regulates the translation of amyloid precursor protein (APP) mRNA. Under resting
conditions, mRNA is bound to and translationally repressed by the fragile X mental retardation protein (FMRP). Upon group 1 mGluR activation,
FMRP dissociates from the mRNA and translation ensues. APP levels are elevated in the dendrites of primary neuronal cultures as well as in
synaptoneurosomes (SN) prepared from embryonic and juvenile fmr-1 knockout (KO) mice, respectively. In order to study the effects of APP
and its proteolytic product Aβ on Fragile X syndrome (FXS) phenotypes, we created a novel mouse model (FRAXAD) that over-expresses
human APPSwe/Aβ in an fmr-1 KO background. Herein, we assess (1) human APPSwe and Aβ levels as a function of age in FRAXAD mice,
and (2) seizure susceptibility to pentylenetetrazol (PTZ) after mGluR5 blockade. PTZinduced seizure severity is decreased in FRAXAD mice pre-
treated with the mGluR5 antagonist MPEP. These data suggest that Aβ contributes to seizure incidence and may be an appropriate therapeutic
target to lessen seizure pathology in FXS, Alzheimer’s disease (AD) and Down syndrome (DS) patients.(IJCEP907006).
Key words: APP, β-amyloid, FMRP, FRAXAD, PTZ, seizure, Tg2576
Full text PDF
Address all correspondence to:
Christine A. Iacobuzio-Donahue, MD, PhD
Departments of Pathology and Oncology
The Sol Goldman Pancreatic Cancer Research Center
Johns Hopkins Medical Institutions
Baltimore, MD, USA
E-mail: westmark@wisc.edu
Original Article
MPEP Reduces Seizure Severity in Fmr-1 KO Mice Over Expressing Human Aβ
Cara J. Westmark, Pamela R. Westmark, James S. Malter
Department of Pathology & Laboratory Medicine and Waisman Center for Developmental Disabilities, University of Wisconsin, Madison, WI
53705, USA
Received July 17, 2009; accepted September 20, 2009; Available online October 10, 2009
Abstract: Metabotropic glutamate receptor 5 (mGluR5) regulates the translation of amyloid precursor protein (APP) mRNA. Under resting
conditions, mRNA is bound to and translationally repressed by the fragile X mental retardation protein (FMRP). Upon group 1 mGluR activation,
FMRP dissociates from the mRNA and translation ensues. APP levels are elevated in the dendrites of primary neuronal cultures as well as in
synaptoneurosomes (SN) prepared from embryonic and juvenile fmr-1 knockout (KO) mice, respectively. In order to study the effects of APP
and its proteolytic product Aβ on Fragile X syndrome (FXS) phenotypes, we created a novel mouse model (FRAXAD) that over-expresses
human APPSwe/Aβ in an fmr-1 KO background. Herein, we assess (1) human APPSwe and Aβ levels as a function of age in FRAXAD mice,
and (2) seizure susceptibility to pentylenetetrazol (PTZ) after mGluR5 blockade. PTZinduced seizure severity is decreased in FRAXAD mice pre-
treated with the mGluR5 antagonist MPEP. These data suggest that Aβ contributes to seizure incidence and may be an appropriate therapeutic
target to lessen seizure pathology in FXS, Alzheimer’s disease (AD) and Down syndrome (DS) patients.(IJCEP907006).
Key words: APP, β-amyloid, FMRP, FRAXAD, PTZ, seizure, Tg2576
Full text PDF
Address all correspondence to:
Christine A. Iacobuzio-Donahue, MD, PhD
Departments of Pathology and Oncology
The Sol Goldman Pancreatic Cancer Research Center
Johns Hopkins Medical Institutions
Baltimore, MD, USA
E-mail: westmark@wisc.edu
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