IJCEP Copyright © 2007-All rights reserved.
Int J Clin Exp Pathol 1(2):157-168;2008

Original Article
Seizure Susceptibility and Mortality in Mice that Over-Express Amyloid Precursor Protein

Cara J. Westmark, Pamela R. Westmark, Ashley M. Beard, Sharon M. Hildebrandt and James S. Malter

Department of Pathology & Laboratory Medicine, Waisman Center for Developmental Disabilities, University of Wisconsin, Madison, WI 53705

Received 16 July 2007; accepted and available online 1 January 2008

Abstract: Alzheimer’s disease and Fragile X syndrome both display synaptic phenotypes, and based on recent studies, likely share dendritic
over expression of amyloid precursor protein (APP) and β-amyloid (Aβ). In order to create a mouse model to specifically study the effects of
APP and Aβ at synapses, we crossed Tg2576, which over-express human APP with the Swedish mutation (hAPPsw), with fmr-1 KO mice. The
progeny, named FRAXAD, displayed increased mortality (23% by 30 days of age) compared to Tg2576 (3%) and WT and fmr-1 KO littermate
controls (0%) consistent with a developmental defect. By 60 days of age, both the Tg2576 and FRAXAD mice approached a 40% mortality rate
compared to 0% for WT and fmr-1 KO littermates. To understand the mechanism underlying increased mortality in APP over-expressing mice,
we assessed seizure thresholds in response to pentylenetetrazol (PTZ). Both the Tg2576 and FRAXAD mice had a lower threshold to PTZ-
induced seizures (average seizure score of ≥4.0) in comparison to non-transgenic littermates (average seizure score 1.9-2.9). Seizures are a
major phenotype of AD, FXS, Down syndrome, autism and epilepsy, and these data suggested that developmental over-expression of
dendritic APP or Aβ increased seizure susceptibility. (IJCEP707007).

Key Words: amyloid, amyloid precursor protein, Fragile X mental retardation protein, FRAXAD, seizure, synapse

Full Text  PDF

Supplementary data:  Supplementary figures & Table ,  video 1, video 2, video 3, video 4 and video 5.

Address all correspondence to: Dr. Cara J. Westmark, Department of Pathology & Laboratory Medicine, Waisman Center for Developmental
Disabilities, University of Wisconsin, Madison, WI 53705. Email:
westmark@facstaff.wisc.edu