title: Seizure susceptibility and mortality in mice that over-express amyloid precursor protein.
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 beta-amyloid (Abeta). In order to create a mouse model to specifically study the effects of APP and Abeta 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 nontransgenic 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 Abeta increased seizure susceptibility.
authors.affiliation: Department of Pathology & Laboratory Medicine, Waisman Center for Developmental Disabilities, University of Wisconsin Madison, WI 53705, USA. westmark@facstaff.wisc.edu
authors.forename: Cara J
authors.initials: CJ
authors.lastname: Westmark
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Westmark
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Beard
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Hildebrandt
authors.forename: James S
authors.initials: JS
authors.lastname: Malter
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