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

International Journal of Clinical and Experimental Pathology

Ashley M Beard¹  James S Malter¹  Sharon M Hildebrandt¹  Cara J Westmark¹  Pamela R Westmark¹ 

关键词: amyloid;    amyloid precursor protein;    Fragile X mental retardation protein;    FRAXAD;    seizure;    synapse;   

DOI  :  

学科分类：生理学与病理学

来源: e-Century Publishing Corporation

【 摘 要 】

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 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 Aβ increased seizure susceptibility.

【 授权许可】

Unknown