DBA/2J Genetic Background Exacerbates Spontaneous Lethal Seizures but Lessens Amyloid Deposition in a Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is a leading cause of dementia in the elderly and is characterized by amyloid plaques, neurofibrillary tangles (NFTs) and neuronal dysfunction. Early onset AD (EOAD) is commonly caused by mutations in amyloid precursor protein (APP) or genes involved in the processing of APP including the presenilins (e.g. PSEN1 or PSEN2). In general, mouse models relevant to EOAD recapitulate amyloidosis, show only limited amounts of NFTs and neuronal cell dysfunction and low but significant levels of seizure susceptibility. To investigate the effect of genetic background on these phenotypes, we generated APP(swe) and PSEN1(de9) transgenic mice on the seizure prone inbred strain background, DBA/2J. Previous studies show that the DBA/2J genetic background modifies plaque deposition in the presence of mutant APP but the impact of PSEN1(de9) has not been tested. Our study shows that DBA/2J.APP(swe)PSEN1(de9) mice are significantly more prone to premature lethality, likely to due to lethal seizures, compared to B6.APP(swe)PSEN1(de9) mice—70% of DBA/2J.APP(swe)PSEN1(de9) mice die between 2-3 months of age. Of the DBA/2J.APP(swe)PSEN1(de9) mice that survived to 6 months of age, plaque deposition was greatly reduced compared to age-matched B6.APP(swe)PSEN1(de9) mice. The reduction in plaque deposition appears to be independent of microglia numbers, reactive astrocytosis and complement C5 activity.