Presenilin 1-related alterations in DNA integrity in a transgenic mouse model of Alzheimer's disease

The present study tested the hypothesis that mutations in amyloid precursor protein (APP) and presenilin (PS) 1 result in alterations in the amount of nuclear (n) DNA repair and nDNA damage in neurons in vivo. To this end, the relative amount of nDNA repair was measured in 8-month-old transgenic mice expressing either human mutant APP (APP751SL mice), human mutant PS1 (PS1M146L mice) or both human mutant APP and PS1 (APP751SL/PS1M146L mice) with unscheduled DNA synthesis, and the relative amount of nDNA single strand breaks (SSB) with in situ nick translation. APP751SL/PS1M146L mice showed a significantly decreased relative amount of nDNA repair in pyramidal cells in hippocampal area CA1/2 compared to APP751SL mice. Furthermore, PS1M146L mice showed a significantly increased relative amount of nDNA SSB in both granule cells in the dentate gyrus and pyramidal cells in area CA1/2 compared to both APP751SL mice and APP751SL/PS1M146L mice. These results might indicate a previously unknown action of mutations in PS1 on DNA integrity, which might be involved in the pathophysiologic processes of mutant PS1 in Alzheimer's disease.