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 (APP751(SL) mice), human mutant PS1 (PS1(M146L) mice) or both human mutant APP and PS1 (APP751(SL)/PS1(M146L) mice) with unscheduled DNA synthesis, and the relative amount of nDNA single strand breaks (SSB) with in situ nick translation. APP751(SL)/PS1(M146L) mice showed a significantly decreased relative amount of nDNA repair in pyramidal cells in hippocampal area CA1/2 compared to APP751(SL) mice. Furthermore, PS1(M146L) 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 APP751(SL) mice and APP751(SL)/PS1(M146L) 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.
Michelsen
Kimmo A
KA
Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. k.michelsen@maastrichtuniversity.nl
Korr
Hubert
H
Steinbusch
Harry W M
HW
Schmitz
Christoph
C
D000544:Alzheimer Disease / Q000235:genetics* / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000502:physiology; D053904:DNA Breaks, Single-Stranded; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000502:physiology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism
C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D058255:Protease Nexins; D011956:Receptors, Cell Surface