Journal
SCIENTIFIC REPORTS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-018-23644-4
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Funding
- National Institute on Aging [R01 AG038739]
- VA Merit [CX001610-01]
- NIH/NCI [R01 CA188500, R01 CA163838]
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Unrepaired DNA double-strand breaks (DSBs) are lethal. The present study compared the extent of DSBs, neuronal apoptosis, and status of two major DSB repair pathways - homologous combinational repair (HR) and nonhomologous end-joining (NHEJ) - in hippocampus of 5-6 month and 16-18 month-old wild-type and APP/PSEN1 mice fed control diet or high fat diet (60% fat from lard). We performed immunohistochemical staining and quantification for nuclear foci formation of gamma-H2AX for DSBs, RAD51, and 53BP1, which represent the functional status of HR and NHEJ, respectively. Increased gamma-H2AX and caspase-3 staining indicated greater DSBs and associated neuronal apoptosis in APP/PSEN1 mice at both ages studied. RAD51-positive foci were fewer in APP/PSEN1 indicating that HR processes may be diminished in these mice, although NHEJ (53BP1 staining) appeared unchanged. High fat diet in young wild-type mice led to similar changes to those observed in APP/PSEN1 mice (gamma-H2AX and caspase-3 staining, and fewer RAD51-positive foci). Overall, these data suggest that APP/PSEN1-and high fat diet-associated early accumulation of DSBs and neuronal cell death, resulted at least in part, from inhibition of HR, one of the major DSB repair pathways.
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