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Altered DNA repair; an early pathogenic pathway in Alzheimer’s disease and obesity.

Altered DNA repair; an early pathogenic pathway in Alzheimer’s disease and obesity.
Author Information (click to view)

Yu H, Harrison FE, Xia F,


Yu H, Harrison FE, Xia F, (click to view)

Yu H, Harrison FE, Xia F,

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Scientific reports 2018 04 048(1) 5600 doi 10.1038/s41598-018-23644-4

Abstract

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 γ-H2AX for DSBs, RAD51, and 53BP1, which represent the functional status of HR and NHEJ, respectively. Increased γ-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 (γ-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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