Presenilin 1-related alterations in DNA integrity in a transgenic mouse model of Alzheimer's disease
Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.Brain research (Impact Factor: 2.84). 02/2010; 1316:139-44. DOI: 10.1016/j.brainres.2009.12.033
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.
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ABSTRACT: Objective To investigate the effect of ovarian estrogen on autophagy and senile plaques (SP) in the brain of adult APP/PS1 double transgenic mice, and inquire into the mechanism of Alzheimer disease (AD) neuropathogenesis due to estrogen deficiency. Methods APP/PS1 AD mice (3-month old) were divided into ovariectomy group (OVX-AD) and sham group (sham-AD). Two months after operation, transmission electron microscopy (TEM) was employed to observe the morphological structures of the brains of AD model mice, and immunohistochemical staining was performed to examine the changes in SP and autophagy-related proteins LC3 and Beclin-1 in the brain of AD model mice. Results Immunohistochemical staining showed that the number of SP in the brain of OVX-AD mice incrcased significantly compared with that in sham-AD mice, and distribution of SP was observed more extensively, including the cortex and hippocampus. The autophagy related proteins LC3 and Beclin-1 positive neurons were decreased greatly in the OVX-AD mice brain compared with that of sham-AD mice. TEM revealed a larger number of swollen and dark neurons in hippocampus of OVX-AD mice, while more autophagosome was observed around the neuronal processes in OVX-AD mice brain compared with sham-AD mice. Conclusion Estrogen deficiency may lead to delayed maturation of autophagy, decrease the activity and weaken the function of autophagy, which in turn may result in aggravation of pathological features of AD.Medical Journal of Chinese People's Liberation Army 01/2015; 40(1):26-29. DOI:10.11855/j.issn.0577-7402.2015.01.06
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