Research Articlep35 Hemizygous Deletion in 5xFAD Mice Increases Aβ Plaque Load in Males but Not in Females
Section snippets
INTRODUCTION
Increased amyloid β (Aβ) peptide deposition has been implicated in early stages of Alzheimer's disease (AD) (Selkoe and Hardy, 2016). Recent PET scan studies and cerebrospinal fluid (CSF) analysis have shown increased Aβ levels prior to the appearance of other pathological hallmarks of AD, such as neurofibrillary tangles and neuronal loss (Bateman et al., 2012, Jack and Holtzman, 2013). Aβ production occurs through the sequential cleavage of the amyloid precursor protein (APP) by β-site APP
Animals
B6 congenic 5xFAD transgenic (Tg) mice were obtained from Jackson Laboratories (Bar Harbor, ME). The 5xFAD mice co-express Swedish, London and Florida mutations in human APP, as well as two presenilin-1 (PS1) mutations under the control of Thy-1 promotor. These mice exhibit plaque deposition at 2 months of age, along with increased microgliosis and astrocytosis (Oakley et al., 2006). These 5xFAD mice were crossed with p35+/− mice maintained on a B6 background (Hallows et al., 2003) to generate
Aβ plaque load is increased in the cortex of p35 hemizygous null male 5xFAD mice but not females
It has been reported previously that 5xFAD mice show increased p25 levels starting around 2 months of age (Oakley et al., 2006, Sadleir and Vassar, 2012). However our examination of 6-month old 5xFAD mice show that p25 and p35 levels are not statistically different between 5xFAD and non-transgenic male or female mice (Fig. 1A). This could be due to the difference in the genetic background of 5xFAD mice used in our study. The animals used in this study were in B6 genetic background whereas the
DISCUSSION
A potential role of p25 in AD has been highlighted by a number of studies reporting elevated levels of p25 in the postmortem brains of AD patients (Patrick et al., 1999, Tseng et al., 2002, Swatton et al., 2004, Sadleir and Vassar, 2012). Likewise, the microRNA family miR-15/107, which post-transcriptionally downregulates p35 expression, is reduced in the hippocampus and temporal cortex of the AD brain (Moncini et al., 2017). These findings suggest that p35 and p25 may play a role in AD.
Acknowledgements
We would like to thank Austin Waddell for his help in brain sectioning. This work was supported in part by start-up funds and a Faculty Research and Creative Endeavors grant from Central Michigan University. TB participated in study design, performed all the experiments, analyzed data, and drafted manuscript. YM analyzed data and edited the manuscript. KP conceived of the study, designed and coordinated research, analyzed data, and drafted and edited the manuscript. All authors read and
Declarations of interest
None.
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