Hippocampal overexpression of Down syndrome cell adhesion molecule in amyloid precursor protein transgenic mice.

Yong-Lin Jia ,Zhihui Fu ,B.h Zhang ,Yanjie Jia

doi:10.1590/1414-431x20176049

Abstract

Down syndrome cell adhesion molecule (DSCAM) is located within the Down syndrome critical region of chromosome 21. DSCAM is a broadly expressed neurodevelopmental protein involved in synaptogenesis, neurite outgrowth, and axon guidance. We previously demonstrated DSCAM overexpression in the cortex of amyloid precursor protein (APP) transgenic mice, suggesting possible regulatory interactions between APP and DSCAM. APP mice exhibit deficits in hippocampus-dependent learning and memory. In this preliminary study, we examined age-related changes in DSCAM expression within the hippocampus in 16 APP transgenic mice (1, 3, 6 and 12 months old). Hippocampus-dependent spatial memory was assessed in APP mice and age-matched wild type littermates (WTs) using the Morris water maze (MWM). The cellular distribution of hippocampal DSCAM and total expression at both mRNA and protein levels were measured by immunohistochemistry, qRT-PCR, and western blotting, respectively. APP mice exhibited spatial memory deficits in the MWM. Intense DSCAM immunoreactivity was observed in the dentate gyrus granule cell layer and hippocampal stratum pyramidale. Total hippocampal DSCAM mRNA and protein expression levels were substantially higher in APP mice than WTs at 1 and 3 months of age. Expression decreased with age in both groups but remained higher in APP mice. DSCAM is overexpressed in the hippocampus over the first 12 months of life in APP mice, but especially during maturation to adulthood. In conclusion, these results suggest an association between DSCAM and APP mice, which is characterized by neuropathology and behavioral deficits. These results provide some clues for future studies on the role of DSCAM overexpression in the precocious cognitive decline observed in APP transgenic mice.

Highlights

Down syndrome (DS) phenotypes are determined by trisomy of a particular region of chromosome 21 known as the Down syndrome critical region (DSCR)
Down syndrome cell adhesion molecule (DSCAM) is highly expressed in the cerebral cortex, granule layer of the dentate gyrus, pyramidal cell layer of Ammon’s horn of the hippocampus, thalamus, and cerebellar Purkinje cells of both wild type littermates (WTs) (Figure 2A,C,E) and amyloid precursor protein (APP) transgenic mice (Figure 2B,D,F)
reverse-transcription polymerase chain reaction (RT-PCR) (Figure 3B) and western blotting (Figure 3A) demonstrated substantial overexpression of DSCAM mRNA and protein in the hippocampus of APP mice compared with WTs during maturation to adulthood (1 and 3 months of age; Po0.05)

Summary

Introduction

Down syndrome (DS) phenotypes are determined by trisomy of a particular region of chromosome 21 known as the Down syndrome critical region (DSCR). Increased copy number of the genes in the DSCR are believed to cause the clinical manifestations of DS through overexpression of their protein products [1]. Neuropathological research has identified congenital and developmental abnormalities associated with precocious dementia in DS. The former include a decrease in granular cell number in the cerebral cortex, most likely the aspinous stellate cell type [2]. Subjects with DS develop senile plaques and neurofibrillary tangles in the prefrontal and hippocampal cortex with concomitant age-related dementia resembling that observed in Alzheimer’s disease (AD)

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Results

Conclusion