Brain Gene Expression of a Sporadic (icv-STZ Mouse) and a Familial Mouse Model (3xTg-AD Mouse) of Alzheimer’s Disease

Yanxing Chen,Moon H Lee,Frank M Laferla,Chun-Ling Dai,Inge Grundke-Iqbal,Khalid Iqbal,Shenggang Sun,Cheng-Xin Gong,Fei Liu,Zhihou Liang,Zhu Tian,Emmanuel Planel

doi:10.1371/journal.pone.0051432

Abstract

Alzheimer’s disease (AD) can be divided into sporadic AD (SAD) and familial AD (FAD). Most AD cases are sporadic and may result from multiple etiologic factors, including environmental, genetic and metabolic factors, whereas FAD is caused by mutations of presenilins or amyloid-β (Aβ) precursor protein (APP). A commonly used mouse model for AD is 3xTg-AD mouse, which is generated by over-expression of mutated presenilin 1, APP and tau in the brain and thus represents a mouse model of FAD. A mouse model generated by intracerebroventricular (icv) administration of streptozocin (STZ), icv-STZ mouse, shows many aspects of SAD. Despite the wide use of these two models for AD research, differences in gene expression between them are not known. Here, we compared the expression of 84 AD-related genes in the hippocampus and the cerebral cortex between icv-STZ mice and 3xTg-AD mice using a custom-designed qPCR array. These genes are involved in APP processing, tau/cytoskeleton, synapse function, apoptosis and autophagy, AD-related protein kinases, glucose metabolism, insulin signaling, and mTOR pathway. We found altered expression of around 20 genes in both mouse models, which affected each of above categories. Many of these gene alterations were consistent with what was observed in AD brain previously. The expression of most of these altered genes was decreased or tended to be decreased in the hippocampus of both mouse models. Significant diversity in gene expression was found in the cerebral cortex between these two AD mouse models. More genes related to synaptic function were dysregulated in the 3xTg-AD mice, whereas more genes related to insulin signaling and glucose metabolism were down-regulated in the icv-STZ mice. The present study provides important fundamental knowledge of these two AD mouse models and will help guide future studies using these two mouse models for the development of AD drugs.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia, and the population of the affected people is growing due to increased life expectancy
An extensively studied and used animal model is the triple transgenic mouse model, the 3xTg-AD mouse, which was generated by co-injecting two independent transgenic constructs encoding the Swedish mutations of human amyloid precursor protein (APP) (APPSwe) and tauP301L into single-cell embryos harvested from the mutant homozygous PS1M146V knock in mice [3]
Our custom-designed qPCR array included 84 genes that have been implicated in AD

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia, and the population of the affected people is growing due to increased life expectancy. The major pathological hallmarks of AD brain are senile plaques, consisting predominantly of extracellular amyloid-b (Ab) peptides, and neurofibrillary tangles (NFTs), consisting of polymerized hyperphosphorylated tau protein. FAD constitutes ,1% of all AD cases and is caused by mutations in b-amyloid precursor protein (APP), presenilin 1 or 2 [1,2]. An extensively studied and used animal model is the triple transgenic mouse model, the 3xTg-AD mouse, which was generated by co-injecting two independent transgenic constructs encoding the Swedish mutations of human APP (APPSwe) and tauP301L into single-cell embryos harvested from the mutant homozygous PS1M146V knock in mice [3]. The 3xTg-AD mouse develops both amyloid plaques and NFTs in an age-and regiondependent manner [3,4,5]

Methods

Results

Conclusion