Early and sustained altered expression of aging-related genes in young 3xTg-AD mice.

V Gatta,L Stuppia,A Granzotto,S L Sensi,M D'Aurora

doi:10.1038/cddis.2014.11

Abstract

Alzheimer's disease (AD) is a multifactorial neurological condition associated with a genetic profile that is still not completely understood. In this study, using a whole gene microarray approach, we investigated age-dependent gene expression profile changes occurring in the hippocampus of young and old transgenic AD (3xTg-AD) and wild-type (WT) mice. The aim of the study was to assess similarities between aging- and AD-related modifications of gene expression and investigate possible interactions between the two processes. Global gene expression profiles of hippocampal tissue obtained from 3xTg-AD and WT mice at 3 and 12 months of age (m.o.a.) were analyzed by hierarchical clustering. Interaction among transcripts was then studied with the Ingenuity Pathway Analysis (IPA) software, a tool that discloses functional networks and/or pathways associated with sets of specific genes of interest. Cluster analysis revealed the selective presence of hundreds of upregulated and downregulated transcripts. Functional analysis showed transcript involvement mainly in neuronal death and autophagy, mitochondrial functioning, intracellular calcium homeostasis, inflammatory response, dendritic spine formation, modulation of synaptic functioning, and cognitive decline. Thus, overexpression of AD-related genes (such as mutant APP, PS1, and hyperphosphorylated tau, the three genes that characterize our model) appears to favor modifications of additional genes that are involved in AD development and progression. The study also showed overlapping changes in 3xTg-AD at 3 m.o.a. and WT mice at 12 m.o.a., thereby suggesting altered expression of aging-related genes that occurs earlier in 3xTg-AD mice.

Highlights

IntroductionGenetic aspects of Alzheimer’s disease (AD) have been intensively investigated for decades (see Tanzi[4] for an extensive review on the topic); crucial information is still missing to successfully compose the puzzle
Genetic aspects of Alzheimer’s disease (AD) have been intensively investigated for decades; crucial information is still missing to successfully compose the puzzle
The 3xTg-AD mice harbor three mutations that do not occur, at the same time, in AD human brains, this cumulative pro-AD background modulates in Tg mice the early on expression of genes, the so-called BioAge genes that are in humans biomarkers for brain aging and found prematurely expressed in AD patients.[60]

Summary

Introduction

Genetic aspects of AD have been intensively investigated for decades (see Tanzi[4] for an extensive review on the topic); crucial information is still missing to successfully compose the puzzle. Gene expression studies in transgenic AD models have helped to unravel genetic factors influencing disease progression at welldefined stages as well as their relation with the development of cognitive deficits.[5]. In the present study we employed a whole genome microarray approach to investigate age-dependent gene expression profile changes in hippocampi obtained from young (3 months of age (m.o.a.)) and old (12 m.o.a.) 3xTg-AD mice. This model offers the selective advantage of combining both amyloid (Ab)- and tau-dependent pathology and is a largely investigated and more comprehensive preclinical model of AD.[6] To control for age-dependent transcript modifications, we investigated changes occurring in age-matched wild-type (WT) mice.

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