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Comparative Gene-Expression Analysis of Alzheimer's Disease Progression with Aging in Transgenic Mouse Model.

ABSTRACT: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive memory dysfunction and a decline in cognition. One of the biggest challenges to study the pathological process at a molecular level is that there is no simple, cost-effective, and comprehensive gene-expression analysis tool. The present study provides the most detailed (Reverse transcription polymerase chain reaction) RT-PCR-based gene-expression assay, encompassing important genes, based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) disease pathway. This study analyzed age-dependent disease progression by focusing on pathological events such as the processing of the amyloid precursor protein, tau pathology, mitochondrial dysfunction, endoplasmic reticulum stress, disrupted calcium signaling, inflammation, and apoptosis. Messenger RNA was extracted from the cortex and hippocampal region of APP/PS1 transgenic mice. Samples were divided into three age groups, six-, nine-, and 12-month-old transgenic mice, and they were compared with normal C57BL/6J mice of respective age groups. Findings of this study provide the opportunity to design a simple, effective, and accurate clinical analysis tool that can not only provide deeper insight into the disease, but also act as a clinical diagnostic tool for its better diagnosis.

SUBMITTER: Abid NB

PROVIDER: S-EPMC6429175 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Comparative Gene-Expression Analysis of Alzheimer's Disease Progression with Aging in Transgenic Mouse Model.

Abid Noman Bin NB Naseer Muhammad Imran MI Kim Myeong Ok MO

International journal of molecular sciences 20190311 5

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive memory dysfunction and a decline in cognition. One of the biggest challenges to study the pathological process at a molecular level is that there is no simple, cost-effective, and comprehensive gene-expression analysis tool. The present study provides the most detailed (Reverse transcription polymerase chain reaction) RT-PCR-based gene-expression assay, encompassing important genes, based on the ...[more]

PMID: 30862043

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Project description:Neuronal-glial interactions are critical for brain homeostasis, and disruption of this process may lead to excessive glial activation and inadequate pro-inflammatory responses. Abnormalities in neuronal-glial interactions have been reported in the pathophysiology of Alzheimer's disease (AD), where lithium has been shown to exert neuroprotective effects, including the up-regulation of cytoprotective proteins. In the present study, we characterize by Gene Ontology (GO) the signaling pathways related to neuronal-glial interactions in response to lithium in a triple-transgenic mouse model of AD (3×-TgAD). Mice were treated for 8 months with lithium carbonate (Li) supplemented to chow, using two dose ranges to yield subtherapeutic working concentrations (Li1, 1.0 g/kg; and Li2, 2.0 g/kg of chow), or with standard chow (Li0). The hippocampi were removed and analyzed by proteomics. A neuronal-glial interaction network was created by a systematic literature search, and the selected genes were submitted to STRING, a functional network to analyze protein interactions. Proteomics data and neuronal-glial interactomes were compared by GO using ClueGo (Cytoscape plugin) with p ≤ 0.05. The proportional effects of neuron-glia interactions were determined on three GO domains: (i) biological process; (ii) cellular component; and (iii) molecular function. The gene ontology of this enriched network of genes was further stratified according to lithium treatments, with statistically significant effects observed in the Li2 group (as compared to controls) for the GO domains biological process and cellular component. In the former, there was an even distribution of the interactions occurring at the following functions: "positive regulation of protein localization to membrane," "regulation of protein localization to cell periphery," "oligodendrocyte differentiation," and "regulation of protein localization to plasma membrane." In cellular component, interactions were also balanced for "myelin sheath" and "rough endoplasmic reticulum." We conclude that neuronal-glial interactions are implicated in the neuroprotective response mediated by lithium in the hippocampus of AD-transgenic mice. The effect of lithium on homeostatic pathways mediated by the interaction between neurons and glial cells are implicated in membrane permeability, protein synthesis and DNA repair, which may be relevant for the survival of nerve cells amidst AD pathology.

Project description:BackgroundThe role of mitochondrial dysfunction has long been implicated in age-related brain pathology, including Alzheimer's disease (AD). However, the mechanism by which mitochondrial dysfunction may cause neurodegeneration in AD is unclear. To model mitochondrial dysfunction in vivo, we utilized mice that harbor a knockin mutation that inactivates the proofreading function of mitochondrial DNA polymerase ? (PolgA D257A), so that these mice accumulate mitochondrial DNA mutations with age. PolgA D257A mice develop a myriad of mitochondrial bioenergetic defects and physical phenotypes that mimic premature ageing, with subsequent death around one year of age.ResultsWe crossed the D257A mice with a well-established transgenic AD mouse model (APP/Ld) that develops amyloid plaques. We hypothesized that mitochondrial dysfunction would affect A? synthesis and/or clearance, thus contributing to amyloidogenesis and triggering neurodegeneration. Initially, we discovered that A?42 levels along with A?42 plaque density were increased in D257A; APP/Ld bigenic mice compared to APP/Ld monogenic mice. Elevated A? production was not responsible for increased amyloid pathology, as levels of BACE1, PS1, C99, and C83 were unchanged in D257A; APP/Ld compared to APP/Ld mice. However, the levels of a major A? clearance enzyme, insulin degrading enzyme (IDE), were reduced in mice with the D257A mutation, suggesting this as mechanism for increased amyloid load. In the presence of the APP transgene, D257A mice also exhibited significant brain atrophy with apparent cortical thinning but no frank neuron loss. D257A; APP/Ld mice had increased levels of 17 kDa cleaved caspase-3 and p25, both indicative of neurodegeneration. Moreover, D257A; APP/Ld neurons appeared morphologically disrupted, with swollen and vacuolated nuclei.ConclusionsOverall, our results implicate synergism between the effects of the PolgA D257A mutation and A? in causing neurodegeneration. These findings provide insight into mechanisms of mitochondrial dysfunction that may contribute to the pathogenesis of AD via decreased clearance of A?.

Dataset Information

Comparative Gene-Expression Analysis of Alzheimer's Disease Progression with Aging in Transgenic Mouse Model.

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Comparative Gene-Expression Analysis of Alzheimer's Disease Progression with Aging in Transgenic Mouse Model.

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