Dataset Information

Pre-histopathological and sex-biased hippocampal pathology in the 5XFAD mouse model of Alzheimer's disease: a multi-omic analysis

ABSTRACT: Like many neurological disorders, Alzheimerâ€™s disease has a sex-biased epidemiological profile, affecting approximately twice as many women as men. The cause of this sex difference has yet to be elucidated. To identify molecular correlates of this sex bias, we investigated molecular pathology in females and males using the 5XFAD genetic mouse model of Alzheimerâ€™s disease. We profiled the transcriptome and proteome of the mouse hippocampus during early stages of disease development (1, 2, and 4 months) with RNA-sequencing and Liquid-chromatography mass spectrometry.

OTHER RELATED OMICS DATASETS IN: GSE97113

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease

SUBMITTER: Joseph Bundy

LAB HEAD: Richard S. Nowakowski

PROVIDER: PXD006587 | Pride | 2018-10-10

REPOSITORIES: Pride

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Publications

Sex-biased hippocampal pathology in the 5XFAD mouse model of Alzheimer's disease: A multi-omic analysis.

Bundy Joseph L JL Vied Cynthia C Badger Crystal C Nowakowski Richard S RS

The Journal of comparative neurology 20181108 2

Alzheimer's disease is a progressive neurodegenerative disorder and the most common form of dementia. Like many neurological disorders, Alzheimer's disease has a sex-biased epidemiological profile, affecting approximately twice as many women as men. The cause of this sex difference has yet to be elucidated. To identify molecular correlates of this sex bias, we investigated molecular pathology in females and males using the 5XFamilial Alzheimer's disease mutations (5XFAD) genetic mouse model of A ...[more]

PMID: 30291623

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Project description:Transforming growth factor (TGF) plays an important role in tooth morphogenesis and mineralization. During postnatal development, the dental pulp (DP) mesenchyme secretes neurotrophic factors that guide trigeminal nerve fibers into and throughout the DP. This process is tightly linked with dentin formation and mineralization. Our laboratory established a mouse model in which Tgfbr2 was conditionally deleted in DP mesenchyme using an Osterix promoter-driven Cre recombinase (Tgfbr2cko). These mice survived postnatally with significant defects in bones and teeth, including reduced mineralization and short roots. Hematoxylin and eosin staining revealed reduced axon-like structures in the mutant mice. Reporter imaging demonstrated that Osterix-Cre activity within the tooth was active in the DP and derivatives, but not in neurons. Immunofluorescence staining for 3 tubulin (neuronal marker) was performed on serial cryosections from control and mutant molars on postnatal days 7 and 24 (P7, P24). Confocal imaging and pixel quantification demonstrated reduced innervation in Tgfbr2cko first molars at both stages compared to controls, indicating that signals necessary to promote neurite outgrowth were disrupted by Tgfbr2 deletion. We performed mRNA-Sequence (RNA-Seq) and gene onotology analyses using RNA from the DP of P7 control and mutant mice to investigate the pathways involved in Tgfbr2-mediated tooth development. These analyses identified downregulation of several mineralization-related and neuronal genes in the Tgfbr2cko DP compared to controls. Select gene expression patterns were confirmed by quantitative real-time PCR and immunofluorescence imaging. Lastly, trigeminal neurons were co-cultured atop Transwell filters overlying primary Tgfbr2f/f DP cells. Tgfbr2 in the DP was deleted via adenovirus-expressed Cre recombinase. Confocal imaging of axons through the filter pores showed increased axonal sprouting from neurons cultured with Tgfbr2-positive DP cells compared to neurons cultured alone. Axon sprouting was reduced when Tgfbr2 was knocked down in the DP cells. Immunofluorescence of dentin sialophosphoprotein in co-cultured DP cells confirmed reduced mineralization potential in cells with Tgfbr2 deletion. Both our proteomics and RNA-Seq analyses indicate that axonal guidance cues, particularly semaphorin signaling, were disrupted by Tgfbr2 deletion. Thus, Tgfbr2 in the DP mesenchyme appears to regulate differentiation and the cells’ ability to guide neurite outgrowth during tooth mineralization and innervation.

Dataset Information

Pre-histopathological and sex-biased hippocampal pathology in the 5XFAD mouse model of Alzheimer's disease: a multi-omic analysis

Publications

Sex-biased hippocampal pathology in the 5XFAD mouse model of Alzheimer's disease: A multi-omic analysis.

Similar Datasets

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