Dataset Information

Experimental menopause in 3xTg-AD mice triggers metabolic and cognitive dysfunction aligned with Alzheimer's disease processes

ABSTRACT: There is a compelling link between menopause and Alzheimer's disease (AD), with few established molecular mechanisms. A lack of experimental models limits validation of causal drivers of these interactions. Here, we characterize the accelerated ovarian failure (OF) model of menopause in the triple-transgenic AD (3xTg-AD) mouse. Ovotoxin, 4-vinylcyclohexene diepoxide accelerated follicular loss, ablating circulating progesterone. OF resulted in decreased performance in the Y-maze, Novel Object Recognition, and Barnes Maze, consistent with accelerated AD. OF aggravated age-related impaired glucose tolerance and caused insulin resistance and these alterations correlated with the degree of cognitive impairment. Transcriptomic analyses of the mouse hippocampus identified 19 differentially regulated genes in OF mice, including some linked to AD, including C4b, Ifit3b, Cxcl13 and Gabrg2. We produced new transcriptomic profiles of dementia-free human entorhinal cortex (n=99) and remodeled entorhinal cortex profiles from patients (n=64; Braak scores 0-6). Analyses of our 19 OF genes, identified that C4B expression was upregulated with both age and Braak score, while several revealed novel co-expression relationships, including between Shootin (SHTN1) and GABA receptor subunit (GABRG2). In summary, accelerated ovarian failure presents key cognitive, metabolic and molecular changes associated with age-related decline in cognitive function, indicating that it can be useful for the identification of novel therapeutic targets

ORGANISM(S): Mus musculus

PROVIDER: GSE268557 | GEO | 2024/07/01

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Unravel the mechanisms underlying brain aging and Alzheimer´s disease (AD) has been difficult because of complexity of the networks that drive these aging-related changes. Analysis of the gene expression in the brain is a valuable tool to study the function of the brain under normal and pathological conditions. Gene microarray technology allows massively parallel analysis of most genes expressed in a tissue, and therefore is an important research tool that potentially can provide the investigative power needed to address the complexity of brain aging and neurodegenerative processes. One of the reasons that account for the resistance of AD pathogenesis to analysis is that clinically normal subjects may exhibit considerable AD pathology, blurring criteria for distinguishing subjects with normal aging or AD. Here, we analyzed hippocampal and cortex frontal gene expression from 32 subjects separated in individuals presenting, 1) both pathologic and clinical AD (definitive AD); 2) AD pathology and normal clinic (pathologic AD); 3) cognitive impairment, without AD pathology (others dementias); and 4) no cognitive impairment, without AD pathology (normal individuals). Our results show that based on gene expression profile these individuals we could verify similarity between the definitive AD group and the group that only had AD-type pathology (pathologic AD). Specimens of hippocampus and cortex frontal used in this study were obtained at autopsy from 32 subjects. Neuropathology, specifically NFT and NP, was assessed in accordance to the Braak staging and CERAD scores, respectively. Based on pathologic and clinic criteria, subjects were categorized into four groups: 1) nine subjects with AD neuropathologic (Braak = IV / V / VI and CERAD ≠ 0) presenting cognitive impairment (CDR ≥ 1), termed “definitive AD” (dAD); 2) five subjects with AD neuropathologic (Braak = IV / V / VI and CERAD ≠ 0) and without cognitive impairment (CDR = 0), termed “pathologic AD” (pAD); 3) nine subjects without AD neuropathologic (Braak = 0 / I / II and CERAD ≠ C) presenting cognitive impairment (CDR ≥ 1), termed “other dementias” (OD); 4) - nine subjects without AD neuropathologic (Braak = 0 / I / II and CERAD ≠ C) and without cognitive impairment (CDR = 0), termed “normal” (N). RNA isolation and Amplification. From total RNA, a two-round linear amplification procedure (T7-based protocol) was carried out for all samples and for a pool of RNAs obtained from 15 distinct human cell lines used as reference. Labeled cDNA was generated in a reverse transcriptase reaction using amplified RNA (aRNA). Equal amounts of test and reference cDNA reverse color Cy-labeled aRNA targets were competitively hybridized against the cDNA probes in a customized cDNA platform with 4,608 ORESTES representing human genes. Dye-swap was performed for each sample as control for dye bias and used as replicate.

Project description:Background: Age-related cognitive deficits negatively affect quality of life and can presage serious neurodegenerative disorders. Despite sleep disruption’s well-recognized negative influence on cognition, and its prevalence with age, surprisingly few studies have tested sleep’s relationship to cognitive aging. Methodology: We measured sleep stages in young adult and aged F344 rats during inactive (enhanced sleep) and active (enhanced wake) periods. Animals were behaviorally characterized on the Morris water maze and gene expression profiles of their parietal cortices were taken. Principal Findings: Water maze performance was impaired, and inactive period deep sleep was decreased with age. However, increased deep sleep during the active period was most strongly correlated to maze performance. Transcriptional profiles were strongly associated with behavior and age, and were validated against prior studies. Bioinformatic analysis revealed increased translation and decreased myelin/ neuronal pathways. Conclusions: The F344 rat appears to serve as a reasonable model for some common sleep architecture and cognitive changes seen with age in humans, including the cognitively disrupting influence of active period deep sleep. Microarray analysis suggests that the processes engaged by this sleep are consistent with its function. Thus, active period deep sleep appears temporally misaligned but mechanistically intact, leading to the following: first, aged brain tissue appears capable of generating the slow waves necessary for deep sleep, albeit at a weaker intensity than in young. Second, this activity, presented during the active period, seems disruptive rather than beneficial to cognition. Third, this active period deep sleep may be a cognitively pathologic attempt to recover age-related loss of inactive period deep sleep. Finally, therapeutic strategies aimed at reducing active period deep sleep (e.g., by promoting active period wakefulness and/or inactive period deep sleep) may be highly relevant to cognitive function in the aging community. KEYWORDS: frontal cortex, rat, young or aged We implanted young and aged Fischer 344 rats (n = 6/ group) with wireless EEG, EMG and movement monitoring devices to measure sleep architecture. Animals were trained in the Morris water maze to assess cognitive function, and frontal cortices were removed for microarray analysis.sleep disruption and cognitive decline.

Project description:Alzheimer’s disease (AD), the most common age-related neurodegenerative disease, is closely associated with and manifested by neuroinflammation, yet the alteration of immune landscape in AD is largely unknown, preventing a deeper mechanistic understanding of neuroinflammation in AD. Two thirds of AD patients are females, and women have a higher risk of developing AD. Women with AD have more extensive brain histological changes than men with AD, more severe cognitive symptoms, and more severe neurodegeneration, suggesting that the disease affects female and male brains differentially. Despite evident AD sex variance, mechanisms and pathways are still poorly understood. Thus, a focus on sex differences in AD is essential to move the field towards effective interventions and to develop sex-specific therapies. To understand the cellular heterogeneity and disease-associated cellular changes in human AD brain, we performed unbiased massively parallel single nucleus RNA sequencing with postmortem frozen human brain tissues of middle temporal gyrus, a brain cortical region strongly affected by AD. From 12 individuals with and without AD, we isolated brain nuclei by sucrose gradient ultracentrifugation, generated single nucleus libraries with 10x Chromium platform (10x Genomics), and sequenced on NovaSeq6000 S4 sequencer (Illumina). We integrated snRNA-seq data of human brains from these 12 individuals of both Alzheimer’s Disease (AD, Braak Stage V/VI, n = 6) and age-matched healthy controls (HC, Braak Stage I/II, n = 6) by single nucleus analysis using Seurat. After quality control filtering, we profiled and analyzed 64,845 single nucleus transcriptomes, clustered all the cells jointly across the 12 donors that include 6 females and 6 males, and identified and annotated the major cell types of the human brain by interrogating the expression patterns of known gene markers, including neurons, excitatory neurons, inhibitory neurons, astrocytes, microglia, oligodendrocytes, oligodendrocyte precursor cells, endothelial cells, and pericytes.

Dataset Information

Experimental menopause in 3xTg-AD mice triggers metabolic and cognitive dysfunction aligned with Alzheimer's disease processes

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets