Single-nucleus RNA sequencing of the hippocampal formation from a genetically diverse Alzheimer's disease mouse model (AD-BXDs)
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE221959 | GEO | 2024/02/01
REPOSITORIES: GEO
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Project description:Alzheimer’s disease (AD), the leading cause of dementia, affects millions of people worldwide. With no disease-modifying medication currently available, the human toll and economic costs are rising rapidly. Under current standards, a patient is diagnosed with AD when both cognitive decline and pathology (amyloid plaques and neurofibrillary tangles) are present. Remarkably, some individuals who have AD pathology remain cognitively normal. Uncovering factors that lead to “cognitive resilience” to AD is a promising path to create new targets for therapies. However, technical challenges discovering novel human resilience factors limit testing, validation, and nomination of novel drugs for AD. In this study, we use single-nucleus transcriptional profiles of postmortem cortex from human individuals with high AD pathology who were either cognitively normal (resilient) or cognitively impaired (susceptible) at time of death, as well as mouse strains that parallel these differences in cognition with high amyloid load. Our cross-species discovery approach highlights a novel role for excitatory layer 4/5 cortical neurons in promoting cognitive resilience to AD, and nominates several resilience genes that include ATP1A1, GRIA3, KCNMA1, and STXBP1. This putative cell type has been implicated in resilience in previous studies on bulk RNA-seq tissue, but our single-nucleus and cross-species approach identifies particular resilience-associated gene signatures in these cells. These novel resilience candidate genes were tested for replication in orthogonal data sets and confirmed to be correlated with cognitive resilience. Based on these gene signatures, we identified several potential mechanisms of resilience, including regulation of synaptic plasticity, axonal and dendritic development, and neurite vesicle transport along microtubules that are potentially targetable by available therapeutics. Because our discovery of resilience-associated genes in layer 4/5 cortical neurons originates from an integrated human and mouse transcriptomic space from susceptible and resilient individuals, we are positioned to test causality and perform mechanistic, validation, and pre-clinical studies in our human-relevant AD-BXD mouse panel.
2023-12-23 | GSE221702 | GEO
Project description:Some individuals show a discrepancy between cognition and the amount of neuropathological changes characteristic for Alzheimer’s disease (AD). This phenomenon has been referred to as ‘resilience’. The molecular and cellular underpinnings of resilience remain poorly understood. To obtain an unbiased understanding of the molecular changes underlying resilience, we investigated global changes in gene expression in the superior frontal gyrus of a cohort of cognitively and pathologically well-defined AD patients, resilient individuals and age-matched controls (n=11-12 per group). 897 genes were significantly altered between AD and control, 1121 between resilient and control and 6 between resilient and AD. Gene set enrichment analysis (GSEA) revealed that the expression of metallothionein (MT) and of genes related to mitochondrial processes was higher in the resilient donors. Weighted gene co-expression network analysis (WGCNA) identified gene modules related to the unfolded protein response, mitochondrial processes and synaptic signaling to be differentially associated with resilience or dementia. As changes in MT, mitochondria, heat shock proteins and the unfolded protein response (UPR) were the most pronounced changes in the GSEA and/or WGCNA, immunohistochemistry was used to further validate these processes. MT was significantly increased in astrocytes in resilient individuals. A higher proportion of the mitochondrial gene MT-CO1 was detected outside the cell body versus inside the cell body in the resilient compared to the control group and there were higher levels of heat shock protein 70 (HSP70) and X-box-binding protein 1 spliced (XBP1s), two proteins related to heat shock proteins and the UPR, in the AD donors. Finally, we show evidence for putative sex-specific alterations in resilience, including gene expression differences related to autophagy in females compared to males. Taken together, these results show possible mechanisms involving MTs, mitochondrial processes and the UPR by which individuals might maintain cognition despite the presence of AD pathology.
2024-04-25 | GSE261817 | GEO
Project description:The AD-BXD mouse population is a powerful emerging model for studying AD resilience. AD-BXD mice query two different levels of genetic information: genometypes and genotypes. The genetically diverse BXD genometypes are a mosaic of the approximately 6 million segregating single nucleotide polymorphisms between C57BL/6J and DBA/2J mice. The transgenic genotype of the 5 times familial Alzheimer’s disease (5xFAD) transgene, which includes human APP carrying three pathogentic variants and human PSEN1 carrying two pathogenic, can be contrasted with non-transgenic control animals (Ntg). Reproducible BXD genometypes allow repeated measurement of the same mosaic genomes, a strategy that boosts the mappable heritability of genetic loci (cite ). This property facilitates QTL mapping of the relatively lower effect size variants that modify susceptibility to Alzheimer’s-like cognitive phenotypes in 5xFAD animals. Further, the same cognitive phenotype can be measured in both 5xFAD and Ntg mice within the same genometype. The ability to contrast a genometype’s performance with different AD genotypes facilitates the measurement of novel and interesting derived phenotypes based upon the property of trait correlation (cite ). Because of these properties, our lab has successfully leveraged AD-BXD mice to identify genetic modifiers of AD-related phenotypes in recent years.
We quantified resilience using a novel regression-based metric. We utilized this measure to map resilience to a locus, then leveraged proteomics data to identify a putative molecular mechanism for the genetic resilience factor. We found potential novel targets for AD by querying elements coregulated in trans to the putative molecular mechanism. Finally, we implicated differential expression of networked synaptic proteins as the likeliest downstream consequences of differences in resilience.
2026-03-24 | PXD045403 | panorama
Project description:Understanding the mechanisms involved in cognitive resilience in Alzheimer’s disease (AD) represents a promising strategy to identify novel treatments for dementia in AD. Previous findings from our group revealed that the study of aged-Tg2576 cognitive resilient individuals is a suitable tool for this purpose. Here, by performing a transcriptomic analysis of the prefrontal cortex of demented and resilient Tg2576 mice, we have been able to hypothesize that pathways involved in inflammation, amyloid degradation, memory function and neurotransmission may be playing a role on cognitive resilience in AD. Intriguingly, the results obtained in this study are suggestive of a reduction of the influx of peripheral immune cells into the brain on cognitive resilient subjects. Indeed, Cd4 mRNA expression is significantly reduced on Tg2576 mice with cognitive resilience and interestingly, we have found a negative correlation between CD4 mRNA levels in the periphery and the score in the Mini-Mental State Exam of AD patients. All of this, highlights the importance of understanding the role of the immune system on the development of neurodegenerative diseases and points out to the infiltration of CD4+ cells in the brain as a key player of cognitive dysfunction in AD.
2023-09-19 | GSE180968 | GEO
Project description:Genome-wide profiling of DNA methylation in blood leukocytes from Chinese patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). The Illumina Infinium MethylationEPIC BeadChip array (850K chip) was used to detect DNA methylation profiles throughout approximately 850,000 CpG sites in peripheral blood white cells of MCI- and AD-affected Chinese patients, as well as cognitively healthy controls. All samples included 20 Chinese patients with MCI, 20 Chinese patients with AD, and 20 cognitively healthy controls.
2023-09-11 | GSE208623 | GEO
Project description:Cg.5XFAD females (MMRRC Stock No #34848-JAX) were bred to males from BXD strains. The resulting F1 progeny were monitored throughout their lifepan to evaluate the effect of genetic background on cognitive and pathological traits. Samples here come from various Ntg-BXD lines at either 6 or 14 months of age. An earlier dataset of similar design (plus Non-transgenic littermates) was deposited as GSE101144. AD littermates of mice sampled here will be deposited as a separate GEO series.
2020-08-17 | GSE119408 | GEO
Project description:Total RNA sequencing of cultured OM cells derived from patients with Alzheimer's disease (AD), individuals with mild cognitive impairment (MCI) and cognitively healthy controls.
| EGAS00001006195 | EGA
Project description:pulldown on enzymes targeted by serine hydrolase probes tetrahydrolipstatin-biotin and fluorophosphonate biotin probe in lysates from the frontal cortex of 36 patients (12 conrol, 12 Alzheimer's, 12 Resilient). below is the abstract: Alzheimer’s Disease (AD) is the most common form of dementia. While it has become clear that alterations in lipid metabolism are associated with AD, it is not well understood how they contribute to both cognitive decline and the pathophysiology of AD. To better understand these changes, we performed lipidomics and activity-based proteomic profiling (ABPP) in the frontal cortex of a cohort of control, AD and resilient donors, the latter referring to individuals with AD pathology without declined cognition. We demonstrate that most changes in the lipidome are related to AD pathology. The class of lipids most strongly changed was ω6-derived oxylipins, which reflect a neuroinflammatory response. This lipid class was particularly increased in the AD patients compared to controls, while it showed a similar but non-significant trend in resilient donors. In contrast, both triacylglycerides (TAGs) and lipid droplets were more abundant in the AD donors compared to the resilient donors, but not to the control donors, indicating alterations in neutral lipids in resilient donors. Enzyme activities profiled by ABPP showed a similar direction in the AD and resilient donors, including decreased activity of ABHD6, a lipase involved in mono-acyl glycerol metabolism. Finally, using multi-omics factor analysis, we show that increased oxylipins, loss of inhibitory cells and reduced synaptic plasticity are associated with Aβ plaque load. This response was present in both the AD and resilient donors. Taken together, our multi-omics data show a response associated with Aβ load shared among AD and resilient donors and, for the first time, reduced lipid droplets in resilient donors.
2026-02-09 | PXD057993 | Pride
Project description:Cg.5XFAD females (MMRRC Stock No #34848-JAX) were bred to males from BXD strains. The resulting F1 progeny were monitored throughout their lifepan to evaluate the effect of genetic background on cognitive and pathological traits. Samples here come from various AD-BXD lines at either 6 or 14 months of age. An earlier dataset of similar design (plus Non-transgenic littermates) was deposited as GSE101144. Ntg littermates of mice sampled here will be deposited as a separate GEO series.
2019-01-29 | GSE119215 | GEO
Project description:Alzheimer disease (AD) is the most common type of dementia. It is a progressive disease initially characterized by memory loss and leading to loss of the ability to respond to the environment. Currently, there is no single molecular or imaging test that can establish an AD diagnosis. A clinical diagnosis is often the results of multiple cognitive tests, spinal fluid or other bodily fluid tests for specific biomarkers and brain imaging, and it is often a diagnosis of exclusion for other diseases. We utilized a whole transcriptome sequencing approach to analyze gene expression in AD patients and control subjects blood samples with the goal of developing a novel panel of biomarkers for the disease. Whole blood sample were collected from 50 AD patients and 50 matched controls. AD patients were defined by a clinical diagnosis supported by 3 cognitive tests (MMSE, ADAS, CDR). Healthy donors have an unremarkable clinical history and their scores in the 3 cognitive tests are within normal ranges.
2026-03-11 | GSE248417 | GEO