Locus coeruleus vulnerability to tau hyperphosphorylation in a rat model
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ABSTRACT:
PROVIDER: PRJNA1138745 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29919700_1.fastq.gz | Fastqsanger.gz | |||
| SRR29919700_2.fastq.gz | Fastqsanger.gz | |||
| SRR29919701_1.fastq.gz | Fastqsanger.gz | |||
| SRR29919701_2.fastq.gz | Fastqsanger.gz | |||
| SRR29919703_1.fastq.gz | Fastqsanger.gz |
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Project description:Post-mortem investigations indicate that the locus coeruleus (LC) is the initial site of hyperphosphorylated pretangle tau, a precursor to neurofibrillary tangles (NFTs) found in Alzheimer's disease (AD). The presence of pretangle tau and NFTs in the LC correlates with AD progression. LC neuron integrity and quantity are linked to cognitive states, with degeneration associated with AD. However, the mechanisms of pretangle tau-induced LC degeneration are unclear. This study examined the transcriptomic and mitochondrial profiles of LC noradrenergic neurons after transduction with pseudophosphorylated human tau. Tau hyperphosphorylation increased the somatic expression of the L-type calcium channel (LTCC), impaired mitochondria health, and led to deficits in spatial and olfactory learning. Sex-dependent alterations in gene expression were observed in rats transduced with pretangle tau. Chronic LTCC blockade prevented behavioral deficits and altered mitochondrial mRNA expression, suggesting a potential link between LTCC hyperactivity and mitochondrial dysfunction. Our research provides insights into the consequences of tau pathology in the originating structure of AD.
2024-11-16 | GSE272794 | GEO
Project description:We analyzed the transcriptomic profile of post-mortem explants from dorsal nucleus of vagus nerve, locus coeruleus and substantia nigra obtained from controls and Braak 4 (BK4) and 5 (BK5) stages of Parkinson’s disease (PD) patients in order to investigate how gene-gene interaction patterns vary along different anatomical regions in patients and controls. The comparative transcriptional networks analyses indicate that the main hubs in PD networks are related to ubquitin/proteasome, oxidative stress, neuroprotection, neurogenesis and PD associated proteins. Transcriptomic profiles of controls and Parkinson’s disease patients were compared using SAM test for LC or Wilcoxon Mann-Whitney test for SN and VA (p<0.005 and p<0.01, respectively) in order to identify differentially expressed transcripts.
2015-01-11 | E-GEOD-43490 | biostudies-arrayexpress
Project description:BackgroundAdvances in ultrasensitive detection of phosphorylated tau (p-tau) in plasma has enabled the use of blood tests to measure Alzheimer's disease (AD) biomarker changes. Examination of postmortem brains of participants with antemortem plasma p-tau levels remains critical to understanding comorbid and AD-specific contribution to these biomarker changes.MethodsWe analyzed 35 population-based Mayo Clinic Study of Aging participants with plasma p-tau at threonine 181 and threonine 217 (p-tau181, p-tau217) available within 3 years of death. Autopsied participants included cognitively unimpaired, mild cognitive impairment, AD dementia, and non-AD neurodegenerative disorders. Global neuropathologic scales of tau, amyloid-β, TDP-43, and cerebrovascular disease were examined. Regional digital pathology measures of tau (phosphorylated threonine 181 and 217 [pT181, pT217]) and amyloid-β (6F/3D) were quantified in hippocampus and parietal cortex. Neurotransmitter hubs reported to influence development of tangles (nucleus basalis of Meynert) and amyloid-β plaques (locus coeruleus) were evaluated.ResultsThe strongest regional associations were with parietal cortex for tau burden (p-tau181 R = 0.55, p = 0.003; p-tau217 R = 0.66, p < 0.001) and amyloid-β burden (p-tau181 R = 0.59, p < 0.001; p-tau217 R = 0.71, p < 0.001). Linear regression analysis of global neuropathologic scales explained 31% of variability in plasma p-tau181 (Adj. R2 = 0.31) and 59% in plasma p-tau217 (Adj. R2 = 0.59). Neither TDP-43 nor cerebrovascular disease global scales independently contributed to variability. Global scales of tau pathology (β-coefficient = 0.060, p = 0.016) and amyloid-β pathology (β-coefficient = 0.080, p < 0.001) independently predicted plasma p-tau217 when modeled together with co-pathologies, but only amyloid-β (β-coefficient = 0.33, p = 0.021) significantly predicted plasma p-tau181. While nucleus basalis of Meynert neuron count/mm2 was not associated with plasma p-tau levels, a lower locus coeruleus neuron count/mm2 was associated with higher plasma p-tau181 (R = -0.50, p = 0.007) and higher plasma p-tau217 (R = -0.55, p = 0.002). Cognitive scores (Adj. R2 = 0.25-0.32) were predicted by the global tau scale, but not by the global amyloid-β scale or plasma p-tau when modeled simultaneously.ConclusionsHigher soluble plasma p-tau levels may be the result of an intersection between insoluble deposits of amyloid-β and tau accumulation in brain, and may be associated with locus coeruleus degeneration.
| S-EPMC9795667 | biostudies-literature
Project description:We analyzed the transcriptomic profile of post-mortem explants from dorsal nucleus of vagus nerve, locus coeruleus and substantia nigra obtained from controls and Braak 4 (BK4) and 5 (BK5) stages of Parkinson’s disease (PD) patients in order to investigate how gene-gene interaction patterns vary along different anatomical regions in patients and controls. The comparative transcriptional networks analyses indicate that the main hubs in PD networks are related to ubquitin/proteasome, oxidative stress, neuroprotection, neurogenesis and PD associated proteins.
2015-01-11 | GSE43490 | GEO
Project description:Pathogenic a-synuclein and tau are critical drivers of neurodegeneration and their mutations cause neuronal loss in patients. Whether the underlying preferential neuronal vulnerability is a cell-type intrinsic property or a consequence of increased expression levels remains elusive. Here, we explore cell-type specific a-synuclein and tau expression in human brain datasets and use deep phenotyping as well as brain- wide single-cell RNA sequencing of >200 live neuron types in fruit flies to ask which cellular environments react most to a-synuclein or tau toxicity. We detect phenotypic and transcriptomic evidence of differential neuronal vulnerability independent of a-synuclein or tau expression levels. Comparing vulnerable with resilient neurons in Drosophila enabled us to predict numerous human neuron subtypes with increased intrinsic susceptibility to pathogenic a-synuclein or tau. By uncovering synapse and Ca2+ homeostasis related genes as tau toxicity modifiers our work paves the way to leverage neuronal identity to uncover modifiers of neurodegeneration-associated toxic proteins.
2023-03-21 | GSE223626 | GEO
Project description:Neuronal diversity of neuropeptide signaling, including galanin, in the mouse locus coeruleus
| PRJNA990681 | ENA
Project description:Autopsy data indicate that the locus coeruleus (LC) is one of the first sites in the brain to accumulate hyperphosphorylated tau pathology, with the rostral part possibly being more vulnerable in the earlier stages of the disease. Taking advantage of recent developments in ultra-high field (7 T) imaging, we investigated whether imaging measures of the LC also reveal a specific anatomic correlation with tau using novel plasma biomarkers of different species of hyperphosphorylated tau, how early in adulthood these associations can be detected and if are associated with worse cognitive performance. To validate the anatomic correlations, we tested if a rostro-caudal gradient in tau pathology is also detected at autopsy in data from the Rush Memory and Aging Project (MAP). We found that higher plasma measures of phosphorylated tau, in particular ptau231, correlated negatively with dorso-rostral LC integrity, whereas correlations for neurodegenerative plasma markers (neurofilament light, total tau) were scattered throughout the LC including middle to caudal sections. In contrast, the plasma Aβ42/40 ratio, associated with brain amyloidosis, did not correlate with LC integrity. These findings were specific to the rostral LC and not observed when using the entire LC or the hippocampus. Furthermore, in the MAP data, we observed higher rostral than caudal tangle density in the LC, independent of the disease stage. The in vivo LC-phosphorylated tau correlations became significant from midlife, with the earliest effect for ptau231, starting at about age 55. Finally, interactions between lower rostral LC integrity and higher ptau231 concentrations predicted lower cognitive performance. Together, these findings demonstrate a specific rostral vulnerability to early phosphorylated tau species that can be detected with dedicated magnetic resonance imaging measures, highlighting the promise of LC imaging as an early marker of AD-related processes.
| S-EPMC10073793 | biostudies-literature
Project description:Molecular and functional sex differences of noradrenergic neurons in the mouse locus coeruleus
| PRJNA390307 | ENA