Ontology highlight
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PROVIDER: PRJNA1284072 | ENA |
REPOSITORIES: ENA
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Project description:Alzheimer's disease (AD) often begins with non-cognitive symptoms such as olfactory deficits, which can predict later cognitive decline, though the mechanisms remain unclear. Pathologically, the brainstem locus coeruleus (LC), the main source of the neurotransmitter noradrenalin (NA) modulating olfactory information processing is affected ealy. Here we show early and distinct loss of noradrenergic input to the olfactory bulb (OB) coinciding with impaired olfaction in an AD mouse model, before appearance of amyloid plaques. Mechanistically, OB microglia recognize and phagocytose LC axons. Reducing phagocytosis genetically preserves LC axons and olfaction. Importantly, patients with prodromal AD display elevated TSPO-PET signals in the OB, similarly to AppNL-G-F mice. We further confirm early LC axon degeneration in post-mortem OBs in patients with early AD. Our findings reveal a mechanism linking early LC damage to hyposmia in AD, suggesting olfactory testing and neurocircuit imaging for early diagnosis and enable timely therapeutic intervention for Alzheimer's disease.
2025-07-21 | GSE302245 | GEO
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:The locus coeruleus noradrenergic (LC-NA) system plays an important role in organizing a physiological response to acute stress. However, if and how the LC affects stress-mediated transcriptomic changes in the brain is still barely understood. Here, we extensively characterize LC mediated transcriptomic response during acute stress in the hippocampus. Combining for the first time bulk mRNA-sequencing and selective chemogenetic and optogenetic manipulations of the LC-NA system
2023-02-02 | GSE218313 | GEO
Project description:Identifying factors underlying selective neuronal vulnerability is crucial for understanding Alzheimer's disease (AD) pathophysiology. The Neuromodulatory Subcortical System (NSS) includes nuclei that exhibit early, but varied vulnerability to tau accumulation and neuronal loss. This varied vulnerability represents a valuable opportunity to explore the underlying mechanisms of AD. In this study, we investigated factors contributing to selective neuronal vulnerability by comparing transcriptomic profiles of two similar NSS nuclei with differing vulnerabilities to AD, the locus coeruleus and substantia nigra. Using paired samples from well-characterized postmortem human tissue from individuals in early Braak stages and free of comorbid neuropathologic diagnoses, we identified pathways related to cholesterol homeostasis and antioxidant pathways response as key potential drivers of vulnerability.
2025-03-26 | GSE273787 | GEO
Project description:Molecular and functional sex differences of noradrenergic neurons in the mouse locus coeruleus
| PRJNA390307 | ENA
Project description:Aims: This study aimed to identify and characterize the intrinsic properties of locus coeruleus (LC) noradrenergic neurons in male and female mice using a genetic approach. We also sought to investigate sex-specific differences in membrane properties, action potential generation, and protein expression profiles to understand the mechanisms underlying neuronal excitability variations. Methods: Utilizing a genetic mouse model by crossing Dbhcre knock-in mice with tdTomato Ai14 transgenic mice, LC neurons were identified using fluorescence microscopy. Neuronal properties, including capacitance, action potential frequency, and rheobase, were assessed using patch-clamp recordings. Spontaneous and evoked activity between sexes was compared. Proteomic analyses of individual LC neuron soma was conducted using mass-spectrometry to discern protein expression profiles. Results: Female LC noradrenergic neurons displayed greater membrane capacitance than those in male mice. Male LC neurons demonstrated greater spontaneous and evoked action potential generation compared to females. Male LC neurons exhibited a lower rheobase and achieved higher peak frequencies with similar current injections. Proteomic analysis revealed inherent differences in protein expression profiles between sexes, with male mice displaying a notably larger unique protein set compared to females. Notably, pathways pertinent to protein synthesis, degradation, and recycling, such as EIF2 and glucocorticoid receptor signaling, showed reduced expression in females. Conclusions: Male LC noradrenergic neurons exhibit higher intrinsic excitability compared to those from females. The discernible sex-based differences in excitability could be ascribed to varying protein expression profiles, especially within pathways that regulate protein synthesis and degradation. This study lays the groundwork for future studies focusing on the interplay between proteomics and neuronal function examined in individual cells.
2024-05-24 | PXD045844 | Pride
Project description:Background: The goal of this study was to determine the transcriptional consequences of norepinephrine transporter (NET) gene deletion in noradrenergic neuron differentiation. The norepinephrine transporter (NET) is the target of powerful mind-altering substances, such as tricyclic antidepressants and the drug of abuse, cocaine. NET function in adult noradrenergic neurons of the peripheral and central nervous systems is that of a scavenger that internalizes norepinephrine from the synaptic cleft. By contrast, norepinephrine (NE) transport has a different role in embryogenesis. It promotes differentiation of neural crest cells and locus ceruleus progenitors into noradrenergic neurons, whereas NET inhibitors, such as the tricyclic antidepressant desipramine and the drug of abuse, cocaine, inhibit noradrenergic differentiation. While NET structure und regulation of NET function is well described, little is known about downstream targets of NE transport. Results: We have determined by long serial analysis of gene expression (LongSAGE) the gene expression profiles of in vitro differentiating wild type and norepinephrine transporter-deficient (NETKO) neural crest derivatives. Comparison analyses with the wild type library (GSM 105765) have identified a number of important differentially expressed genes, including genes relevant to noradrenergic neuron differentiation and to the phenotype of NETKO mice. Furthermore we have identified novel differentially expressed genes. Conclusions: Loss of NET function during embryonic development deregulates signaling pathways that are critically involved in neural crest formation and noradrenergic neuron differentiation. The library was constructed from total RNA of 60 neural crest culture at culture day 7. The neural tubes were dissected from E9.5 embryos that lack the norepinephrine transporter gene.
2008-06-23 | E-GEOD-11788 | biostudies-arrayexpress
Project description:Molecular and functional sex differences of noradrenergic neurons in the mouse locus coeruleus [Affymetrix]
| PRJNA390313 | ENA
Project description:Molecular and functional sex differences of noradrenergic neurons in the mouse locus coeruleus [Illumina]
| PRJNA390312 | ENA
Project description:The Alzheimer's Disease and Parkinson's Disease risk locus Fyn kinase is implicated in protein pathophysiology and NF-κB microglia inflammatory signaling. To investigate in vivo mechanisms of Fyn driven neurodegeneration, we built a zebrafish neural specific Gal4:UAS model of constitutively active FynY531F signaling. Using in vivo live imaging we demonstrate neural FynY531F expression leads to dopaminergic neuron loss and mitochondrial aggregation in 5 day larval brain. Gene expression analyses reveal reduction in neuroprotective genes, and elevated inflammatory cytokines Il-1β, IL-12 and TNF-α and genes associated with oxidative stress. These phenotypes correlate with microglia activation in the larval brain. Chemical inhibition demonstrates dopaminergic neuron loss is dependent on Fyn and NF-κB/Caspase 1 signaling. We identify Stat3 activation as a novel downstream effector of Fyn signaling that acts synergistically with NF-κB in dopaminergic neuron degeneration. These results show Fyn drives neurodegeneration through NF-κB inflammatory signaling and Stat3 pathways. Activation of Stat3 provides a potential link from Fyn to mitochondrial dysfunction associated with dopaminergic neuron loss.
2024-11-25 | GSE271955 | GEO