Tau hyperphosphorylation in Locus Coeruleus mediates early-onset sleep disruption in mouse model of AD amyloidosis by causing neuronal hyperexcitability
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PROVIDER: PRJNA1192249 | ENA |
REPOSITORIES: ENA
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Project description:Sleep disturbances are common in patients with neurodegeneration, including Alzheimer's disease (AD), which can occur at early stages of AD and are proposed as potent risk factors for disease onset and progression. The underlying causes of this early-onset sleep disturbances remain unclear. Here we found that 5xFAD transgenic mice display significantly reduced sleep and prolonged wakefulness as early as 2 months of age. This early-onset sleep disruption correlates with increased tonic neuronal activity in the Locus Coeruleus (LC), which is mediated by heightened neuronal excitability due to impaired Kv4 and Kv7 channel conductance. Notably, we discovered that these young transgenic mice develop brain region-specific tau hyperphosphorylation (p-tau) in the LC. To investigate the pathological role of LC p-tau, we induce p-tau by inoculating synthetic human tau fibril into the LC of wild-type mice. This fibril inoculation replicated the reduction in Kv conductance and increased LC neuronal excitability in a tau-dependent manner. Modulating Kv4 and Kv7 channels restored normal excitability in both fibril-inoculated wild-type mice and young 5xFAD mice. Furthermore, fibril inoculation was sufficient to induce 5xFAD-like sleep disruptions in wild-type mice. Finally, pharmacological reduction of p-tau, both ex vivo and in vivo, effectively restored normal electrophysiological properties of LC neurons and normalized sleep/wake patterns in fibril-inoculated wild-type mice and young 5xFAD mice. Therefore, our findings identify a neural mechanism underlying early-onset sleep disturbances in a mouse model of AD amyloidosis and highlight the pathological consequences of LC tau hyperphosphorylation.
2025-09-01 | GSE283155 | GEO
Project description:Locus coeruleus vulnerability to tau hyperphosphorylation in a rat model
| PRJNA1138745 | ENA
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: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 correlates with AD progression and symptomatology. LC neuron integrity and quantity are linked to cognitive performance, with degeneration strongly associated with AD. Despite their importance, 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 mitochondrial 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.
| S-EPMC11896524 | biostudies-literature
Project description:Soluble aggregates of the microtubule-associated protein tau have been challenging to assemble and characterize, despite their important role in the development of tauopathies. We found that sequential hyperphosphorylation by protein kinase A in conjugation with either glycogen synthase kinase 3betaor stress activated protein kinase 4 enabled recombinant wild-type tau of isoform 0N4R to spontaneously polymerize into small amorphous aggregates in vitro. We employed tandem mass spectrometry to determine the phosphorylation sites.
2022-04-13 | PXD033127 | Pride
Project description:Alzheimer’s disease (AD), though defined as a cognitive disorder, often presents neuropsychiatric symptoms such as anxiety, depression, agitation and sleep disruptions years before the onset of frank memory impairment. A hallmark prodromal feature is the accumulation of hyperphosphorylated “pretangle” tau (pTau) in the locus coeruleus (LC), the brain’s primary source of norepinephrine (NE), prior to any other region. While clinical studies link LC tau burden to behavioral abnormalities, causal mechanisms remain unclear. We developed a translationally-relevant mouse model that recapitulates the ‘LC-first’ phenomenon observed in humans using cell type-specific viral expression of pathogenic P364S mutant human tau in LC neurons. Three months post-infusion, pTau accumulation coincided with anxiety- and compulsive-like behaviors and reduced sleep spindles without altering overall sleep architecture. Consistent with the behavioral phenotypes, electrophysiological recordings revealed significant increases in spontaneous and evoked LC activity, accompanied by astrocytic reactivity with no apparent neuronal death. Transcriptomic analysis identified upregulation of the pacemaker potassium/sodium channel Hcn2 in the LC, which may contribute to neuronal hyperexcitability. To further define molecular mechanisms linking pTau to behavioral and cellular phenotypes, we developed a cell type-specific proteomics approach, which revealed synaptic and metabolic alterations in LC neurons associated with tau pathology. Interestingly, early anxiety-like behaviors observed at 3 months diminished at later timepoints (6-9 months) and were replaced by anxiolytic phenotypes. These findings demonstrate that pTau triggers phenotypes reflective of LC-NE hyperactivity in the early stages of AD pathogenesis, laying the foundation for the development of LC-based disease-modifying targets to address neuropsychiatric manifestations.
2026-01-12 | GSE314950 | GEO
Project description:The type III RNase Dicer is responsible for the maturation and function of microRNA (miRNA) molecules in the cell. It is now well documented that Dicer and the fine-tuning of the miRNA gene network are important for neuronal integrity. However, the underlying mechanisms involved in neuronal death, particularly in the adult brain, remain poorly defined. Here, we show that absence of Dicer in the adult forebrain is accompanied by a mixed neurodegenerative phenotype. While neuronal loss is observed in the hippocampus, cellular shrinkage is predominant in the cortex. Interestingly, neuronal degeneration coincides with the hyperphosphorylation of endogenous tau at several epitopes previously associated with neurofibrillary pathology. Transcriptome analysis of enzymes involved in tau phosphorylation identified ERK1 as one of the candidate kinases responsible for this event in vivo. We further demonstrate that miRNAs belonging to the miR-15 family are potent regulators of ERK1 expression in mouse neuronal cells and co-expressed with ERK1/2 in vivo. Last, we show that miR-15a is specifically downregulated in Alzheimer’s disease brain. In sum, these results support the hypothesis that changes in the miRNA network may contribute to a neurodegenerative phenotype by affecting tau phosphorylation. Dicer KO vs. control
2010-08-28 | E-GEOD-23847 | biostudies-arrayexpress
Project description:The ciliate Stentor coeruleus microbiome
| PRJEB30974 | ENA