Biology subjects

Jang, W. E.

Publications and source records attributed to Jang, W. E..

3 recordsLinked to original sources

bioRxiv2026

Chronic Sleep Disruption Activates the Transcriptional Unfolded Protein Response and Induces Compartment-Specific Proteomic Changes in Mice

Sleep disruption (SD) is associated with adverse brain health and increased risk of dementia, including Alzheimer's disease (AD), yet the pathological mechanisms underlying this association are not fully understood. Preclinical studies have shown that acute SD impairs cognition by altering vulnerable synapses (molecular composition, ultrastructure, and function). However, the cumulative effects of chronic SD on the adult brain and its vulnerable synapses, that might contribute to AD risk, remain poorly defined. Here, we investigated the impact of chronic SD on brain transcriptomic signatures and subcellular compartment-specific proteomic profiles to identify genes, proteins, and signaling pathways that might confer AD risk. Chronic SD induced a modest transcriptional stress response globally, whereas alterations were more pronounced in the synaptosomal (synapse-enriched P2 fractions) and whole-brain proteomes. Remarkably, chronic SD elicited unique proteomic alterations at the synaptic compartment were distinct from whole-brain effects, including increased proteins involved in synaptic vesicle endocytosis, regulation of dendritic spine morphogenesis, and regulation of long-term synaptic depression, compared to increased proteins involved in immune/inflammatory, glial responses and neuronal function at the whole-brain level. Consistent with the chronic SD-induced molecular signatures, we observed subtle ultrastructural changes in vulnerable CA1 hippocampal synapses, including reduced pre-synapse size and decreased synaptic vesicle density, which suggest that chronic SD modifies synaptic transmission and plasticity. Together, our findings indicate that chronic SD differentially impacts the brain and the synaptic proteome, nominating candidate therapeutic targets and signaling pathways for future mechanistic studies of chronic SD and how SD contributes to increased AD risk.

neuroscience↗

bioRxiv2026

Pathogenic tau in the mouse locus coeruleus induces noradrenergic hyperactivity and neuropsychiatric phenotypes reminiscent of early Alzheimers disease

Alzheimers 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. An early pathological feature is the accumulation of hyperphosphorylated "pretangle" tau (pTau) in the locus coeruleus (LC), the brains primary source of norepinephrine (NE). While clinical studies link LC pTau burden to behavioral abnormalities, causal mechanisms remain unclear. We developed a translationally-relevant mouse model that recapitulates the LC-first phenomenon using cell type-specific viral expression of pathogenic P364S mutant human tau in LC neurons. Three months post-infusion, pTau accumulation induced 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 firing of LC neurons, accompanied by robust astrocytic reactivity with no apparent cell death. Transcriptomic analysis identified upregulation of Hcn2 and downregulation of Clic6, suggesting changes in neuronal excitability. To further define molecular mechanisms, we developed a cell type-specific proteomics approach, which showed synaptic and metabolic alterations associated with LC-specific tau pathology. Early anxiety-like behaviors observed at 3 months diminished at later timepoints (6-9 months) and were replaced by anxiolytic characteristics. 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 therapies to address neuropsychiatric manifestations.

neuroscience↗

bioRxiv2026

Deeper neuronal and glial proteomic insights using an optimized pipeline for proximity labeling proteomics

Proximity-based proteomics using TurboID has enabled cell-type-specific profiling without the need for cell purification, although major bottlenecks in sample lysis, biotinylated protein enrichment, digestion, and mass spectrometry (MS) parameters have limited depth of proteome coverage. Here, we systematically optimized these variables using TurboID-based labeling of BV2 microglia in vitro and brain astrocytes in vivo to define conditions that maximize proteome coverage. In microglia, the optimized protocol using 8 M urea lysis with on-bead S-Trap digestion and data-independent acquisition MS (DIA-MS) identified 4,016 proteins, double the depth of prior studies, and revealed metabolic, ribosomal, lipid-processing, autophagy, and trafficking signatures. Brain astrocyte proteomes were best recovered using SDS lysis with S-Trap digestion and DIA-MS, yielding a proteome of over 3,600 highly enriched proteins, twice the depth of prior astrocyte-TurboID studies. The expanded astrocyte proteomes captured canonical astrocyte markers as well as membrane-associated, vesicular trafficking, and presynaptic protein signatures, consistent with labeling of astrocyte-neuron interface regions, including proteins involved in receptor signaling, lipid metabolism, and plasticity at tripartite synapses, and several AD risk proteins. The increased peptide recovery following S-Trap digestion allowed the reduction of starting material to 20 {micro}g protein for DIA-MS, and enabled multiplexed tandem mass tag (TMT-MS) proteomics using even smaller samples. When applied to synaptosomes enriched from mouse brains with neuronal TurboID labeling, our pipeline identified a synapse-specific proteome of 2,529 proteins, revealing synaptic, mitochondrial and disease-relevant signatures not detectable in prior studies. By tackling critical bottlenecks from tissue processing to MS, our optimized pipelines enable cell-type and compartment-specific proximity-labeling proteomics to obtain comprehensive biological and disease-relevant insights across various biological fields.

neuroscience↗