Biology subjects

Orr, T. C.

Publications and source records attributed to Orr, T. C..

3 recordsLinked to original sources

bioRxiv2025

Single-cell Spatial Transcriptional Profiling Uncovers Heterogeneous Cellular Responses to Pathogenic Tau in a Mouse Model of Neurodegeneration

Intracellular tau accumulation contributes to neurodegeneration and systemic dysfunction. Although tau primarily aggregates in neurons as neurofibrillary tangles (NFTs), it also affects other cell types through poorly understood mechanisms. To define the molecular characteristics of tangle-bearing neurons and their influence on surrounding cells, we used CosMx SMI to evaluate the expression of 950 genes in more than 265,000 cells from rTg(tauP301L)4510 tauopathy and control mouse brains. In the cerebral cortex, tau pathology disrupted the excitatory-inhibitory neuron balance and altered pathways critical for myelination, similar myelin changes were observed in postmortem brain tissue from patients with progressive supranuclear palsy. In the hypothalamus, tau accumulation was associated with transcriptional changes linked to pathways involved in body weight and metabolic regulation. These findings reveal molecular mechanisms underlying both cell-autonomous and non-autonomous effects of tauopathy and identify targets for further investigation into tau pathogenesis and its systemic impact.

neuroscience↗

bioRxiv2025

Spatial Multi-Omics Workflow and Analytical Guidelines for Alzheimer's Neuropathology

Spatial biology technologies enable high-dimensional profiling within intact tissues, revealing how molecular and cellular organization drives function and disease. As these platforms gain broader adoption, standardized analytical frameworks are needed to ensure data quality and reproducibility. Here, we present an end-to-end pipeline for the GeoMx Digital Spatial Profiler that simultaneously generates whole-transcriptome and 637-protein measurements from user-defined regions within the same tissue sections. The workflow integrates morphology-guided region selection, quality control, normalization, and multi-modal data interpretation. Applied to formalin-fixed cortical tissues from Alzheimers disease, dementia with Lewy bodies, amyotrophic lateral sclerosis, and controls, the framework resolves spatially distinct molecular domains. Transcript and protein signals diverge across amyloid plaque cores and surrounding glial-rich regions, with RNA-protein concordance varying by disease condition, while single-neuron profiling with and without pathogenic tau deposition illustrates protein assay sensitivity. This dataset provides a rigorously validated resource for spatial multi-omic analyses and establishes broadly applicable guidelines for reliable, reproducible profiling of complex tissues.

neuroscience↗

bioRxiv2021

Sulfonylureas target the neurovascular response to decrease Alzheimer's pathology

Hyperexcitability is a defining feature of Alzheimers disease (AD), where aberrant neuronal activity is both a cause and consequence of AD. Therefore, identifying novel targets that modulate cellular excitability is an important strategy for treating AD. ATP-sensitive potassium (KATP) channels are metabolic sensors that modulate cellular excitability. Sulfonylureas are KATP channel antagonists traditionally used to combat hyperglycemia in diabetic patients by inhibiting pancreatic KATP channels, thereby stimulating insulin release. However, KATP channels are not limited to the pancreas and systemic modulation of KATP channels has pleotropic physiological effects, including profound effects on vascular function. Here, we demonstrate that human AD patients have higher cortical expression of vascular KATP channels, important modulators of vasoreactivity. We demonstrate that peripheral treatment with the sulfonylurea and KATP channel inhibitor, glyburide, reduced the aggregation and activity-dependent production of amyloid-beta (A{beta}), a hallmark of AD, in mice. Since glyburide does not readily cross the blood brain barrier, our data suggests that glyburide targets vascular KATP channel activity to reduce arterial stiffness, improve vasoreactivity, and normalize pericyte-endothelial cell morphology, offering a novel therapeutic target for AD. Graphical abstractTargeting vascular KATP channel activity for the treatment of Alzheimers disease pathology. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

neuroscience↗