Biology subjects

Doering, A.

Publications and source records attributed to Doering, A..

3 recordsLinked to original sources

bioRxiv2026

Cerebrovascular Single-Nucleus RNA-Seq Reveals Heat Shock Activation and Vascular Remodeling in Alzheimer's Disease and Primary Tauopathies

Cerebrovascular alterations are widely observed in both Alzheimers Disease (AD) and primary tauopathies. Here, we hypothesized that mechanisms of cerebrovascular alterations are shared between AD and primary tauopathies. We performed single-nucleus RNA sequencing of postmortem human inferior temporal gyrus to characterize transcriptomic changes across cerebrovascular cell types in AD and primary tauopathies (Corticobasal Degeneration, Picks disease, and Progressive Supranuclear Palsy). Differential gene expression analyses revealed disease-specific transcriptional programs across vascular cell populations. However, genes involved in the heat-shock response were consistently upregulated across all diseases, suggesting a conserved cerebrovascular stress response during neurodegeneration. We further identified marked cerebrovascular remodeling in AD relative to primary tauopathies, along with dysregulation of genes mapping to AD risk loci in endothelial cells. Transcriptomic findings were validated using tissue clearing, light-sheet microscopy, and immunofluorescence quantification of vascular markers. These results define a conserved vascular stress program alongside AD-specific remodeling, highlighting the vasculature as a therapeutic target in neurodegeneration.

neuroscience↗

bioRxiv2025

Resolving Cellular Morphology in the Human Brain with Multiparametric Diffusion MR Spectroscopy

Diffusion-weighted magnetic resonance spectroscopy (dMRS) noninvasively probes the diffusion of mostly intracellular metabolites and can therefore report on brain microstructure with a cell-type specificity that water-based diffusion MRI cannot achieve. However, the morphological information accessible to conventional dMRS is limited: estimating both cell-body (soma) and neurite dimensions from a single diffusion-encoding scheme is an ill-posed problem, and neither ultra-high b-value nor diffusion-time-dependent measurements alone distinguish soma size from neurite radius. Here we introduce multiparametric dMRS in the human brain, combining diffusion-time- dependent encoding (apparent diffusion coefficient, ADC, and diffusion kurtosis, K, sampled over diffusion times of 6 ms to 250 ms and b-values up to 8 ms {micro}m-2) with double-diffusion-encoded spectroscopy (DDES). Using Monte-Carlo analysis, we show that fitting a two-compartment (soma + neurite) tissue model to diffusion-time data alone is degenerate, admitting two near-indistinguishable solutions. Adding the orthogonal angular information from DDES breaks this degeneracy: jointly fitting both experiments converges to a single, biophysically plausible solution irrespective of initialization, yielding cell-type- specific estimates of intrinsic diffusivity, soma radius, neurite radius, and neurite signal fraction for neuronal (NAA, glutamate) and glial (choline, myo-inositol) metabolites. Metabolite microscopic anisotropy approaches unity, consistent with predominantly intra-neurite diffusion, while simultaneously acquired water data reveal short-range structural disorder and intercompartmental exchange ({approx}15 ms). Multiparametric dMRS thus extends the standard model of metabolite diffusion by a soma compartment and offers a route toward in vivo, cell-type- specific morphometry of neurons and glia in humans--a foundation for biomarkers in conditions where soma and neurite morphology are altered.

neuroscience↗

bioRxiv2021

Early Disruption of Photoreceptor Cell Architecture and Loss of Vision in a Humanized Pig Model of Usher Syndrome

Usher syndrome (USH) is the most common form of monogenic deaf-blindness. Loss of vision is untreatable and, so far, there are no suitable animal models for testing therapeutic strategies. By introducing a human mutation into the harmonin-encoding USH1C gene in pigs, we generated the first translational animal model for USH type 1 with characteristic hearing defect, vestibular dysfunction and visual impairment. Changes in photoreceptor architecture, quantitative motion analysis and electroretinography were characteristics of the reduced retinal virtue in USH1C pigs. Primary cells from those animals and USH1C patients showed significantly elongated primary cilia, compared to wild-type, confirming the nature of USH as a true and general ciliopathy and proving the therapeutic capacity of gene supplementation and gene repair approaches.

genetics↗