Biology subjects

Fitz, N. F.

Publications and source records attributed to Fitz, N. F..

4 recordsLinked to original sources

bioRxiv2026

Integration of transcriptional signatures from brain tissue and plasma extracellular vesicles of a preclinical tauopathy mouse model

Tauopathies, including Alzheimers disease, involve progressive neurodegeneration and sustained neuroinflammation. We present a multi-compartment transcriptomic atlas of 9.6-month-old PS19 tauopathy mice compared with wild-type (WT) controls (n=8/group), profiling cortical mRNA, cortical non-coding RNA (ncRNA), and plasma small extracellular vesicle (pEV) ncRNA. In the PS19 cortex, mRNA sequencing identified 917 differentially expressed genes (DEGs), with microglial deconvolution revealing a robust transition toward disease-associated microglia (DAM) gene signature and downregulation of genes involved in oxidative phosphorylation and cholesterol biosynthesis relative to WT. Cortical ncRNA profiling identified 466 differentially expressed ncRNAs, primarily circular RNAs (circRNAs; n=331). In pEVs, 822 ncRNAs were differentially abundant, of which 657 circRNAs were identified in PS19 compared to WT mice. Cross-compartment integration demonstrated that pEV miRNA gene targets functionally mirrored genes involved in the brains inflammatory and metabolic failure. We identified a core shared signature of 33 ncRNAs, including miR-5114 (up in brain, down in pEV), circ_0008242 and circ_0002153 (up in brain and pEV), and circ_0007688 (down in brain and pEV) differentially enriched across both brain and periphery in PS19 compared to WT mice. These results demonstrate that the pEV non-coding landscape effectively tracks central tau-mediated changes in the brain transcriptional response. This study identifies circRNAs as the most numerically perturbed ncRNA class and provides a foundation for non-invasive biomarker development in tauopathy.

neuroscience↗

bioRxiv2026

Linking cross-species trajectories of cerebrovascular remodeling in aging and Alzheimer's disease to brain vessel transcriptome

Cerebrovascular remodeling driven by subtle molecular changes starts early in the asymptomatic stage of Alzheimers disease (AD). Despite progress in human vascular imaging and postmortem tissue analysis, there is limited data on the early features of small vessel reorganization, particularly in the context of cell-specific molecular drivers. This is largely because of the invasive nature of the tools for direct cellular observation and analysis. Since early detection is key, histopathology falls short with end-point data from people that died in late stages of the disease. This is a critical knowledge gap, because the early vascular processes are thought to be strongly correlated with health outcomes, tipping the scales from mild cognitive impairment to AD. To meet these translational challenges, we performed near life-span in vivo two-photon imaging and MRI of the cerebrovascular tree in a mouse model of amyloidosis. We identified precisely when subtle abnormalities in vessel tortuosity and red blood cell velocity first emerge in the context of differential amyloid accumulation in vessels walls and tissues. We then isolated the brain vessels for transcriptional analysis at this flagship timepoint and performed cross-species analysis linking changes in vascular cells to genes and pathways common to both mice and humans. Importantly, using 7T MRI of aging humans, we directly associated vascular remodeling trajectories of mice and humans and identified a remarkably analogous tortuosity course in the smallest brain vessels. Our integrated framework across scales and species advances neuroimaging biomarker understanding and uncovers early mechanistic routs of dysfunctional angiogenesis and actin-mediated contractility.

neuroscience↗

bioRxiv2025

Brain single-cell transcriptional responses to bexarotene-activated RXR in Alzheimer's disease model

Pharmacological activation of brain Retinoid X Receptors (RXRs) enhances cognition and facilitates amyloid-beta (A{beta}) clearance in Alzheimers disease (AD) mouse models, partly by upregulating Apolipoprotein E (Apoe), a major AD genetic risk factor. However, the specific cellular contributions to these effects are unclear. Here, we used single-cell transcriptomic profiling to investigate cell subpopulation-specific responses to bexarotene, an RXR agonist, in APP/PS1 mice. Our analysis revealed that bexarotene activated cholesterol biosynthesis and lipid metabolism transcriptional programs in homeostatic astrocytes and oligodendrocytes. Astrocytes also upregulated neurodevelopmental genes, while oligodendrocytes and endothelial cells showed enhanced protein folding and cellular growth pathways. Bexarotene further modulated immune responses, promoting A{beta}-responsive signatures in disease-associated microglia and reactive astrocytes, while dampening pro-inflammatory responses in homeostatic microglia and endothelial cells. Furthermore, Apoe expression was significantly elevated across multiple cell types, especially in microglia and oligodendrocytes. Cell-cell communication analysis highlighted increased astrocyte-centered signaling, with APOE-driven pathways emerging as a prominent mediator. These findings clarify the cell-specific complexity of RXR-mediated regulation and underscore APOE as a central mediator of bexarotenes neuroprotective effects. This study provides mechanistic insights into RXR-targeted interventions, and supports APOE-associated pathways as promising therapeutic targets in AD.

neuroscience↗

bioRxiv2025

Transcriptomic Response to Neuromuscular Electrical Stimulation in Muscle, Brain and Plasma EVs in WT and Klotho-deficient Mice

Neuromuscular electrical stimulation (NMES) was shown to improve motor activities and daily living. Prior studies indicated extracellular vesicles (EVs) play a role in cellular communication. Here, we evaluated transcriptomic profiles of tibialis anterior muscle, brain, and plasma-derived EVs following NMES of WT and Klotho heterozygous (KlHET). Muscle RNA-seq data demonstrated that in both genotypes the most upregulated functional categories were related to glucose metabolism and response to insulin with pathways uniquely affected in each genotype. There was a similarity of non-coding RNA transcriptome of plasma EVs with functional patterns suggesting response to oxygen and insulin, and long-term synaptic potentiation. Brain transcriptome showed little functional overlap between WT and KlHET mice. In WT, brain upregulation of genes were related to blood flow and cell adhesion processes while KlHET shows upregulation of immune function. Results indicate that similar metabolic function is impacted in the location of stimulation, but the distal impact of stimulation on the brain is associated with Klotho deficiency.

genomics↗