Biology subjects

Prater, K. E.

Publications and source records attributed to Prater, K. E..

5 recordsLinked to original sources

bioRxiv2026

Pregnancy History and Loss of Normal PSEN2 Function Impact Female Late-Life Cognitive Processing, Inhibitory Signaling, and Gliosis

Background. Alzheimer's disease (AD) is well-documented to be more progressive in affected females. It is thus critical to define how female-specific life experiences interact with AD-related risk factors to impact disease trajectory and functional burden. For example, pregnancy exerts dramatic influences on the maternal immune system, behavior, and neuroplasticity, specifically in hippocampal and limbic structures. The long-term clinical impacts from pregnancy history (parity) on late-life AD outcomes are, however, conflicting. Thus, we investigated the late-life functional impacts of parity on rodent cognitive function, inhibitory neuron density, and glial biology with loss of normal function of the AD-related risk factor, presenilin 2 (PSEN2). Methods. Female PSEN2 knockout (KO) and wild-type (WT) mice with (multiparous) and without (nulliparous) pregnancy history were challenged at 10-15 months-old in the T-maze (TM) and Open Field Test (OFT), followed by immunofluorescence for neuronal signaling and gliosis markers. Results. Neither parity history nor PSEN2 deficiency impacted hippocampally-mediated spatial working memory of aged female mice in the TM. However, both PSEN2 KO and multiparous mice exhibited decreased OFT locomotor behavior. Multiparous mice also showed reduced OFT center zone exploration (p=0.0045) suggesting a more anxious phenotype. Parity history generally increased inhibitory marker expression in dorsal hippocampus (p=0.017), prefrontal cortex (p=0.021), and amygdala (p=0.035). Parity generally blunted oligodendrocyte marker expression in CA1 (p<0.05), while boosting astrocyte and microglia marker expression in CA3 of dorsal hippocampus. Conclusion. This work suggests that although parity history and PSEN2 deficiency exert individual differing age-related effects on cognition and neurobiology, they do not act synergistically.

neuroscience↗

bioRxiv2026

Title: Multimodal profiling reveals Mycobacterium tuberculosis restricts lung mitochondrial immunometabolism to promote pathogenesis

Early events in the lung that shape protective immune responses to M. tuberculosis (Mtb) infection are not well understood but are critical for developing better vaccines and immunomodulatory therapies for tuberculosis. Here, we used high-dimensional flow cytometry, single-cell transcriptomics, and untargeted metabolomics to define the early lung immune environment that precedes the development of protective versus pathogenic outcomes following aerosolized Mtb infection of mice. We show that Mtb induced sustained glycolysis in the lung while restricting oxidative phosphorylation (OXPHOS) and impairing mitochondria, in part through the Mtb serine protease Hip1, leading to low energy output and suboptimal macrophage-T cell interactions that promoted pathogenic immunity. However, robust induction of mitochondrial OXPHOS, amino acid metabolism, and fatty acid oxidation in the early lung resulted in high ATP output and enhanced innate-T cell signaling networks that stimulated protective immune responses. Moreover, we identified a novel mitochondrial immunometabolic lung signature associated with protective outcomes to Mtb infection in animal models and humans. Our studies identify induction of mitochondrial dysfunction as a mechanism employed by Mtb to manipulate lung immunometabolism to its benefit and reveal that maintenance of intact mitochondrial metabolism in the early lung is pivotal for generating protective outcomes to Mtb infection.

immunology↗

bioRxiv2025

Multi-modal choroid plexus pathology in aging and Alzheimer's disease

Brain barriers, cerebrospinal fluid (CSF) dynamics, and peripheral factors are implicated as significant contributors to Alzheimers disease (AD). The choroid plexus (ChP) is a blood-brain interface that produces CSF and forms the blood-CSF barrier. However, how ChP pathology develops across the lifespan and contributes to AD has not been systematically characterized. Here, we report a multi-modal ChP atlas integrating single-nucleus transcriptomics from 49 individuals, AI-assisted quantitative histopathology across >500 postmortem samples age 16 to 105, spatial transcriptomics, and functional studies in 5xFAD mice. We identify fibrosis, calcification, and macrophage abnormalities as hallmarks of ChP aging, with AD pathology conferring additional effects, including expansion of a pro-inflammatory fibroblast-macrophage signaling niche. In 5xFAD mice, macrophage dysfunction is associated with impaired epithelial barrier maintenance and repair. Together, these data provide a foundational resource for understanding ChP dysfunction in aging and AD and propose the macrophage-fibroblast-epithelial barrier axis as a driver of ChP pathology.

neuroscience↗

bioRxiv2025

Genetic risk in endolysosomal network genes correlates with endolysosomal dysfunction across neural cell types in Alzheimer's disease

Late-onset Alzheimer disease (LOAD) has a complex genomic architecture. LOAD risk variants suggest multiple pathways, including the endolysosomal network (ELN), contribute to the pathobiology of Alzheimer disease (AD). Whether genetic risk in specific pathways correlates with corresponding biological dysfunction remains largely unknown. We developed an endolysosomal pathway-specific polygenic risk score (ePRS) using 14 well-established AD risk alleles implicating ELN genes. We investigated the association between ePRS and AD neuropathology, then examined cell-specific endolysosomal morphology and transcriptomic profiles in post-mortem dorsolateral prefrontal cortex samples from donors stratified by ePRS burden. We found that the ePRS was significantly associated with AD diagnosis and neuropathological measures, comparable to a pathway-agnostic PRS despite representing far fewer loci. High ePRS correlated with increased neuronal endosome volume, number and perinuclear aggregation independent of AD pathology. Single-nucleus RNA sequencing revealed cell type-specific transcriptomic changes associated with ePRS status, influencing glutamatergic signaling, protein homeostasis, responses to DNA damage and immune function. Neurons, astrocytes, oligodendrocytes, and microglia each showed varied gene expression patterns associated with ePRS burden. Together, these results provide evidence that AD genetic risk variants harboring ELN genes correlate with endolysosomal dysfunction in human brain tissue. These findings suggest that pathway-specific genetic risk contributes to corresponding cellular pathology in AD and nominates candidate mechanisms by which ELN AD variants contribute to pathogenesis.

neuroscience↗

bioRxiv2021

Subtype transcriptomic profiling of myeloid cells in Alzheimer Disease brain illustrates the diversity in active microglia phenotypes

Microglia contribute to Alzheimers Disease (AD) progression and are candidate therapeutic targets. Human microglia exhibit an array of transcriptional phenotypes implying that accurate manipulation of microglial function will require clarity of their molecular states and context dependent regulation. To increase the number of microglia analyzed per subject we employed fluorescence activated nuclei sorting prior to single-nucleus RNA-seq on human prefrontal cortices. We observed microglia phenotypes previously unrecognized in human brain gene expression studies and mapped their transcriptomic relationships by trajectory inference. Three clusters were enriched for endolysosomal pathways, one of which showed differential expression of AD GWAS genes in addition to genes implicated in nucleic acid detection and interferon signaling. Analysis of the "homeostatic" microglia cluster revealed a uniquely AD subcluster. Our study demonstrates the value of deeply profiling microglia to explore the biological implications of microglia transcriptomic diversity.

neuroscience↗