Biology subjects

Schwartz, J. L.

Publications and source records attributed to Schwartz, J. L..

6 recordsLinked to original sources

bioRxiv2026

Dual kinase inhibition provides early clues to restoration of neuroimmune homeostasis in an AAV-haSyn model of Parkinsons disease

Background Previous studies of drugs targeting mixed linage kinase type 3 (MLK3) and/or leucine rich repeat kinase type 2 (LRRK2) in sporadic Parkinsons disease (PD) have failed to meet clinical endpoints despite multiple lines of evidence implicating these kinases in pathogenesis. This has reduced enthusiasm for MLK3 and LRRK2 as druggable targets. Largely overlooked is the evidence that these targets remain valid but must be considered in combination to achieve a therapeutic outcome. This provides the rationale for this study. Methods We conducted a pilot study modeling early, pre-symptomatic PD with subsequent evaluation of therapeutic potential of a multi-kinase inhibitor (URMC-099) in alleviating disease pathology. Sprague Dawley rats received unilateral intranigral injections of low dose AAV-haSyn. After a two-week recovery period, all animals were administered either once-daily intraperitoneal (i.p.) injection of URMC-099 or its vehicle control until their terminal endpoint. Induction of early PD, and its alleviation with URMC-099, was evaluated by lateralized motor impairment using the cylinder test and immunohistochemical analysis of neuropathology in the substantia nigra (SN) and striatum. Finally, an in vitro microglial PD model exposed to aSyn pre-formed fibrils and treated with URMC-099 was used to further evaluate the mechanism underlying therapeutic activity. Results A unilateral model of early and progressive AAV-haSyn model for PD was used to demonstrate the therapeutic potential of a targeted multi-kinase inhibitor to attenuate PD-associated neuropathology and prevent the manifestation of lateral motor deficits. Immunohistochemical analysis revealed protection of neuronal cellular integrity along the nigral-striatal pathway with once-daily i.p. URMC-099. The mitigation of degenerative neuropathology was linked to targeted inhibition of MLK3 and LRRK2 and complemented by reduced levels of gliosis in astrocytes and microglia in the SN. Single-microglia segmentation analysis suggested URMC-099 treatment preserved dynamic effector state switching in microglia to enhance autophagic flux to reduce the overall burden of pathologic aSyn. Transcriptomic analysis of a complementary in vitro microglia model corroborated the retention of a homeostatic-like effector state with URMC-099 treatment that was unique to MLK3/LRRK2 dual inhibition. Conclusions Unilateral injection of low dose AAV-haSyn successfully resulted in a lateralized model of early, progressive PD. Dual inhibition of aberrant MLK3 and LRRK2 activity with once-daily i.p. URMC-099 therapy significantly mitigated the development of PD pathology and progression in an early manifest phenotype. Our results present a potential mechanism of therapeutic action dependent on the dual inhibition of MLK3 and LRRK2. This presents a novel therapeutic modality that may be beneficial to a broad population of etiologic PD patients.

neuroscience↗

bioRxiv2026

Longitudinal Salivary Immunophenotyping Reveals Distinct Cellular Signatures of Periodontal Disease Activity and Resolution

AimTo investigate whether salivary immune cell profiling can serve as a non-invasive approach to monitor periodontal disease activity and therapeutic response by characterizing innate and adaptive immune cell dynamics in periodontitis. Materials and MethodsThis longitudinal study included systemically healthy adults with periodontitis and healthy controls. Periodontal parameters (PPD, BOP, plaque/calculus, and radiographic bone loss) were recorded by calibrated examiners ({kappa}=0.85) following established criteria. Stimulated saliva and gingival biopsies were collected before and 4-6 weeks after non-surgical periodontal therapy (NSPT), and from healthy controls. Multiparametric flow cytometry was used to characterize myeloid and lymphoid cell populations and polarization markers. Bacterial transcripts and host inflammatory markers were assessed by qRT-PCR. Statistical analyses were performed using one-way ANOVA. ResultsPeriodontitis subjects exhibited significantly elevated salivary bacterial transcripts, which decreased but did not normalize following NSPT. Both myeloid and lymphoid immune cell populations increased in periodontitis compared with healthy controls and declined after therapy. This was accompanied by a pronounced pro-inflammatory shift with elevated IFN-{gamma}-producing macrophages, dendritic cells, Th1/Th17 cells, and B cells, including the novel identification of IFN-{gamma}-producing B cells in saliva and mirrors the gingival immune cell profiles. In contrast, anti-inflammatory populations (IL-10-producing myeloid cells, Tr1 cells, and regulatory B cells) were reduced in disease and partially restored following NSPT. ConclusionsSalivary immunophenotyping non-invasively monitors PD activity and therapeutic response by capturing dynamic immune changes that reflect gingival signatures and track post-therapy resolution. Clinical RelevanceO_ST_ABSScientific rationaleC_ST_ABSSalivary immune profiling offers a real-time, non-invasive tool for assessing periodontal disease status and treatment outcomes, with potential applications in precision diagnostics and personalized periodontal care. Principle findingsPeriodontitis was associated with increased salivary bacterial burden and a marked pro-inflammatory immune profile involving both innate and adaptive immune cells, including newly identified IFN-{gamma}-producing B cells. Non-surgical periodontal therapy partially restored anti-inflammatory immune responses and reduced inflammatory cell populations, supporting salivary immunophenotyping as a promising non-invasive biomarker approach for monitoring disease activity and treatment response. Practical implicationsSalivary immune cell profiling could serve as a simple, non-invasive tool to monitor periodontal disease activity and response to therapy in clinical practice. Identification of specific inflammatory cell subsets may also aid in developing personalized diagnostic and therapeutic strategies for periodontitis.

immunology↗

bioRxiv2026

Salivary microRNA Profiling of Long COVID Subjects Reveals Host-Encoded Regulators of Inflammation and Viral Persistence

Periodontal disease and COVID-19 are linked by convergent immunoinflammatory pathways, yet the molecular basis of their interaction remains poorly defined. Here, we present a comprehensive salivary microRNA profile from individuals with prior SARS-CoV-2 infection, sampled approximately 3-6 months after diagnosis and meeting criteria for long COVID, providing new insight into the post-viral oral microenvironment. Salivary miRNA sequencing revealed widespread repression in patients with PD, consistent with persistent immune dysregulation. Relative to COVID-19-negative/PD-negative controls, thirty-two miRNAs were differentially expressed in COVID-19-positive/PD-positive individuals, all significantly downregulated. A similar signature was observed in a post-vaccination cohort for the selected dysregulated miRNAs. Integrative pathway analyses identified these miRNAs as regulators of core inflammatory circuits, including Ras, MAPK, and NF{kappa}B signaling, converging on IL-1{beta}- and TNF-centered networks relevant to both PD and COVID-19. Mechanistically, restoration of three downregulated miRNAs, miR- miR-30e-3p 106-3p-3p, and miR-652-3p attenuated NF{kappa}B activation and cytokine release in TLR-stimulated human oral keratinocytes, while their functional suppression using inhibitors potentiates inflammation. These miRNAs were also predicted to target SARS-CoV-2 spike and nucleocapsid transcripts, an interaction validated by dual-luciferase reporter assays. Their overexpression further reduced spike and nucleocapsid expression in Beta- and Omicron-infected epithelial cells, as measured by flow cytometry and RT-qPCR confirming host miRNAs as potent endogenous SARS-CoV-2 restriction factor. Together, these findings identify salivary host miRNAs as mechanistic regulators of oral inflammatory tone and viral persistence, establishing a molecular link between periodontal inflammation and post-COVID oral pathology.

immunology↗

bioRxiv2025

A genetic driver of epileptic encephalopathy impairs gating of synaptic glycolysis

The brain is a disproportionately large consumer of fuel, estimated to expend [~]20% of the whole-body energy budget, and therefore it is critical to adequately control brain fuel expenditures while satisfying its on-demand needs for continued function. The brain is also metabolically vulnerable as the inability to adequately fuel cellular processes that support information transfer between cells leads to rapid neurological impairment. We show here that a genetic driver of early onset epileptic encephalopathy (EOEE), SLC13A5, a Na+/citrate cotransporter (NaCT), is critical for gating the activation of local presynaptic glycolysis. We show that SLC13A5 is in part localized to a presynaptic pool of membrane-bound organelles and acts to transiently clear axonal citrate during electrical activity, in turn activating phosphofructokinase 1. We show that loss of SLC13A5 or mistargeting to the plasma membrane results in suppressed glycolytic gating, activity dependent presynaptic bioenergetic deficits and synapse dysfunction. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=168 HEIGHT=200 SRC="FIGDIR/small/660213v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1f90e27org.highwire.dtl.DTLVardef@1055b7org.highwire.dtl.DTLVardef@6b9ce8org.highwire.dtl.DTLVardef@10a72bf_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

ApoE4 drives maladaptive heterogeneity and immunometabolic responses of astrocytes

Apolipoprotein E4 (APOE4) is the strongest risk allele associated with the development of late onset Alzheimers disease (AD). Across the CNS, astrocytes are the predominant expressor of APOE while also being critical mediators of neuroinflammation and cerebral metabolism. APOE4 has been consistently linked with dysfunctional inflammation and metabolic processes, yet insights into the molecular constituents driving these responses remain unclear. Utilizing complementary approaches across humanized APOE mice and isogenic human iPSC astrocytes, we demonstrate that ApoE4 alters the astrocyte immunometabolic response to pro-inflammatory stimuli. Our findings show that ApoE4-expressing astrocytes acquire distinct transcriptional repertoires at single-cell and spatially-resolved domains, which are driven in-part by preferential utilization of the cRel transcription factor. Further, inhibiting cRel translocation in ApoE4 astrocytes abrogates inflammatory-induced glycolytic shifts and in tandem mitigates production of multiple pro-inflammatory cytokines. Altogether, our findings elucidate novel cellular underpinnings by which ApoE4 drives maladaptive immunometabolic responses of astrocytes.

neuroscience↗

bioRxiv2022

APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge

The E4 allele of Apolipoprotein E (APOE) is associated with both metabolic dysfunction and a heightened pro-inflammatory response - two findings that may be intrinsically linked through the concept of immunometabolism. Here, we combined bulk, single-cell, and spatial transcriptomics with cell-specific and spatially resolved metabolic analyses to systematically address the role of APOE across age, neuroinflammation, and AD pathology. RNAseq highlighted immunometabolic changes across the APOE4 glial transcriptome, specifically in subsets of metabolically distinct microglia enriched in the E4 brain during aging or following an inflammatory challenge. E4 microglia display increased Hif1 expression, a disrupted TCA cycle, and are inherently pro-glycolytic, while spatial transcriptomics and MALDI mass spectrometry imaging highlight an E4-specific response to amyloid that is characterized by widespread alterations in lipid metabolism. Taken together, our findings emphasize a central role for APOE in regulating microglial immunometabolism.

neuroscience↗