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bioRxiv2026

Pathology-Targeted EP4 Agonism Reverses Fibrosis in a Rat Model of DMD

Duchenne muscular dystrophy (DMD) presents a critical therapeutic gap in adolescent patients, where extensive fibro-fatty muscle replacement and depletion of the regenerative niche render existing interventions insufficient. Prostaglandin E2 signaling through the EP4 receptor stimulates bone and muscle regeneration and repair, but systemic off-target effects have limited the clinical translation of EP4 agonism in diseases such as DMD. We therefore evaluated irodanoprost (IROD), a bone-targeted prodrug of an EP4-selective agonist, in a DMD rat model, comparing early- and late-intervention cohorts. In adolescent rats, 8 weeks of treatment reduced body weight deficit by 41.4% and restored hindlimb muscle mass and maximum tetanic force to wild-type levels. IROD dose-dependently inhibited fibro-adipogenic progenitor differentiation into -SMA myofibroblasts, facilitating active resolution of established fibrosis below pre-treatment baseline. This was accompanied by re-activation of a synchronized regenerative program marked by clustered eMHC fibers, restoring the total myofiber pool to wild-type levels. A strong linear correlation between intramuscular fat reduction and fibrosis resolution suggests that MRI-based fat imaging may serve as a non-invasive surrogate for monitoring anti-fibrotic efficacy. The efficacy of IROD is likely aided by the fact that while it selectively distributes to bone in healthy animals, we observed markedly enhanced accumulation of the drug in dystrophic muscle. These findings establish IROD as a pathology-targeted approach capable of resolving the fibro-fatty niche and restoring regenerative capacity in advanced DMD. SummaryPathology-targeted EP4 agonism resolves established fibrosis and restores myofiber regeneration in a rat model of adolescent Duchenne dystrophy. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/728674v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@20447dorg.highwire.dtl.DTLVardef@70929dorg.highwire.dtl.DTLVardef@a99628org.highwire.dtl.DTLVardef@1c158f4_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2026

Cell-Type-Selective Cortical Pathology and Functional Deficits in Synucleinopathy

Aggregates of -synuclein (-syn), a hallmark of synucleinopathies, accumulate in the cerebral cortex accompanied by the emergence of motor symptoms, which are associated with altered cortical neuronal activity. However, the mechanism by which -syn pathology drives cortical network dysfunction, and how these alterations contribute to impaired motor execution and learning, remain unknown. Here, we adopted a multi-disciplinary approach to elucidate the pathophysiological characteristics in transgenic mice that express mutant human -syn, with minimal nigrostriatal degeneration. In vivo two-photon imaging revealed distinct alteration patterns in excitatory and parvalbumin (PV)-expressing inhibitory cortical neurons accompanying fine motor deficits during learning. Cell type specific ex vivo whole-cell recording further revealed selectively altered intrinsic properties in excitatory but not PV neurons, consistent with the preferential accumulation of -syn inclusions in excitatory rather than PV neurons within the same cortical region. These results indicate cell-type selective vulnerability in motor cortex of early stage synucleinopathy, leading to disrupted excitatory/inhibitory balance and dysregulated cortical plasticity, driving early-stage motor symptoms. This study provides evidence for selective vulnerability of excitatory neurons in cortical synucleinopathy.

neuroscience↗

bioRxiv2026

Somatic CRISPR editing of Msh3 mitigates Huntington's disease pathology in mice

Huntingtons disease (HD) is a fatal, dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in Huntingtin (HTT) exon 1. Further progressive CAG repeat expansion occurs in somatic cells, particularly in neurons, and drives the timing of clinical onset. Therefore, therapeutic strategies to slow somatic expansion are predicted to be disease-modifying. Somatic CAG expansion is driven by mismatch repair protein MSH3, a leading therapeutic target supported by human genetic data. To gain insight into the impact of targeting MSH3 at different stages of the disease process we used somatic CRISPR-Cas9 editing to knock out Msh3 in HttQ111 mice at ages of 6, 16, 24 weeks exhibiting progressively increasing somatic expansion. Intervention at all three ages slowed striatal CAG expansion, reduced nuclear huntingtin pathology and suppressed transcriptional dysregulation, with earlier intervention having greater impact. Msh3 knockout also suppressed the production of the exon 1 Htt1a transcript. The results of our study provide important preclinical information relevant to an MSH3 therapeutic in humans that would be expected to impact a subset of cells in the brain, provide insight into the influence of timing of intervention on therapeutic effectiveness and deepen our understanding of how targeting MSH3 could alter the trajectory of HD.

genetics↗

bioRxiv2026

Functional and structural characterization of dendritic spine pathology in a mouse model of tauopathy

Abnormal deposition of the microtubule-associated protein tau has long been associated with neurodegenerative diseases. While spine loss and neuronal death are hallmarks of tauopathy, how pathological tau affects synaptic activity in vivo and whether functional properties of individual synapses dictate the survival fate of dendritic spines remain elusive. Here we examined the visual response properties of dendrites and spines of layer 2/3 primary visual cortical neurons, using longitudinal two-photon calcium imaging in P301S mouse model of tauopathy. We found that neuronal outputs in tau mutant mice were hyperactive and poorly tuned whereas dendritic spine responses were also poorly tuned but hypoactive. Moreover, we found that spines that were stably retained across two imaging sessions were larger in size and more sharply tuned but less active compared to those that turned over in controls. Such structure-to-function relationship was not observed in mutants. Our findings illustrate how the preferential maintenance of well-tuned inputs in healthy neural circuitry may be affected by tauopathy, resulting in neurons with poorly tuned visual responses.

neuroscience↗

bioRxiv2026

Decoding and Targeting Coordinated CDKN1A and CDKN2A Senescence Programs in ECM-Dominant Cardiovascular Pathologies

Cellular senescence is a hallmark of aging and an emerging therapeutic target; however, its role as a context-specific driver of disease remains incompletely defined, and senolytic therapies have shown inconsistent clinical benefit. Here, we identify extracellular matrix (ECM)-dominant pathologies as a major class of senescence-driven disease, characterized by inflammation, matrix degeneration, and progressive tissue dysfunction. Using integrated single-cell transcriptomics, spatial profiling, and multiplex imaging across human specimens and murine models, we demonstrate that senescent fibroblasts, rather than canonical myofibroblasts, constitute the principal disease-driving cell state in myxomatous mitral valve disease (MMVD) and related conditions. These cells exhibit coordinated CDKN1A inflammatory and CDKN2A ECM-remodeling programs that form a feed-forward circuit linking immune activation to matrix disorganization and functional decline. Senescence extends beyond fibroblasts to endothelial and immune compartments, establishing a multicellular senescent milieu that reinforces intercellular crosstalk and disease progression. Senolytic treatment (dasatinib plus quercetin or fisetin) restores ECM architecture and improves cardiac function, outperforming pathway-specific anti-inflammatory and antifibrotic approaches. Cross-disease analyses further reveal conservation of this coordinated CDKN1A/CDKN2A senescence programs across multiple ECM-dominant cardiovascular diseases, including aortic aneurysm and calcific valve disease. Notably, in vivo single-cell transcriptomic profiling following multiple senolytic treatments provides whole-transcriptome resolution of context-dependent cellular responses. Collectively, these findings establish context-specific senescence as a central organizing mechanism in ECM-dominant diseases and support a shift from generalized anti-aging strategies toward precision senolytic prevention or therapy. Given that valvular and aortic diseases affect millions and increase markedly with age to a prevalence comparable to major cancers, these results indicate a potential solution to a substantial and underrecognized clinical burden.

Cell Biology↗

bioRxiv2026

Temporal and Regional Circular RNA profiling in a Tauopathy Mouse Model: Implications for Tau Pathology and Neurodegeneration

MicroRNAs (miRNA), are non-coding RNA that act as post-transcriptional regulators of gene expression in various organs including the brain where they play an important role in neurodegeneration. Circular RNAs are single-stranded, covalently closed loop RNA molecules recognized as upstream regulators of miRNA. Previous studies have shown that circRNAs are dysregulated in Alzheimers and other neurodegenerative diseases. However, a systematic, age-and region-specific circRNA atlas in primary tauopathy is lacking. To this end, we performed comprehensive circRNA sequencing of hippocampal and cortical tissues from a model of human tauopathy, h-Tau mice, at 3, 6, and 12 months of age. We identified circRNA-miRNA sponging networks that target and regulate key tau disease-associated pathways, including kinases, phosphatases, histone deacetylase, glutamatergic and GABAergic synapse, and microglial efferocytosis. Our study demonstrates an age- and region-specific circRNA landscape in the brain of a model of human tauopathy and identify candidate circRNA-miRNA-mRNA regulatory axes converging on core tau pathological processes. These findings support the novel hypothesis that specific circRNAs have the potential to be used as biomarkers and therapeutic targets against tau-driven neurodegeneration.

neuroscience↗

bioRxiv2026

Stress Granule Coarsening Is a Pathological Inflection Point for Cardiac Electrophysiological Dysfunction

Arrhythmia risk rises early in many forms of cardiac stress, often before contractile failure is evident. Stressed cardiomyocytes accumulate biomolecular condensates, known as stress granules (SGs), whose contribution to this electrical vulnerability has been unclear. We mapped where SGs reside and followed their life cycle under acute and chronic oxidative stress across complementary model systems and assessed electrophysiological consequences with pharmacological tools targeting granule assembly, microtubule integrity, and calcium channel function. Under both stress regimes, SGs localized preferentially to z-lines and intercalated discs, marking these mechanically critical sites as hubs of condensate assembly. Merging of granules, referred to as coarsening, rather than initial formation, emerged as a pathological connection. Early granules were broadly cytoprotective, whereas progressive coarsening was accompanied by disruption of alpha-actinin and L-type calcium channel (Cav1.2) nanodomains and by shortening of action potential (AP) duration. Coarsened granules disorganized Cav1.2 nanodomains through a microtubule-dependent mechanism, and arresting coarsening with nocodazole preserved nanodomain integrity and restored AP morphology. The transition from nascent to coarsened SGs therefore represents a targetable inflection point, and limiting coarsening may prevent proarrhythmic remodeling during cardiac oxidative stress.

bioengineering↗

bioRxiv2026

Orally available designed miniproteins inhibit enterotoxigenic Bacteroides fragilis pathology by blocking toxin receptor binding

Toxigenic bacterial infections in the gut are a significant contributor to the global burden of disease. Advanced tools for protein and live biotherapeutic engineering offer potentially transformative strategies for treating such diseases, while avoiding the collateral effects of traditional antibacterials. Here we used de novo protein design to identify inhibitors of the metzincin family protease Bacteroides fragilis toxin (BFT). These inhibitors, which bind distal to the active site, interfere with toxin-mediated E-cadherin cleavage and downstream proinflammatory signaling by blocking claudin-4 receptor binding. We tested the inhibitors as disulfide-stabilized variants administered directly to the cecum or in drinking water, as well as through in situ secretion by an engineered live biotherapeutic. Across these delivery modalities, the inhibitors successfully neutralized the toxin and effectively prevented BFT-associated gut pathology, including tumor formation. These results highlight the potential of de novo designed proteins as precise, non-antibiotic interventions to mitigate bacterial toxin-driven disease in the gut.

microbiology↗

bioRxiv2026

Peptide allosteric inhibitor of TNFR1 signaling attenuates inflammation and rheumatoid arthritis pathology in human TNF transgenic mice

Inhibition of tumor necrosis factor receptor 1 (TNFR1) represents a major therapeutic strategy for chronic autoimmune and inflammatory diseases such as rheumatoid arthritis (RA). As current anti-TNF therapies can cause adverse side effects due to global blockade of the ligand, receptor-specific inhibition of TNFR1 signaling has emerged as a highly sought-after strategy. We have recently identified a novel peptide-based allosteric inhibitor, FKC (FKCRRWQWRMKK), that targets TNFR1 conformationally active region to alter receptor conformational states and disable receptor-ligand signaling complex. Here, we evaluated the therapeutic efficacy of FKC in a human TNF (hTNF) transgenic mouse model of RA. FKC treatment improves clinical RA scores in hTNF mice, accompanied by enhanced grip strength and increased walking distance. Importantly, FKC treatment inhibits TNF/TNFR1-mediated inflammation and attenuates RA pathology in hTNF mice. Together, our findings establish FKC as a promising new class of peptide-based therapeutics for chronic inflammatory diseases through selective inhibition of TNFR1 signaling.

immunology↗

bioRxiv2026

Trisomy 21 cerebral organoids exhibit Alzheimer's disease amyloid and apolipoprotein E co-pathologies

Adults with Down syndrome (DS) develop Alzheimers disease (AD) brain pathology by age 40 due to triplication of the Amyloid Precursor Protein (APP) gene on chromosome 21. Inheritance of the apolipoprotein E-e4 (APOE4) allele of the APOE gene on chromosome 19 remains the greatest genetic risk factor for AD in the typical population, yet its role in DS-associated AD (DS-AD) neuropathogenesis in people with DS is unclear. We generated human induced pluripotent stem cell (hiPSC)-derived neurons, astrocytes, and cerebral organoids (COs) using cells from people with DS and from euploid individuals. Aged DS COs were smaller than aged euploid COs and showed robust amyloid-{beta} neuropathology that was positively correlated with the levels of apoE expression. We then captured extracellular vesicles (EVs) from the conditioned media of COs and observed a decrease in the levels of secreted AD-related proteins, including amyloid, contained within the EVs and in the media from which the EVs were isolated. We also identified distinct neuronal and astrocytic gene expression signatures in DS COs relative to euploid COs, including a set of genes known to interact with both APOE and APP at the gene and/or protein levels. Lastly, we determined that, despite differences in the expression levels of the specific genes involved, several common pathways were upregulated in T21 hiPSC-derived neurons, astrocytes, and COs, including apoptosis, the endolysosome, and structural stabilization pathways. Taken together, our findings provide novel insights into molecular mechanisms that may contribute to DS-AD and indicate that apoE plays an important role in the disease process.

neuroscience↗

bioRxiv2026

The neuropathy-causing GARS1{triangleup}ETAQ mutation drives pathology in subsets of motor and sensory neurons in mice

Charcot-Marie-Tooth disease type 2D (CMT2D) results from gain-of-function mutations in GARS1, which encodes glycyl-tRNA synthetase (GlyRS), the enzyme responsible for charging transfer RNA (tRNA) with glycine. There are several CMT2D mouse models, but Gars{Delta}ETAQ/+ is the only one that bears a patient-sourced mutation. Created using CRISPR/Cas9 to model a 12-nucleotide de novo GARS1 deletion identified in an unusually severe CMT2D patient, Gars{Delta}ETAQ/+ mice have previously been shown to display several neuromuscular phenotypes; motor axon loss, denervated neuromuscular junctions (NMJs) and reduced muscle function. Here, we extend these analyses to provide a more comprehensive understanding of both motor and sensory nerve deficits across hind- and fore-limbs. At 3 months, Gars{Delta}ETAQ/+ mice possess sex-independent alterations in the levels of neuropathy biomarkers - including decreased NfL and increased periaxin - alongside reduced muscle endurance and strength, and impairments in the sensory modalities of mechanosensation, proprioception and nociception. Underpinning these dysfunctions, we identified site-specific defects comprising altered sensory neuron populations, muscle spindle loss, reduced motor neuron size, disrupted NMJ innervation and maturation, and reduced axonal transport of signalling endosomes in vivo. Together, these experiments show that Gars{Delta}ETAQ/+ mice display robust and selective peripheral nerve pathology that manifests in a general distal-to-proximal fashion, priming this CMT2D allele for testing treatments and evaluating mechanisms underlying peripheral nerve vulnerability. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/736541v1_ufig1.gif" ALT="Figure 1"> View larger version (70K): org.highwire.dtl.DTLVardef@b48a41org.highwire.dtl.DTLVardef@e0c22dorg.highwire.dtl.DTLVardef@1ec2f5forg.highwire.dtl.DTLVardef@11a3311_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

Immunoproteasome Deficiency Impairs Microglial Clearance and Worsens Tau and Amyloid Pathology

Immunoproteasome induction is prominent in Alzheimers disease (AD), but whether it protects proteostasis or amplifies neuroinflammation remains unresolved. Here, we generated immunoproteasome-deficient PS19 tauopathy and APP/human tau double-knock-in mice by crossing each disease model with L7M1 mice lacking two immunoproteasome catalytic subunits. Immunoproteasome deficiency increased phospho-tau burden, exacerbated amyloid-{beta} pathology and heightened microglial reactivity without suppressing constitutive 26S proteasome activity. In primary microglia and longitudinal two-photon imaging, immunoproteasome-deficient microglia engaged and engulfed tau aggregate-bearing material but failed to resolve internalized cargo, revealing a post-engulfment degradative checkpoint. Single-nucleus transcriptomics identified a remodeled P2ry12low/Trem2high microglial state with impaired phagolysosomal and mitochondrial programs. Reanalysis of human single-nucleus transcriptomic datasets showed that reduced microglial immunoproteasome expression was associated with cargo-processing gene-program changes similar to those observed in immunoproteasome-deficient mouse microglia. Together, these findings identify immunoproteasome biogenesis as a protective glial stress response that supports microglial aggregate clearance in AD.

neuroscience↗

bioRxiv2026

Phagocytic activity of perivascular cell promotes CNS injury pathology

Injury, stroke, and neurological diseases cause persistent accumulation of cellular debris that deteriorates lesion microenvironment and impedes central nervous system (CNS) repair. Debris clearance in the injured CNS has long been attributed primarily to microglia and infiltrating macrophages. Here, we identify perivascular cells as previously unrecognized phagocytes that expand after injury and exhibit robust phagocytic activity. Perivascular cell phagocytosis is conserved across multiple mouse models of CNS injury and human stroke lesions. These cells exhibit key hallmarks of phagocytosis, including LC3-associated phagocytosis for efficient lysosomal degradation. Mechanistically, phosphatidylserine serves as the eat-me signal and Axl mediates myelin debris uptake. Myelin phagocytosis drives perivascular cell proliferation, fibrosis and lesion progression. Genetic deletion of Axl in perivascular cells or pharmacological inhibition with the FDA-approved Axl inhibitor Gilteritinib reduces pathology and improves functional recovery after spinal cord injury. Together, these findings establish Axl-dependent perivascular cell phagocytosis as a therapeutic target for CNS repair.

neuroscience↗

bioRxiv2026

Peripheral T-cell co-signalling states mark vulnerability and resilience to cerebral Aβ pathology

Adaptive immune responses may influence vulnerability and resilience in Alzheimers disease (AD), but relevant T-cell states remain unclear. We profiled peripheral immune cells by mass cytometry in 200 participants across distinct age groups, early AD and exceptional old age without dementia, relating immune features to amyloid-{beta} (A{beta}) PET, plasma biomarkers and longitudinal structural and cognitive outcomes. Inducible T-cell co-stimulator (ICOS) expression across CD4 and CD8 memory T-cells was associated with cerebral A{beta} pathology. In mild cognitive impairment (MCI), higher ICOS expression on CD8 memory T-cells strengthened the association between A{beta} load and hippocampal atrophy. A{beta}-derived peptides induced proliferative ICOS+CD25+ memory CD4 and CD8 T-cell responses predominantly in A{beta}-positive participants in an independent cohort. Conversely, higher programmed cell death protein 1 (PD-1) expression on CD8 effector-memory T-cells was associated with attenuated A{beta}-related episodic-memory decline in exceptionally old participants and was higher in stable MCI than in MCI-to-AD converters. These findings identify distinct co-stimulatory and co-inhibitory T-cell correlates of vulnerability and resilience.

immunology↗

bioRxiv2026

Reduced PDE4D expression and activity in Acrodysostosis Type 2 patient fibroblasts underlie disease pathology

BackgroundAcrodysostosis type 2 (ACRDYS2) is a rare autosomal dominant disease characterized by skeletal defects and cognitive deficit, with clinical symptoms observed in multiple other tissues including the skin. It is caused by mutations in a phosphodiesterase, PDE4D, a key regulator of cAMP/PKA (cyclic adenosine monophosphate / protein kinase A) signalling. Despite its well-defined genetic causes, the molecular mechanisms underlying the disease remain poorly understood, with studies based largely on engineered cellular models reaching conflicting interpretations. MethodsTo investigate how endogenous dynamics are affected by PDE4D mutations in unmanipulated cells, we studied PDE4D transcript and protein expression, activity and downstream signalling in native dermal fibroblast from ACRDYS2 patients and healthy controls. ResultsSignificant reduction in total PDE4D expression in patient cells was observed both at the transcript and protein level, with marked decreases in the long isoforms PDE4D4 and PDE4D7; a reduction in PDE4D9 mRNA was also observed. PDE4D enzymatic activity was reduced in ACRDYS2 fibroblasts, though total PDE activity was largely preserved. Reduced PDE4D expression was associated with an increase in the phosphorylated form of the cAMP-responsive transcription factor CREB and elevated PRKAR1A (PKA type 1 regulatory subunit alpha) transcript levels, suggesting altered downstream signalling. Interestingly, expression of the related phosphodiesterase family member PDE4B was increased, consistent with a compensatory response to reduced PDE4D function. ConclusionsThis is the first study demonstrating reduced PDE4D expression and isoform-specific dysregulation in native ACRDYS2 cells. Together, our results support a model in which reduction in PDE4D activity and compensatory changes in other PDE4 family members contribute to the molecular pathology of ACRDYS2, providing new insights into the molecular mechanisms underlying this disorder.

cell biology↗

bioRxiv2026

Altered microglial communication in brains with Alzheimers Disease pathology

Microglia are the resident immune cells of the central nervous system and are highly versatile, continuously monitoring the brain microenvironment with their motile processes and responding to perturbations in diverse ways. Recent studies have revealed substantial functional heterogeneity among microglial states, suggesting that analyzing individual subpopulations is essential to capture specialized signaling programs and disease-associated interactions that would otherwise be obscured in bulk analyses. To better understand how these cells interact, we performed a ligand-receptor communication analysis using single-nucleus RNA sequencing data from the dorsolateral prefrontal cortex, comprising 16 microglial subpopulations together with other myeloid cells identified in brain tissue, including macrophages and monocytes. We characterized the signaling roles of these cell populations, compared individuals with and without neuropathologically defined Alzheimers disease, and associated cell-pair interactions with AD-related clinical and neuropathological traits. We found that AD was characterized by altered microglial composition and rewiring of intercellular communication, including disease-specific signaling pathways and distinct interaction hubs. Lipid-associated microglia were associated with tau pathology, whereas nuclear receptor signaling microglia were linked to hippocampal sclerosis. These findings were replicated in three independent datasets. Overall, this work provides an initial but comprehensive map of microglial communication in the aging human brain and identifies candidate signaling interactions for future functional validation.

neuroscience↗

bioRxiv2026

Computational Pathology and Spatial Microdosimetry Guide Radiopharmaceutical Selection for TROP2-Targeted Alpha versus Beta Radionuclide Drug Conjugates (RDCs)

Background: Trophoblast cell surface antigen 2 (TROP2, encoded by TACSTD2) is a transmembrane glycoprotein overexpressed in multiple aggressive epithelial carcinomas. While antibody drug conjugates targeting TROP2 have achieved regulatory approvals, acquired payload resistance and systemic off-target toxicities limit sustained remissions. Radionuclide Drug Conjugates (RDCs) represent a potent alternative modality capable of delivering cytotoxic ionizing radiation directly to target cells. However, selecting the optimal therapeutic radioisotope between long-range beta emitters (177Lu) and short-range, high linear energy transfer (LET) alpha emitters (225Ac) under heterogeneous TROP2 spatial distributions remains an unaddressed clinical challenge. Methods: We developed an automated computational pathology and spatial microdosimetry pipeline to resolve microscopic TROP2 expression gradients and simulate absorbed radiation dose distributions from digitized whole-tissue immunohistochemistry (IHC) sections (N = 14). Optical density matrices were de-convoluted in Hematoxylin-Eosin-DAB (HED) color space to isolate the DAB chromogen. Continuous 2D spatial density distributions and topological surface profiles were reconstructed. Physical radiation energy deposition was modeled using radial dose point kernels for 177Lu (mean range ~670 m, LET 0.2 keV/m) and 225Ac (mean range ~65 m, LET 100 keV/m, 4 alpha particles per decay cascade). Therapeutic Index (TI, ratio of mean target to non-target absorbed dose), target coverage, and spatial specificity were quantified across all specimens. Results: Quantitative image deconvolution revealed that TROP2 expression across the cohort was characteristically focal and clustered, with a mean positive area fraction of 1.55 +/- 2.22% (range: 0.08% to 6.85%) and mean DAB signal intensity of 0.256 +/- 0.043. In all 14 evaluated specimens (100%), 225Ac-labeled RDCs demonstrated superior tumor-to-stroma dose localization compared to 177Lu-labeled RDCs. The cohort-wide mean Therapeutic Index was significantly higher for 225Ac (1.26 +/- 0.14) than for 177Lu (1.01 +/- 0.02, p < 0.0001, paired two-tailed t-test). Because the path length of 177Lu beta particles exceeded target cell nest dimensions by up to 30-fold, 177Lu suffered from severe off-target crossfire spillover into antigen-negative stroma. In contrast, 225Ac confined high-LET ionization tracks strictly within the micro-geographic boundaries of TROP2-expressing clusters. Conclusions: In tumors displaying focal or sparse TROP2 micro-architecture, Targeted Alpha Therapy with 225Ac-RDCs offers a superior biophysical profile over beta-emitting 177Lu-RDCs, maximizing cluster cell kill while sparing adjacent normal tissue stroma. This computational microdosimetry framework provides a practical tool to guide rational isotope pairing in RDC drug design.

cancer biology↗

bioRxiv2026

SorCS1 promotes synaptic and cognitive resilience despite amyloid pathology in Alzheimer's disease model mice

Alzheimer's disease (AD) lacks effective therapies despite extensive efforts targeting amyloid {beta} (A{beta}) and its precursor processing. Synapse loss is the strongest correlate of cognitive decline, driven partly by A{beta} oligomers (A{beta}Os), which bind multiple synaptic membrane proteins including the synaptic organizer neurexin and disrupt synaptic integrity and function. The protein sorting receptor SorCS1 blocks interactions between A{beta}Os and {beta}-isoforms of neurexins ({beta}-Nrxns), but its therapeutic relevance in vivo remains unclear. Using 5xFAD mice, which overproduce A{beta}Os, combined with forebrain specific neuronal SorCS1 overexpression, we show that SorCS1 preserves working memory, synaptic integrity, and basal excitatory transmission without altering amyloid deposition, in part by restoring synaptic {beta}-Nrxn expression. SorCS1 also reduces tau hyperphosphorylation in 5xFAD synaptosomes and binds the tau kinase GSK3{beta}. These results identify SorCS1 as an AD resilience promoting factor that maintains synaptic connectivity and attenuates tau pathology, revealing a therapeutic strategy that operates independently of amyloid reduction.

neuroscience↗