Biology subjects

Gniadzik, W.

Publications and source records attributed to Gniadzik, W..

3 recordsLinked to original sources

bioRxiv2025

Modeling Alzheimer's Disease with APOE4 Neuron-Glial Brain Assembloids Reveals IGFBPs as Therapeutic Targets

Alzheimers disease (AD) research has been hindered by the lack of models that faithfully recapitulate the full profile of disease progression in a human genetic background. We developed a 3D assembloid model ("Masteroid") using iPSC-derived neurons, astrocytes, and microglia from APOE4/4 and isogenic control lines. Neurons were seeded with tau oligomers, then combined with astrocytes and microglia to form mature 3D Masteroids, followed by amyloid-{beta} oligomer exposure. After four weeks, AD-Masteroids exhibited hallmark pathologies, including extracellular amyloid-{beta} deposits, intracellular tau aggregation, neurodegeneration, astrogliosis, and microglial activation, with APOE4 exacerbating all phenotypes. Single-cell RNA sequencing further identified novel roles of IGFBP pathways in amyloid-{beta} and tau-mediated pathology. This innovative platform provides a robust system to dissect cellular and molecular mechanisms of AD progression and offers a powerful tool for therapeutic discovery. HighlightsO_LIThe 3D human neuron-glia assembloid ("Masteroid"), composed of neurons, astrocytes, microglia, and oligodendrocytes, faithfully recapitulates human brain ultrastructure and intercellular interactions. C_LIO_LIExposure to oligomeric tau and A{beta} induced hallmark Alzheimers pathologies, including amyloid deposition, tau aggregation, neurodegeneration, and gliosis. C_LIO_LIThe APOE4 genotype exacerbated all pathological features, highlighting its role in driving multicellular interactions that accelerate disease progression. C_LIO_LIThe IGF signaling axis was identified as a key mediator of A{beta}- and tau-induced pathology and a potential therapeutic target. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=183 SRC="FIGDIR/small/683162v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@f91740org.highwire.dtl.DTLVardef@165726eorg.highwire.dtl.DTLVardef@13b957forg.highwire.dtl.DTLVardef@d40307_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Functional rescue of a fatal ERAD mutation via alternative splicing

Endoplasmic reticulum (ER)-associated degradation (ERAD) is essential for cellular proteostasis, with the SEL1L-HRD1 protein complex targeting misfolded proteins in the ER for proteasomal degradation. Disruption of this pathway underlies a recently identified infant-onset neurodevelopmental disorder (ENDI syndrome), characterized by profound developmental delay, microcephaly, and immune deficiency. Its most severe form, ENDI with agammaglobulinemia (ENDI-A), is driven by a bi-allelic SEL1L Cys141Tyr (C141Y) mutation within the fibronectin II (FNII) domain, for which no treatment currently exists. Here, we serendipitously uncover a striking mechanism of intrinsic rescue in knock-in mouse models of the C141Y mutation: enhanced usage of an alternative splice donor site within exon 4 bypasses the mutant FNII-encoding region, restoring ERAD activity and rescuing key disease phenotypes including perinatal lethality, growth retardation, B cell deficiency, and neurodevelopmental defects. Building on this discovery, we demonstrate that antisense oligonucleotide (ASO)-mediated exon skipping in patient-derived fibroblasts generates a truncated yet functional SEL1L protein, fully rescuing ERAD function and ER proteostasis. These results establish RNA splicing modulation as a viable therapeutic strategy for ERAD deficiency and extend the clinical potential of exon-skipping therapy to diseases of protein misfolding. ONE-SENTENCE SUMMARYThis study reports the discovery of using antisense oligonucleotides (ASOs) to rescue the biallelic SEL1L C141Y variant, offering a potential therapeutic strategy.

cell biology↗

bioRxiv2025

Tau Oligomerization Drives Neurodegeneration via Nuclear Membrane Invagination and Lamin B Receptor Binding in Alzheimer's disease

The microtubule-associated protein tau aggregates into oligomeric complexes that highly correlate with Alzheimers disease (AD) progression. Increasing evidence suggests that nuclear membrane disruption occurs in AD and related tauopathies, but whether this is a cause or consequence of neurodegeneration remains unclear. Using the optogenetically inducible 4R1N Tau::mCherry::Cry2Olig (optoTau) system in iPSC-derived neurons, we demonstrate that tau oligomerization triggers nuclear rupture and nuclear membrane invagination. Pathological tau accumulates at sites of invagination, inducing structural abnormalities in the nuclear envelope and piercing into the nuclear space. These findings were confirmed in the humanized P301S tau (PS19) transgenic mouse model, where nuclear envelope disruption appeared as an early-onset event preceding neurodegeneration. Further validation in post-mortem AD brain tissues revealed nuclear lamina disruption correlating with pathological tau emergence in early-stage patients. Notably, electron microscopy shows that tau-induced nuclear invagination triggers global chromatin reorganization, potentially driving aberrant gene expression and protein translation associated with AD. These findings suggest that nuclear membrane disruption is an early and possibly causative event in tau-mediated neurodegeneration, establishing a mechanistic link between tau oligomerization and nuclear stress. Further investigation into nuclear destabilization could inform clinical strategies for mitigating AD pathogenesis.

neuroscience↗