Biology subjects

Gruber-Schoffnegger, D.

Publications and source records attributed to Gruber-Schoffnegger, D..

4 recordsLinked to original sources

bioRxiv2026

A brain immune phenotype independent of Alzheimer's Disease associates with amyloid susceptibility and systemic inflammation

Transcriptomic and proteomic studies have consistently demonstrated substantial molecular heterogeneity across patients with Alzheimer's disease (AD) and other neurodegenerative disorders, leading to the proposal of multiple disease subtypes. However, almost all previous studies have focused on heterogeneity within diseased cohorts, whereas comparatively little attention has been paid to the molecular diversity of neurologically healthy individuals. In the present study, we demonstrate that one of the most prominent transcriptomic programs characterized by a strong immune component previously interpreted as an AD-specific immune subtype is in fact a brain phenotype that exists independently of AD yet interacts with AD susceptibility and is selectively associated with amyloid pathology. The transcriptional effect of the immune phenotype exceeds that of AD pathology-induced changes and is accompanied by alterations of brain cellular compositions and a distinct systemic inflammation. Our findings suggest that part of the molecular heterogeneity observed in neurological diseases might arise from pre-existing brain phenotypes rather than representing disease-specific subtypes. These insights support a precision medicine approach for Alzheimer's disease, whereby individuals with an immune phenotype of the brain could be prospectively identified and monitored, enabling the application of targeted preventive strategies before substantial neuropathology and cognitive decline emerge.

neuroscience↗

bioRxiv2026

Multimodal evidence for impaired glymphatic brain clearance as a mediator of "inflammaging" in schizophrenia - integrating insights from in vivo neuroimaging, omics, and post-mortem single nucleus-RNA-Seq data

Persistent cognitive impairment and reduced life expectancy in schizophrenia may arise from inflammation-driven accelerated aging ("inflammaging"), yet the underlying mechanisms remain unclear. Impaired glymphatic clearance, dependent on polarized aquaporin-4 (AQP4) localization at astrocytic endfeet, offers a plausible mechanistic link between inflammation and brain aging. Here, we integrate in vivo neuroimaging with post-mortem single-nucleus transcriptomics from distinct patient cohorts to demonstrate glymphatic dysfunction in schizophrenia and define its molecular basis. We identify reduced astrocytic expression of components of the dystrophin-associated protein complex (SNTA1, DAG1) required for AQP4 polarization. Both in vivo neuroimaging and post-mortem gene expression signatures of glymphatic dysfunction are restricted to an inflammatory subgroup characterized by peripheral immune activation and pro-inflammatory glial transcriptional profiles. Moreover, imaging signatures of glymphatic impairment are associated with schizophrenia polygenic risk scores enriched for immune - and oxidative stress - related aging pathways as well as cognitive dysfunction. At the cellular level, glymphatic dysfunction coincides with loss of homeostatic programs in microglia and astrocytes, increased inflammatory signaling, and endothelial signatures of blood-brain barrier disruption. Across modalities, glymphatic impairment is linked to accelerated aging, including increased brain and epigenetic age, and aging-related gene expression signatures.

neuroscience↗

bioRxiv2026

Characterization and pharmacological modulation of Alzheimers disease-associated human microglial states

Microglia are central mediators of Alzheimers disease (AD) pathogenesis, yet the mechanisms driving disease-associated microglial states and their therapeutic modulation remain poorly understood. Here, we integrated single-nucleus transcriptomic datasets across the AD spectrum and identified disease- and lipid-associated microglia (DLaM) as a major AD-enriched population linked to genetic risk, neuropathology and cognitive decline. To model this state experimentally, we screened AD-relevant perturbations in human induced pluripotent stem cell (hiPSC)-derived microglia and found that ferric ammonium citrate (FAC) reproducibly induced a DLaM-like state characterized by lipid accumulation, lysosomal dysfunction and impaired A{beta} phagocytosis. Using a transcriptomics-based state-reversion screen, we identified LY2090314 as a potent modulator that restored microglial function and induced a distinct lysosomal-metabolic state. These findings establish a framework for transcriptomic disease-state-guided therapeutic discovery in AD.

neuroscience↗

bioRxiv2023

TRPML1 activation ameliorates lysosomal phenotypes in CLN3 deficient retinal pigment epithelial cells

Mutations in the lysosomal membrane protein CLN3 cause Juvenile Neuronal Ceroid Lipofuscinosis (JNCL). Activation of the lysosomal ion channel TRPML1 has previously been shown to be beneficial in several neurodegenerative disease models. Here, we tested whether TRPML1 activation rescues disease-associated phenotypes in CLN3-deficient retinal pigment epithelial (ARPE-19 CLN3-KO) cells. ARPE-19 CLN3-KO cells accumulate LAMP1 positive organelles and show lysosomal storage of mitochondrial ATPase subunit C (SubC), globotriaosylceramide (Gb3), and glycerophosphodiesters (GPDs), whereas lysosomal bis(monoacylglycero)phosphate (BMP/LBPA) lipid levels were significantly decreased. Activation of TRPML1 reduced lysosomal storage of Gb3 and SubC but failed to restore BMP levels in CLN3-KO cells. TRPML1-mediated decrease of storage was TFEB-independent, and we identified TRPML1-mediated enhanced lysosomal exocytosis as a likely mechanism for clearing storage including GPDs. Therefore, ARPE-19 CLN3-KO cells represent a human cell model for CLN3 disease showing many of the described core lysosomal deficits, some of which can be improved using TRPML1 agonists.

cell biology↗