Xenografted human microglia display diverse transcriptomic states in response to Alzheimer’s disease-related amyloid-β pathology

Journal article

This thesis explores virus-induced neuropathology using human stem cell-derived organotypic models that mimic the molecular and cellular complexity of the central nervous system (CNS). Chapter 1 introduces the challenges in studying viral neurological disease, emphasizing the limitations of traditional models and the potential of neural organoids as human-relevant systems. Chapter 2 highlights the importance of unified terminology and context-dependent host–virus interactions in understanding neuropathology.Part I focuses on modeling neuropathology caused by human Parechoviruses (HPeV) and Human Immunodeficiency Virus (HIV). Neural organoids were used to show that the neurovirulent HPeV-3, but not HPeV-1, induces strong immune and metabolic disturbances rather than differences in viral replication or tropism. Reanalysis revealed disrupted immunometabolism and glutamate excitotoxicity, implicating host metabolic imbalance in disease severity. Using microglia-containing organoids, HIV infection studies showed that microglia facilitate viral persistence, elevate HIV gene expression, and promote inflammatory amino acid metabolism, highlighting their role as reservoirs contributing to HIV-associated neurocognitive disorders.Part II applies organoid platforms for antiviral testing. Halofuginone Hydrobromide showed broad-spectrum antiviral potential in organoid systems but limited efficacy at clinically relevant concentrations, demonstrating the translational value of organoids for assessing both efficacy and toxicity.Together, these studies establish human iPSC-derived neural organoids as powerful models for studying viral infection, immune–metabolic crosstalk, and therapeutic interventions. Their multicellular architecture and human relevance position them as essential tools for mechanistic discovery, antiviral screening, and the advancement of precision medicine in neurovirology

Authors: Mancuso, R; Fattorelli, N; Martinez-Muriana, A; Davis, E; Wolfs, L

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Neuroscience
• Volume: 27
• Issue: 5
• Pages: 886-900
• Publication date: 2024-03-27
• DOI: 10.1038/s41593-024-01600-y
• EISSN: 1546-1726
• ISSN: 1097-6256
• Language: English
• Keywords: Gene; Medicine; Immune system; Pathology; Human brain; Microglia; Neuroscience; Chemokine; Amyloid (mycology); Transcriptome; Immunology; Disease; Alzheimer's disease; Gene expression; Biology; Neurodegeneration; TREM2; Inflammation; Genetics