Summary The pathological hallmarks of neurodegeneration are the aberrant post-translational modification and aggregation of proteins. Genetic factors, like APOE4, increase the prevalence and severity of tau, amyloid, and α-synuclein pathologies. However, the human brain is largely inaccessible during this process, limiting mechanistic understanding. Here, we developed an iPSC-based 3D model that integrates neurons, glia, myelin, and cerebrovascular cells into a human brain-like tissue (“miBrain”). Single-nucleus RNA sequencing of miBrains confirmed the presence of diverse cell populations and revealed transcriptional responses to α-synuclein pathology. Like the human brain, pathogenic α-synuclein is increased in APOE4/4 miBrains. Combinatorial experiments revealed that endolysosomal dysfunction caused by cholesterol accumulation in APOE4/4 astrocytes impairs the degradation of soluble α-synuclein leading to a pathogenic transformation that seeds α-synuclein inclusions in neurons. Collectively, this study establishes a robust model for investigating protein inclusions in human iPSC-derived brain tissue and highlights the role of astrocytes and cholesterol in APOE4-mediated pathologies.
Louise A. Mesentier-Louro, Camille Goldman, Sebastian Gaese et al.· Cell Stem Cell· 1 citation
Neurogenesis, a critical process implicated in diverse brain disorders, is greatly diminished in the adult human brain, complicating direct investigations into its mechanistic role in disease. In the olfactory epithelium (OE), olfactory sensory neurons (OSNs) maintain homeostasis via continual neurogenesis throughout life, providing a niche to investigate neurogenesis in vivo. However, the molecular mechanisms underlying this process and its similarities to brain neurogenesis remain largely unknown. Here, we performed single-nucleus RNA-seq on specimens of human OE from 6 living adult donors, yielding high-quality transcriptomes representing 145,720 cells. Integrating with two independent OE single-cell transcriptomics datasets, different developmental stages of OSNs were identified, including neural precursor cells (globose basal cells, GBCs), as well as immature and mature OSNs. We inferred trajectories and assessed the transcriptional and regulatory dynamics of OSN development. Genes and transcription factors (TFs) involved in regulating neuronal differentiation and neurogenesis were highly expressed in GBCs and early immature OSNs, but were downregulated in mature neurons. OSNs and cortical excitatory neurons exhibited convergence during early developmental stages, including dynamically expressed genes, TFs, biological processes, and polygenic enrichment for psychiatric disorders. In addition, expression trajectory alignment between OSNs and cortical excitatory neurons (CENs) revealed that OSNs could partially track the expression dynamics of autism spectrum disorder (ASD) risk genes in CENs. Overall, cells in the neuronal lineage of the OE represent a potential proxy to study gene programs involved in neurogenesis in the human brain, providing an accessible model for investigating neurodevelopmental dysfunction in psychiatric disorders. Adult human brain neurogenesis is difficult to investigate directly. Here, authors show that the adult olfactory epithelium recapitulates key transcriptional and regulatory programs of cortical neurogenesis, providing an accessible model for studying psychiatric disease-associated neurodevelopment.
Liting Song, J. Fullard, Claire Coleman et al.· Nature Communications· 0 citations
Myeloid cells, including microglia and perivascular macrophages, are central to Alzheimer’s disease (AD) neurobiology, yet their role remains incompletely understood. We profiled 832,505 human myeloid cells from the prefrontal cortex of 1,607 donors spanning the lifespan and showing varying degrees of AD neuropathology. We delineated six subclasses comprising 13 transcriptionally distinct subtypes and identified adaptive changes associated with aging and AD progression. Here we show that a disease-associated microglial subtype, characterized by elevated GPNMB expression and enriched for polygenic AD risk, expands with AD pathology and shows increased phagocytic activity. We identify MITF as an upstream regulator required to maintain this microglial state. Cell–cell interaction analyses prioritize APOE–SORL1 and APOE–TREM2 signaling pairs associated with disease progression. Using human and mouse models, we demonstrate that the neuroprotective effects of this microglial subtype depend on TREM2. These findings provide mechanistic insights into myeloid cell function in aging and AD, aiding therapeutic discovery. Molecular profiling of myeloid cells from the prefrontal cortex of 1,607 donors with varying degrees of Alzheimer’s disease neuropathology delineates distinct myeloid subtypes and identifies changes associated with aging and disease progression.
Donghoon Lee, James M. Vicari, Christian Porras et al.· Nature Genetics· 0 citations
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