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Hirano bodies contain tau protein.
Hirano bodies are intraneuronal inclusions whose frequency increases with age and Alzheimer's disease. These paracrystalline inclusions have been shown previously using immunocytochemistry to share epitopes with actin, tropomyosin, alpha-actinin and vinculin. Hirano bodies have not previously been demonstrated to share components with neurofibrillary tangles, another intraneuronal inclusion characteristic of Alzheimer's disease. In this study, we show that Hirano bodies bind antibodies to the microtubule-associated protein tau, a component of Alzheimer neurofibrillary tangles.
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APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types.
The apolipoprotein E4 (APOE4) variant is the single greatest genetic risk factor for sporadic Alzheimer's disease (sAD). However, the cell-type-specific functions of APOE4 in relation to AD pathology remain understudied. Here, we utilize CRISPR/Cas9 and induced pluripotent stem cells (iPSCs) to examine APOE4 effects on human brain cell types. Transcriptional profiling identified hundreds of differentially expressed genes in each cell type, with the most affected involving synaptic function (neurons), lipid metabolism (astrocytes), and immune response (microglia-like cells). APOE4 neurons exhibited increased synapse number and elevated Aβ42 secretion relative to isogenic APOE3 cells while APOE4 astrocytes displayed impaired Aβ uptake and cholesterol accumulation. Notably, APOE4 microglia-like cells exhibited altered morphologies, which correlated with reduced Aβ phagocytosis. Consistently, converting APOE4 to APOE3 in brain cell types from sAD iPSCs was sufficient to attenuate multiple AD-related pathologies. Our study establishes a reference for human cell-type-specific changes associated with the APOE4 variant. VIDEO ABSTRACT.
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Neuroinvasion of SARS-CoV-2 in human and mouse brain.
Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2.
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Lessons from Frankenstein 200 years on: brain organoids, chimaeras and other 'monsters'.
Mary Shelley's Frankenstein has captured the public imagination ever since it was first published over 200 years ago. While the narrative reflected 19th-century anxieties about the emerging scientific revolution, it also suggested some clear moral lessons that remain relevant today. In a sense, Frankenstein was a work of bioethics written a century and a half before the discipline came to exist. This paper revisits the lessons of Frankenstein regarding the creation and manipulation of life in the light of recent developments in stem cell and neurobiological research. It argues that these lessons are becoming more relevant than ever.
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Generation and assembly of human brain region-specific three-dimensional cultures.
The ability to generate region-specific three-dimensional (3D) models to study human brain development offers great promise for understanding the nervous system in both healthy individuals and patients. In this protocol, we describe how to generate and assemble subdomain-specific forebrain spheroids, also known as brain region-specific organoids, from human pluripotent stem cells (hPSCs). We describe how to pattern the neural spheroids toward either a dorsal forebrain or a ventral forebrain fate, establishing human cortical spheroids (hCSs) and human subpallial spheroids (hSSs), respectively. We also describe how to combine the neural spheroids in vitro to assemble forebrain assembloids that recapitulate the interactions of glutamatergic and GABAergic neurons seen in vivo. Astrocytes are also present in the human forebrain-specific spheroids, and these undergo maturation when the forebrain spheroids are cultured long term. The initial generation of neural spheroids from hPSCs occurs in <1 week, with regional patterning occurring over the subsequent 5 weeks. After the maturation stage, brain region-specific spheroids are amenable to a variety of assays, including live-cell imaging, calcium dynamics, electrophysiology, cell purification, single-cell transcriptomics, and immunohistochemistry studies. Once generated, forebrain spheroids can also be matured for >24 months in culture.
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Genetic Ablation of AXL Does Not Protect Human Neural Progenitor Cells and Cerebral Organoids from Zika Virus Infection.
Zika virus (ZIKV) can cross the placental barrier, resulting in infection of the fetal brain and neurological defects including microcephaly. The cellular tropism of ZIKV and the identity of attachment factors used by the virus to gain access to key cell types involved in pathogenesis are under intense investigation. Initial studies suggested that ZIKV preferentially targets neural progenitor cells (NPCs), providing an explanation for the developmental phenotypes observed in some pregnancies. The AXL protein has been nominated as a key attachment factor for ZIKV in several cell types including NPCs. However, here we show that genetic ablation of AXL has no effect on ZIKV entry or ZIKV-mediated cell death in human induced pluripotent stem cell (iPSC)-derived NPCs or cerebral organoids. These findings call into question the utility of AXL inhibitors for preventing birth defects after infection and suggest that further studies of viral attachment factors in NPCs are needed.
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Multi-omics characterization of developing forebrain organoids unravels the dynamic molecular events of Rett syndrome pathogenesis.
BACKGROUND: Rett Syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in the MECP2 gene. Despite its monogenic nature, the molecular events contributing to RTT pathogenesis are not fully elucidated. METHODS: We applied a multi-omics approach to comprehensively analyse the spatiotemporal gene and protein expression patterns in MeCP2-mutant (RTT) and isogenic control (IC) forebrain organoids. Dorsal and ventral forebrain organoids were cultured for 75 days using patient-derived RTT and IC hiPSC lines. Transcriptomics and proteomics profiles were characterized at days 0, 13, 40, and 75, corresponding to distinct neurodevelopmental phases. RESULTS: The spatiotemporal transcriptomic analysis revealed alterations in GABAergic signaling at the latest neurodevelopmental stages, while changes in neuronal development, DNA-associated processes, and post-transcriptional regulation were found to occur across different stages. These changes were also observed at the protein level and in independent validation datasets. Notably, differentially expressed lncRNA genes such as MIR137HG and PWRN1 may act as regulators of these affected processes. Moreover, our results provide systematic evidence for the involvement of imprinted genes in RTT pathology. CONCLUSIONS: Together, our study lays the foundation for future studies to functionally validate the significance of the identified processes and molecular targets in RTT pathogenesis, and to assess their value as therapeutic targets.
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[Electron microscopy studies on brain and spinal ganglia of mice fetuses (day 12-17) after application of vincristine].
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Protocol for characterization of spatiotemporal network dynamics in cortical and hippocampal assembloids.
This protocol generates neural assembloids from human induced pluripotent stem cells (hiPSCs) to model human brain circuitry. It details the differentiation of excitatory-predominant hippocampal (Hc) and cortical (Cx) organoids and their fusion with inhibitory interneuron-predominant ganglionic eminence (GE) organoids. We then detail procedures for maintaining assembloids to promote interneuron migration and network integration, followed by functional assessment using two-photon calcium imaging to measure neuronal activity. For complete details on the use and execution of this protocol, please refer to McCrimmon et al.1.
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Neuropilin-1 Mediates SARS-CoV-2 Infection of Astrocytes in Brain Organoids, Inducing Inflammation Leading to Dysfunction and Death of Neurons.
Coronavirus disease 2019 (COVID-19) is frequently associated with neurological deficits, but how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces these effects remains unclear. Here, we show that astrocytes are readily infected by SARS-CoV-2, but surprisingly, neuropilin-1, not angiotensin-converting enzyme 2 (ACE2), serves as the principal receptor mediating cell entry. Infection is further positively modulated by the two-pore segment channel 2 (TPC2) protein that regulates membrane trafficking and endocytosis. Astrocyte infection produces a pathological response closely resembling reactive astrogliosis characterized by elevated type I interferon (IFN) production, increased inflammation, and the decreased expression of transporters of water, ions, choline, and neurotransmitters. These combined events initiated within astrocytes produce a hostile microenvironment that promotes the dysfunction and death of uninfected bystander neurons. IMPORTANCE SARS-CoV-2 infection primarily targets the lung but may also damage other organs, including the brain, heart, kidney, and intestine. Central nervous system (CNS) pathologies include loss of smell and taste, headache, delirium, acute psychosis, seizures, and stroke. Pathological loss of gray matter occurs in SARS-CoV-2 infection, but it is unclear whether this is due to direct viral infection, indirect effects associated with systemic inflammation, or both. Here, we used induced pluripotent stem cell (iPSC)-derived brain organoids and primary human astrocytes from the cerebral cortex to study direct SARS-CoV-2 infection. Our findings support a model where SARS-CoV-2 infection of astrocytes produces a panoply of changes in the expression of genes regulating innate immune signaling and inflammatory responses. The deregulation of these genes in astrocytes produces a microenvironment within the CNS that ultimately disrupts normal neuron function, promoting neuronal cell death and CNS deficits.