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Pushing the boundaries of brain organoids to study Alzheimer's disease.
Progression of Alzheimer's disease (AD) entails deterioration or aberrant function of multiple brain cell types, eventually leading to neurodegeneration and cognitive decline. Defining how complex cell-cell interactions become dysregulated in AD requires novel human cell-based in vitro platforms that could recapitulate the intricate cytoarchitecture and cell diversity of the human brain. Brain organoids (BOs) are 3D self-organizing tissues that partially resemble the human brain architecture and can recapitulate AD-relevant pathology. In this review, we highlight the versatile applications of different types of BOs to model AD pathogenesis, including amyloid-β and tau aggregation, neuroinflammation, myelin breakdown, vascular dysfunction, and other phenotypes, as well as to accelerate therapeutic development for AD.
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Neonicotinoid Pesticides Affect Developing Neurons in Experimental Mouse Models and in Human Induced Pluripotent Stem Cell (iPSC)-Derived Neural Cultures and Organoids.
Neonicotinoids are synthetic, nicotine-derived insecticides used worldwide to protect crops and domestic animals from pest insects. The reported evidence shows that they are also able to interact with mammalian nicotine receptors (nAChRs), triggering detrimental responses in cultured neurons. Exposure to high neonicotinoid levels during the fetal period induces neurotoxicity in animal models. Considering the persistent exposure to these insecticides and the key role of nAChRs in brain development, their potential neurotoxicity on mammal central nervous system (CNS) needs further investigations. We studied here the neurodevelopmental effects of different generations of neonicotinoids on CNS cells in mouse fetal brain and primary cultures and in neuronal cells and organoids obtained from human induced pluripotent stem cells (iPSC). Neonicotinoids significantly affect neuron viability, with imidacloprid (IMI) inducing relevant alterations in synaptic protein expression, neurofilament structures, and microglia activation in vitro, and in the brain of prenatally exposed mouse fetuses. IMI induces neurotoxic effects also on developing human iPSC-derived neurons and cortical organoids. Collectively, the current findings show that neonicotinoids might induce impairment during neuro/immune-development in mouse and human CNS cells and provide new insights in the characterization of risk for the exposure to this class of pesticides.
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Involvement of extracellular vesicle microRNA clusters in developing healthy and Rett syndrome brain organoids.
Rett syndrome (RTT) is a neurodevelopmental disorder caused by de novo mutations in the MECP2 gene. Although miRNAs in extracellular vesicles (EVs) have been suggested to play an essential role in several neurological conditions, no prior study has utilized brain organoids to profile EV-derived miRNAs during normal and RTT-affected neuronal development. Here we report the spatiotemporal expression pattern of EV-derived miRNAs in region-specific forebrain organoids generated from female hiPSCs with a MeCP2:R255X mutation and the corresponding isogenic control. EV miRNA and protein expression profiles were characterized at day 0, day 13, day 40, and day 75. Several members of the hsa-miR-302/367 cluster were identified as having a time-dependent expression profile with RTT-specific alterations at the latest developmental stage. Moreover, the miRNA species of the chromosome 14 miRNA cluster (C14MC) exhibited strong upregulation in RTT forebrain organoids irrespective of their spatiotemporal location. Together, our results suggest essential roles of the C14MC and hsa-miR-302/367 clusters in EVs during normal and RTT-associated neurodevelopment, displaying promising prospects as biomarkers for monitoring RTT progression.
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Clathrin: a unique protein associated with intracellular transfer of membrane by coated vesicles.
Coated vesicles have been purified from brain, adrenal medulla, and a nonsecreting lymphoma cell line. A single major protein species, clathrin, with an apparent molecular weight of 180,000, forms the coat of all these vesicles. Peptide mapping suggests that the amino acid sequence of clathrin is conserved, irrespective of tissue or species studied. Coated vesicles of different sizes are found. The coats are constructed with variable numbers of clathrin subunits, arranged in closed networks of hexagons and pentagons. The amount of clathrin in lymphoma cells suggests that coated vesicles transfer substantial amounts of membrane within cells, not necessarily in association with a secretory process.
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Commentary: A Primer on Human Brain Organoids for the Neurosurgeon.
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Reversible restoration of the birefringence of cold-treated, isolated mitotic apparatus of surf clam eggs with chick brain tubulin.
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Letermovir shows antiviral and neuroprotective effects in differentiating neurons and cerebral organoids mimicking human developing brain.
Human cytomegalovirus (HCMV) is the leading viral cause of congenital defects. The triggers of viral neuropathogenesis during congenital infection (cCMV) are still unclear, and treatment options are limited. We used both a two-dimensional model of dynamic neurogenesis and cerebral organoids (COs), recapitulating the developing brain in the first trimester of gestation, to investigate the neuropathogenesis induced by HCMV. We also evaluated antiviral and neuroprotective effects of different compounds, both approved, direct-acting drugs and investigational, host-directed antivirals. In differentiating neurons, treatment with direct-acting antivirals blocked HCMV active replication and provided some protection from virus-induced defects. COs exposed to two different strains of HCMV showed viral spread throughout the organoids, dysregulation of key players of neurogenesis, alteration of the tissue cytoarchitecture, and triggering of innate antiviral and pro-inflammatory responses. Inter-strain differences in virus release and growth attenuation were detected in infected COs. Regardless of the strain, treatment with direct-acting antivirals, particularly letermovir, completely abolished HCMV replication, protected COs from virus-induced disorganization of tissue architecture, and dampened innate immune and pro-inflammatory response activation. Importantly, we also demonstrated the efficacy of the antiviral treatment in HCMV-infected COs in blocking an already established infection. This study contributes to shed light on HCMV-induced neuropathogenesis that occurs during congenital infection. Importantly, we demonstrated the neuroprotective effects of letermovir in models of human developing brain, holding promise for its evaluation as a candidate therapeutic agent to ameliorate cCMV-associated neurodevelopmental defects.
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Human iPSC-Derived Brain Cells, Organoids, and Organoids-on-Chips: Advancing Neurological Disease Modeling to Improve Clinical Outcome.
Neurological disorders are the leading cause of overall disease and disability worldwide, affecting more than 3.4 billion people globally and over 180 million Americans. Yet there are no curative treatments available for any of the cardinal neurological diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) and Huntington's disease (HD). Many compounds that demonstrate excellent activity in preclinical models fail in clinical trials. The most compelling reason for this failure is attributed to inherent limitations of rodent models that fail to replicate complex human biology. The transformation of patient-derived somatic cells into induced pluripotent stem cells (iPSCs) that can become functional human neurons is an emerging technology that is expected to revolutionize medical treatments and personal medicine. Here, we review the available evidence for the efficacy of iPSC-derived neurons, organoids, assembloids and organ-on-chip in models of AD, PD, ALS-FTD and HD. We focus on how these human-relevant iPSC-derived brain cells are crucial for understanding neurological disease pathogenesis and accelerating drug discovery. We also discuss the current limitations of this technology and how alternative models such as induced neurons (iNs) are generated by directly reprogramming fibroblasts that preserve age-associated epigenetic signatures and may serve as better models for neurological disorders.
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New frontiers in modeling tuberous sclerosis with human stem cell-derived neurons and brain organoids.
Recent advances in human stem cell and genome engineering have enabled the generation of genetically defined human cellular models for brain disorders. These models can be established from a patient's own cells and can be genetically engineered to generate isogenic, controlled systems for mechanistic studies. Given the challenges of obtaining and working with primary human brain tissue, these models fill a critical gap in our understanding of normal and abnormal human brain development and provide an important complement to animal models. Recently, there has been major progress in modeling the neuropathophysiology of the canonical "mTORopathy" tuberous sclerosis complex (TSC) with such approaches. Studies using two- and three-dimensional cultures of human neurons and glia have provided new insights into how mutations in the TSC1 and TSC2 genes impact human neural development and function. Here we discuss recent progress in human stem cell-based modeling of TSC and highlight challenges and opportunities for further efforts in this area.
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Ultrastructural changes in the central nervous system in experimental hypoglycemia.