Utilizing human cerebral organoids to model breast cancer brain metastasis in culture.

BACKGROUND: Metastasis, the spread, and growth of malignant cells at secondary sites within a patient's body, accounts for over 90% of cancer-related mortality. Breast cancer is the most common tumor type diagnosed and the leading cause of cancer lethality in women in the United States. It is estimated that 10-16% breast cancer patients will have brain metastasis. Current therapies to treat patients with breast cancer brain metastasis (BCBM) remain palliative. This is largely due to our limited understanding of the fundamental molecular and cellular mechanisms through which BCBM progresses, which represents a critical barrier for the development of efficient therapies for affected breast cancer patients. METHODS: Previous research in BCBM relied on co-culture assays of tumor cells with rodent neural cells or rodent brain slice ex vivo. Given the need to overcome the obstacle for human-relevant host to study cell-cell communication in BCBM, we generated human embryonic stem cell-derived cerebral organoids to co-culture with human breast cancer cell lines. We used MDA-MB-231 and its brain metastatic derivate MDA-MB-231 Br-EGFP, other cell lines of MCF-7, HCC-1806, and SUM159PT. We leveraged this novel 3D co-culture platform to investigate the crosstalk of human breast cancer cells with neural cells in cerebral organoid. RESULTS: We found that MDA-MB-231 and SUM159PT breast cancer cells formed tumor colonies in human cerebral organoids. Moreover, MDA-MB-231 Br-EGFP cells showed increased capacity to invade and expand in human cerebral organoids. CONCLUSIONS: Our co-culture model has demonstrated a remarkable capacity to discern the brain metastatic ability of human breast cancer cells in cerebral organoids. The generation of BCBM-like structures in organoid will facilitate the study of human tumor microenvironment in culture.

Expression of Human L-Dopa Decarboxylase (DDC) under Conditions of Oxidative Stress.

Oxidative stress is known to influence mRNA levels, translation, and proteolysis. The importance of oxidative stress has been demonstrated in several human diseases, including neurodegenerative disorders. L-Dopa decarboxylase (DDC) is the enzyme that converts L-Dopa to dopamine (DA). In spite of a large number of studies, little is known about the biological significance of the enzyme under physiological and pathological conditions. Here, we investigated the relationship between DDC expression and oxidative stress in human neural and non-neural cells. Oxidative stress was induced by treatment with H2O2. Our data indicated that mRNA and protein expression of DDC was enhanced or remained stable under conditions of ROS induction, despite degradation of total RNA and increased cytotoxicity and apoptosis. Moreover, DDC silencing caused an increase in the H2O2-induced cytotoxicity. The current study suggests that DDC is involved in the mechanisms of oxidative stress.

Mitochondrial, cell cycle control and neuritogenesis alterations in an iPSC-based neurodevelopmental model for schizophrenia.

Schizophrenia is a severe psychiatric disorder of neurodevelopmental origin that affects around 1% of the world's population. Proteomic studies and other approaches have provided evidence of compromised cellular processes in the disorder, including mitochondrial function. Most of the studies so far have been conducted on postmortem brain tissue from patients, and therefore, do not allow the evaluation of the neurodevelopmental aspect of the disorder. To circumvent that, we studied the mitochondrial and nuclear proteomes of neural stem cells (NSCs) and neurons derived from induced pluripotent stem cells (iPSCs) from schizophrenia patients versus healthy controls to assess possible alterations related to energy metabolism and mitochondrial function during neurodevelopment in the disorder. Our results revealed differentially expressed proteins in pathways related to mitochondrial function, cell cycle control, DNA repair and neuritogenesis and their possible implication in key process of neurodevelopment, such as neuronal differentiation and axonal guidance signaling. Moreover, functional analysis of NSCs revealed alterations in mitochondrial oxygen consumption in schizophrenia-derived cells and a tendency of higher levels of intracellular reactive oxygen species (ROS). Hence, this study shows evidence that alterations in important cellular processes are present during neurodevelopment and could be involved with the establishment of schizophrenia, as well as the phenotypic traits observed in adult patients. Neural stem cells (NSCs) and neurons were derived from induced pluripotent stem cells (iPSCs) from schizophrenia patients and controls. Proteomic analyses were performed on the enriched mitochondrial and nuclear fractions of NSCs and neurons. Whole-cell proteomic analysis was also performed in neurons. Our results revealed alteration in proteins related to mitochondrial function, cell cycle control, among others. We also performed energy pathway analysis and reactive oxygen species (ROS) analysis of NSCs, which revealed alterations in mitochondrial oxygen consumption and a tendency of higher levels of intracellular ROS in schizophrenia-derived cells.

Assembling Spheroids of Rat Primary Neurons Using a Stress-Free 3D Culture System.

Neural injuries disrupt the normal functions of the nervous system, whose complexities limit current treatment options. Because of their enhanced therapeutic effects, neurospheres have the potential to advance the field of regenerative medicine and neural tissue engineering. Methodological steps can pose challenges for implementing neurosphere assemblies; for example, conventional static cultures hinder yield and throughput, while the presence of the necrotic core, time-consuming methodology, and high variability can slow their progression to clinical application. Here we demonstrate the optimization of primary neural cell-derived neurospheres, developed using a high-throughput, stress-free, 3D bioreactor. This process provides a necessary baseline for future studies that could develop co-cultured assemblies of stem cells combined with endothelial cells, and/or biomaterials and nanomaterials for clinical therapeutic use. Neurosphere size and neurite spreading were evaluated under various conditions using Image J software. Primary neural cells obtained from the hippocampi of three-day-old rat pups, when incubated for 24 h in a reactor coated with 2% Pluronic and seeded on Poly-D-Lysine-coated plates establish neurospheres suitable for therapeutic use within five days. Most notably, neurospheres maintained high cell viability of ≥84% and expressed the neural marker MAP2, neural marker ß-Tubulin III, and glial marker GFAP at all time points when evaluated over seven days. Establishing these factors reduces the variability in developing neurospheres, while increasing the ease and output of the culture process and maintaining viable cellular constructs.

SAM/SAH Mediates Parental Folate Deficiency-Induced Neural Cell Apoptosis in Neonatal Rat Offspring: The Expression of Bcl-2, Bax, and Caspase-3.

Research demonstrated that folate deficiency in either the mother or father could impact the biological functions of the offspring's of neural cells. Folate deficiency can also impair the methionine cycle, thus contributing to the conversion of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), which could potentially cause damage to the central nervous system. The study focused on the effect of parental folate deficiency on neural cell apoptosis in offspring neonatal rats and whether it is mediated by the levels of SAM and SAH in brains. The experimental design was conducted by feeding female and male Sprague Dawley (SD) rats with either folate-deficient or folate-normal diets, sacrificing the offspring within 24 h and isolating their brain tissue. Rats were divided into four groups: the maternal-folate-deficient and paternal-folate-deficient (D-D) group; the maternal-folate-deficient and paternal-folate-normal (D-N) group; the maternal-folate-normal and paternal-folate-deficient (N-D) group; and the maternal-folate-normal and paternal-folate-normal (N-N) group. There was down-regulation of B-cell lymphoma 2 (Bcl-2) expression, up-regulation of Bcl-2-associated X protein (Bax) and Caspase-3 expression of neural cells, and pathological changes in the brain ultrastructure, as well as decreased SAM levels, increased SAH levels, and a decreased SAM/SAH ratio in the rat fetal brain via parental folate deficiency. In conclusion, parental folate deficiency could induce the apoptosis of neural cells in neonatal offspring rats, while biparental folate deficiency had the greatest effect on offspring, and the unilateral effect was greater in mothers than in fathers. This process may be mediated by the levels of SAM and SAH in the rat fetal brain.

Modulating Specific Pathways In Vitro to Understand the Synaptic Dysfunction of Schizophrenia.

Schizophrenia is an incurable mental disorder that affects 1% of the world population and is among the most disabling human diseases. On average, 70% of patients abandon medication due to its low efficacy and the presence of severe side effects. To change these conditions, it is necessary to understand the pathophysiology of schizophrenia at the molecular level. Besides the long-established neurodevelopmental hypothesis, works based on neuroimaging, postmortem brain proteomics, and pharmacological, genetic, and animal model studies have shown dysfunction and deficits in synaptic transmission. Currently, genetic editing has been growing, and the use of this technique has been improved in the discovery of protein functions; in addition to that, some recent studies have attributed a path to the use of genetic engineering in the treatment of diseases with a genetic nature.

From 2D to 3D Co-Culture Systems: A Review of Co-Culture Models to Study the Neural Cells Interaction.

The central nervous system (CNS) controls and regulates the functional activities of the organ systems and maintains the unity between the body and the external environment. The advent of co-culture systems has made it possible to elucidate the interactions between neural cells in vitro and to reproduce complex neural circuits. Here, we classified the co-culture system as a two-dimensional (2D) co-culture system, a cell-based three-dimensional (3D) co-culture system, a tissue slice-based 3D co-culture system, an organoid-based 3D co-culture system, and a microfluidic platform-based 3D co-culture system. We provide an overview of these different co-culture models and their applications in the study of neural cell interaction. The application of co-culture systems in virus-infected CNS disease models is also discussed here. Finally, the direction of the co-culture system in future research is prospected.

Cellular mechanisms underlying neurological/neuropsychiatric manifestations of COVID-19.

Patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection manifest mainly respiratory symptoms. However, clinical observations frequently identified neurological symptoms and neuropsychiatric disorders related to COVID-19 (Neuro-SARS2). Accumulated robust evidence indicates that Neuro-SARS2 may play an important role in aggravating the disease severity and mortality. Understanding the neuropathogenesis and cellular mechanisms underlying Neuro-SARS2 is crucial for both basic research and clinical practice to establish effective strategies for early detection/diagnosis, prevention, and treatment. In this review, we comprehensively examine current evidence of SARS-CoV-2 infection in various neural cells including neurons, microglia/macrophages, astrocytes, pericytes/endothelial cells, ependymocytes/choroid epithelial cells, and neural stem/progenitor cells. Although significant progress has been made in studying Neuro-SARS2, much remains to be learned about the neuroinvasive routes (transneuronal and hematogenous) of the virus and the cellular/molecular mechanisms underlying the development/progression of this disease. Future and ongoing studies require the establishment of more clinically relevant and suitable neural cell models using human induced pluripotent stem cells, brain organoids, and postmortem specimens.

In Vitro Studies on Therapeutic Effects of Cannabidiol in Neural Cells: Neurons, Glia, and Neural Stem Cells.

(‒)-Cannabidiol (CBD) is one of the major phytocannabinoids extracted from the Cannabis genus. Its non-psychoactiveness and therapeutic potential, partly along with some anecdotal-if not scientific or clinical-evidence on the prevention and treatment of neurological diseases, have led researchers to investigate the biochemical actions of CBD on neural cells. This review summarizes the previously reported mechanistic studies of the CBD actions on primary neural cells at the in vitro cell-culture level. The neural cells are classified into neurons, microglia, astrocytes, oligodendrocytes, and neural stem cells, and the CBD effects on each cell type are described. After brief introduction on CBD and in vitro studies of CBD actions on neural cells, the neuroprotective capability of CBD on primary neurons with the suggested operating actions is discussed, followed by the reported CBD actions on glia and the CBD-induced regeneration from neural stem cells. A summary section gives a general overview of the biochemical actions of CBD on neural cells, with a future perspective. This review will provide a basic and fundamental, but crucial, insight on the mechanistic understanding of CBD actions on neural cells in the brain, at the molecular level, and the therapeutic potential of CBD in the prevention and treatment of neurological diseases, although to date, there seem to have been relatively limited research activities and reports on the cell culture-level, in vitro studies of CBD effects on primary neural cells.

Evaluation of the neuroprotective effects of Vitamin E on the rat substantia nigra neural cells exposed to electromagnetic field: An ultrastructural study.

Electromagnetic fields (EMFs) could induce oxidative stress (OS) in human tissues. Lipid peroxidation (LPO) is the main hallmark of OS that harms neural cell components, primarily lipids in the myelin sheaths and membranes. Vitamin E is a lipophilic antioxidant that protects cells from OS-related damages and inhibits the LPO process. In this study, male rats were assigned into three groups of Control, EMF, and EMF+ Vitamin E. The EMF producer equipment produced an alternate current of 50 Hz, 3 Mili Tesla (mT). At the end of the experiment, half of the substantia nigra in every sample was used for measurement of the malondialdehyde (MDA) level as the end-product of the LPO and activity of superoxide dismutase (SOD) enzyme. The next half of the tissue was prepared for transmission electron microscopy (TEM). In the EMF group, MDA level was enhanced and SOD value decreased significantly compared to the control group, but Vitamin E could restore these changes. In rats undergone EMF, heterochromatic nucleus and destruction in some portions of the nuclear membrane were detected. The segmental separation or destruction of myelin sheath lamellae was observed in nerve fibers. In treated animals, the nucleus was round, less heterochromatic, with a regular membrane. Separation of myelin sheath lamellae in some nerve fibers was slighter than the radiation group. Considering the results, EMF exposure induces LPO and triggers ultrastructural changes in the cell membranes, nucleus, and myelin sheath of substantia nigra cells, but Vitamin E consumption weakens these neuropathological alterations.

Basic insights into Zika virus infection of neuroglial and brain endothelial cells.

Zika virus (ZIKV) has recently emerged as an important human pathogen due to the strong evidence that it causes disease of the central nervous system, particularly microcephaly and Guillain-Barré syndrome. The pathogenesis of disease, including mechanisms of neuroinvasion, may include both invasion via the blood-brain barrier and via peripheral (including cranial) nerves. Cellular responses to infection are also poorly understood. This study characterizes the in vitro infection of laboratory-adapted ZIKV African MR766 and two Asian strains of (1) brain endothelial cells (hCMEC/D3 cell line) and (2) olfactory ensheathing cells (OECs) (the neuroglia populating cranial nerve I and the olfactory bulb; both human and mouse OEC lines) in comparison to kidney epithelial cells (Vero cells, in which ZIKV infection is well characterized). Readouts included infection kinetics, intracellular virus localization, viral persistence and cytokine responses. Although not as high as in Vero cells, viral titres exceeded 104 plaque-forming units (p.f.u.) ml-1 in the endothelial/neuroglial cell types, except hOECs. Despite these substantial titres, a relatively small proportion of neuroglial cells were primarily infected. Immunolabelling of infected cells revealed localization of the ZIKV envelope and NS3 proteins in the cytoplasm; NS3 staining overlapped with that of dsRNA replication intermediate and the endoplasmic reticulum (ER). Infected OECs and endothelial cells produced high levels of pro-inflammatory chemokines. Nevertheless, ZIKV was also able to establish persistent infection in hOEC and hCMEC/D3 cells. Taken together, these results provide basic insights into ZIKV infection of endothelial and neuroglial cells and will form the basis for further study of ZIKV disease mechanisms.

Prohibitin 1/2 mediates Dengue-3 entry into human neuroblastoma (SH-SY5Y) and microglia (CHME-3) cells.

BACKGROUND: Very few studies have identified receptor molecules for dengue virus (DENV) on neural cells. This study was designed to identify putative receptor/(s) involved in entry of DENV-3 in human neural cells of various lineages; neuronal-SH-SY5Y, astroglial-U-87 MG and microglial-CHME-3 cells. RESULT: Virus overlay protein binding assay, LC-MS/MS and SEQUEST identified prohibitin1/2 (PHB1/2) as interacting proteins on SH-SY5Y, CHME-3, and U-87 MG cells. Infection inhibition and siRNA assays confirmed the role of PHB1/2 in the entry of DENV-3 into SH-SY5Y and CHME-3 cells but not in U-87 MG cells. Indirect immunofluorescence and flow-cytometry demonstrated the presence of PHB1/2 on the surface of SH-SY5Y and CHME-3 cells. Co-immunoprecipitation and Western blot, as well as double labelling, reconfirmed the interaction between PHB1/2 and DENV-3 EDIII protein. CONCLUSION: These observations together for the first time indicate that PHB1/2 may serve as a putative receptor for DENV-3 in SH-SY5Y and CHME-3 cells. The study provided insights into DENV-3 and neural cell interactions.

Excessive apoptosis and ROS induced by ethionine affect neural cell viability and differentiation.

The central nervous system (CNS) diseases are still a major cause of morbidity and mortality throughout the world, which imposes heavy burden on the development of society. Ethionine is a non-proteinogenic amino acid having similar chemical structure and activity to that of methionine, with which it competes. Previous studies have confirmed that ethionine affects various cellular functions by inhibiting the biosynthesis of proteins, RNA, DNA, and phospholipids, or all of them. The relationship of ethionine with some CNS diseases, including neural tube defects, has been investigated recently. However, the detailed effects of ethionine on the nerve cell bioactivities and the underlying mechanisms have not been fully explored. Herein, we systematically investigated the influences of ethionine on the proliferation, differentiation, and apoptosis of neural stem cells (NSCs) and post-mitotic nerve cells. We demonstrated that ethionine inhibited cell viability by disrupting the balance between proliferation and apoptosis, prevented NSCs from differentiating into neurons and astrocytes, and blocked cell progression from G1 to S phase via reducing cyclin D1 function in nerve cells including NSCs, a mouse hippocampal neuron cell line (HT-22), and a mouse brain neuroma cell line (Neuro-2a). We speculated that the inhibitory effect of ethionine on cell viability and differentiation are associated with increased reactive oxygen species production. Our results also supported the concept that ethionine may be an underlying cause of abnormal folate metabolism-induced CNS diseases. Our findings may provide important direction for the application of abnormal folate metabolism-induced CNS diseases in future NSC-based therapies.

How Long Are Reperfusion Therapies Beneficial for Patients after Stroke Onset? Lessons from Lethal Ischemia Following Early Reperfusion in a Mouse Model of Stroke.

Ischemic stroke caused by cerebral artery occlusion induces neurological deficits because of cell damage or death in the central nervous system. Given the recent therapeutic advances in reperfusion therapies, some patients can now recover from an ischemic stroke with no sequelae. Currently, reperfusion therapies focus on rescuing neural lineage cells that survive in spite of decreases in cerebral blood flow. However, vascular lineage cells are known to be more resistant to ischemia/hypoxia than neural lineage cells. This indicates that ischemic areas of the brain experience neural cell death but without vascular cell death. Emerging evidence suggests that if a vascular cell-mediated healing system is present within ischemic areas following reperfusion, the therapeutic time window can be extended for patients with stroke. In this review, we present our comments on this subject based upon recent findings from lethal ischemia following reperfusion in a mouse model of stroke.

Molecular and Cellular Substrates for the Friedreich Ataxia. Significance of Contactin Expression and of Antioxidant Administration.

In this study, the neural phenotype is explored in rodent models of the spinocerebellar disorder known as the Friedreich Ataxia (FA), which results from mutations within the gene encoding the Frataxin mitochondrial protein. For this, the M12 line, bearing a targeted mutation, which disrupts the Frataxin gene exon 4 was used, together with the M02 line, which, in addition, is hemizygous for the human Frataxin gene mutation (Pook transgene), implying the occurrence of 82-190 GAA repeats within its first intron. The mutant mice phenotype was compared to the one of wild type littermates in regions undergoing differential profiles of neurogenesis, including the cerebellar cortex and the spinal cord by using neuronal (ß-tubulin) and glial (Glial Fibrillary Acidic Protein) markers as well as the Contactin 1 axonal glycoprotein, involved in neurite growth control. Morphological/morphometric analyses revealed that while in Frataxin mutant mice the neuronal phenotype was significantly counteracted, a glial upregulation occurred at the same time. Furthermore, Contactin 1 downregulation suggested that changes in the underlying gene contributed to the disorder pathogenesis. Therefore, the FA phenotype implies an alteration of the developmental profile of neuronal and glial precursors. Finally, epigallocatechin gallate polyphenol administration counteracted the disorder, indicating protective effects of antioxidant administration.

The Story of Nanoparticles in Differentiation of Stem Cells into Neural Cells.

Stem cells have been long looked at as possible therapeutic vehicles in regenerative medicine largely due to their multi-lineage differentiation potential and paracrine actions. Therefore, development of new procedures for the differentiation of stem cells into different cell types holds great potential for opening new opportunities in regenerative medicine. In addition to various methods for inducing stem cell differentiation, the utilization of nanomaterials for differentiation of stem cells has recently received considerable attention and has become a potential tool for such purpose. Multiple lines of evidence revealed that nanomaterial-based scaffolds, inorganic nanoparticles (NPs), and biodegradable polymers have led to significant progress in regulation of stem cell differentiation. Several studies indicated that different NPs including selenium, gold, graphene quantum dots (QDs) and silica could be employed for the regulation of differentiation of stem cells such as human mesenchymal stem cells (hMSCs). In addition, magnetic core-shell NPs could be applied for the regulation of neural stem cell (NSC) differentiation. Taken together, these findings suggested that NPs are potential candidates which could be utilized for the differentiation of stem cells into various cell types such as neural cells. Herein, we summarized the application of NPs for differentiation of stem cells into various cells in particular neural cells.

Biofunctionalized self-assembly of peptide amphiphile induces the differentiation of bone marrow mesenchymal stem cells into neural cells.

Bone marrow mesenchymal stem cells (BMSCs) are multipotential differentiation cells which can differentiate into different cell types such as osteoblasts, chondrocytes, adipocytes, cardiomyocytes, hepatocytes, endothelial cells, and neuronal cells. Such multipotential differentiation makes them attractive for stem cell-based therapy aimed at treating previously incurable disorders. In the present work, we encapsulated BMSCs into a hydrogel with a three-dimensional (3D) network of nanofibers, formed from self-assembling of peptide amphiphile. The self-assembling of peptide amphiphile into hydrogel was triggered by mixing cell suspensions with dilute aqueous solutions of amphipathic peptide. Moreover, this hydrogel was designed to present cells the neurite-promoting laminin epitope IKVAV at nearly van der Waals density, which induced the successful differentiation of BMSCs into neural cells.

MicroRNA-182 inhibits HCMV replication through activation of type I IFN response by targeting FOXO3 in neural cells.

Human cytomegalovirus (HCMV) has led to kinds of clinical disorders and great morbidity worldwide, such as sensorineural hearing loss (SNHL), mental retardation, and developmental delays in immunocompromised individuals. Congenital HCMV infection is a leading cause of birth defects, primarily manifesting as neurological disorders. Previous studies reported that HCMV has evolved a variety of mechanisms to evade the immune system, such as dysregulation of miRNAs. However, reports concerning the role of miRNA in HCMV infection in neural cells are limited. Here, we reported that a host microRNA, miR-182, was significantly up-regulated by HCMV infection in U-251MG and NPCs cells. Subsequently, our results of in vitro and in vivo experiments demonstrated that miR-182 was a positive regulator of interferon regulatory factor 7 (IRF7) by directly targeting FOXO3, resulting in the induction of IFN-I response and suppression of HCMV replication in neural cells. Taken together, our findings provide detailed molecular mechanisms of the antiviral function of miR-182 against HCMV infection in neural cells, and suggest an intrinsic anti-HCMV therapeutic target.

Tropism of Newcastle disease virus strains for chicken neurons, astrocytes, oligodendrocytes, and microglia.

BACKGROUND: Newcastle disease (ND), which is caused by infections of poultry species with virulent strains of Avian orthoavulavirus-1, also known as avian paramyxovirus 1 (APMV-1), and formerly known as Newcastle disease virus (NDV), may cause neurological signs and encephalitis. Neurological signs are often the only clinical signs observed in birds infected with neurotropic strains of NDV. Experimental infections have shown that the replication of virulent NDV (vNDV) strains is in the brain parenchyma and is possibly confined to neurons and ependymal cells. However, little information is available on the ability of vNDV strains to infect subset of glial cells (astrocytes, oligodendrocytes, and microglia). The objective of this study was to evaluate the ability of NDV strains of different levels of virulence to infect a subset of glial cells both in vitro and in vivo. Thus, neurons, astrocytes and oligodendrocytes from the brains of day-old White Leghorn chickens were harvested, cultured, and infected with both non-virulent (LaSota) and virulent, neurotropic (TxGB) NDV strains. To confirm these findings in vivo, the tropism of three vNDV strains with varying pathotypes (SA60 [viscerotropic], TxGB [neurotropic], and Tx450 [mesogenic]) was assessed in archived formalin-fixed material from day-old chicks inoculated intracerebrally. RESULTS: Double immunofluorescence for NDV nucleoprotein and cellular markers showed that both strains infected at least 20% of each of the cell types (neurons, astrocytes, and oligodendrocytes). At 24 h post-inoculation, TxGB replicated significantly more than LaSota. Double immunofluorescence (DIFA) with markers for neurons, astrocytes, microglia, and NDV nucleoprotein detected the three strains in all three cell types at similar levels. CONCLUSION: These data indicate that similar to other paramyxoviruses, neurons and glial cells (astrocytes, oligodendrocytes, and microglia) are susceptible to vNDV infection, and suggest that factors other than cellular tropism are likely the major determinant of the neurotropic phenotype.

Aluminum-Induced Neural Cell Death.

Aluminum (Al), an abundant element in the earth's crust, is well-known for its neurotoxicity. Nonetheless, its causal role in neurodegenerative diseases, particularly in Alzheimer's disease (AD), is still in debate. Ample studies have shown that neural cell death and cognitive deficits induced by Al are similar to those in AD. In the present chapter, we demonstrate separately the Al-induced cell death in neuron, neuroglia cells, and co-cultured neural cells from newborn rats to illustrate the neurotoxic effects. Moreover, we not only examine the classic cell death pathways of apoptosis and necrosis but also compare with autophagy and a newly discovered cell death pathway known as necroptosis, which demonstrates its crucial roles in Al-induced neural cell death. Finally, we verify the cell death pathways attributed to the neural cell death in Al-induced AD-like mice model. The series research could provide an underlined mechanism and potential therapeutic agents to Al-induced neurodegenerative diseases.