miR-129 Regulates Cell Viability in Alzheimer’s Disease Through Targeting Amyloid Precursor Protein (APP)

This study intends to explore miR-129’s effect on cell viability of Alzheimer’s disease by regulating the target gene APP. The hippocampal neurons were assigned into model group (MO group); mimetic group (SI group); inhibitor group (IN group) followed by analysis of hippocampal neuronal cell proliferation and activity, APP protein content, miR-129 expression and cell apoptosis by CCK-8 assay, Western blot method, MTT assay, qRT-PCR and flow cytometry. miR-129 expression of hippocampal neurons in IN group was lowest. Compared with IN and MO groups, SI group had significantly increased miR-129 level and reduced number of hippocampal neuron apoptosis (P < 0.05). Compared with IN group, MO group had significantly reduced cell apoptosis (P < 0.05). SI group had highest number of hippocampal neurons proliferation followed by IN group. SI group had highest OD value followed by MO group and IN group. The cell activity of SI group was higher than that of IN group and MO group (both P < 0.05). Compared with SI group, rat neuron activity in MO group was significantly higher than IN group (P < 0.05). The APP protein expression of hippocampal neuron cells in SI group was lowest followed by MO group and IN group (P < 0.05). In conclusion, the low miR-129 expression can inhibit the activity of hippocampal neurons possibly through up-regulation of APP protein content.

Paraneoplastic and Other Autoimmune Encephalitides: Antineuronal Antibodies, T Lymphocytes, and Questions of Pathogenesis

Autoimmune and paraneoplastic encephalitides represent an increasingly recognized cause of devastating human illness as well as an emerging area of neurological injury associated with immune checkpoint inhibitors. Two groups of antibodies have been detected in affected patients. Antibodies in the first group are directed against neuronal cell surface membrane proteins and are exemplified by antibodies directed against the N-methyl-D-aspartate receptor (anti-NMDAR), found in patients with autoimmune encephalitis, and antibodies directed against the leucine-rich glioma-inactivated 1 protein (anti-LGI1), associated with faciobrachial dystonic seizures and limbic encephalitis. Antibodies in this group produce non-lethal neuronal dysfunction, and their associated conditions often respond to treatment. Antibodies in the second group, as exemplified by anti-Yo antibody, found in patients with rapidly progressive cerebellar syndrome, and anti-Hu antibody, associated with encephalomyelitis, react with intracellular neuronal antigens. These antibodies are characteristically found in patients with underlying malignancy, and neurological impairment is the result of neuronal death. Within the last few years, major advances have been made in understanding the pathogenesis of neurological disorders associated with antibodies against neuronal cell surface antigens. In contrast, the events that lead to neuronal death in conditions associated with antibodies directed against intracellular antigens, such as anti-Yo and anti-Hu, remain poorly understood, and the respective roles of antibodies and T lymphocytes in causing neuronal injury have not been defined in an animal model. In this review, we discuss current knowledge of these two groups of antibodies in terms of their discovery, how they arise, the interaction of both types of antibodies with their molecular targets, and the attempts that have been made to reproduce human neuronal injury in tissue culture models and experimental animals. We then discuss the emerging area of autoimmune neuronal injury associated with immune checkpoint inhibitors and the implications of current research for the treatment of affected patients.

Protection against Neurological Symptoms by Consuming Corn Silk Water Extract in Artery-Occluded Gerbils with Reducing Oxidative Stress, Inflammation, and Post-Stroke Hyperglycemia through the Gut-Brain Axis

Corn silk (Stigma maydis), rich in flavonoids, is traditionally used to treat edema, depression, and hyperglycemia and may alleviate ischemic stroke symptoms in Chinese medicine. This study examined whether corn silk water extract (CSW) could alleviate ischemic stroke symptoms and post-stroke hyperglycemia in Mongolian gerbils with transient cerebral ischemia and reperfusion (I/R). After being given 0.05% (I/R-LCSW) and 0.2% (I/R-HCSW), 0.02% aspirin (I/R-aspirin), and cellulose (I/R-control) in their 40 energy% fat diets for three weeks, the gerbils underwent an artery occlusion for eight minutes and reperfusion. They took the assigned diet for an additional three weeks. Sham-operated gerbils without artery occlusion had the same diet as Sham-control. CSW intake reduced neuronal cell death in gerbils with I/R and dose-dependently improved the neurological symptoms, including drooped eyes, crouched posture, flexor reflex, and walking patterns. CSW intake also alleviated the short-term memory and spontaneous alteration and grip strength compared to the I/R-control group. The protection against ischemic stroke symptoms was associated with the reduced tumor necrosis factor-α, interleukin-1β, superoxide, and lipid peroxide levels, promoting superoxide dismutase activity in the hippocampus in the CSW groups, compared to the I/R-control. The blood flow measured by Doppler was improved with CSW compared to the I/R-control. Furthermore, CSW intake prevented the post-stroke hyperglycemia related to decreasing pancreatic β-cell mass as much as the Sham-control, and it was related to protection against β-cell apoptosis, restoring the β-cell mass similar to the Sham-control. CSW intake elevated the relative abundance of Lactobacillus, Bifidobacterium, Allobaculum, and Akkermansia compared to the I/R-control. Picrust2 analysis showed that CSW increased the propionate and butyrate metabolism and the starch and glucose metabolism but reduced lipopolysaccharide biosynthesis compared to the I/R-control. In conclusion, CSW intake protects against neuronal cell death and post-hyperglycemia by reducing oxidative stress and inflammation and increasing blood flow and the β-cell mass. The alleviation was associated with promoting the gut-brain axis by changing the gut microbiome community.

Seeing the Forest and Its Trees Together: Implementing 3D Light Microscopy Pipelines for Cell Type Mapping in the Mouse Brain

The brain is composed of diverse neuronal and non-neuronal cell types with complex regional connectivity patterns that create the anatomical infrastructure underlying cognition. Remarkable advances in neuroscience techniques enable labeling and imaging of these individual cell types and their interactions throughout intact mammalian brains at a cellular resolution allowing neuroscientists to examine microscopic details in macroscopic brain circuits. Nevertheless, implementing these tools is fraught with many technical and analytical challenges with a need for high-level data analysis. Here we review key technical considerations for implementing a brain mapping pipeline using the mouse brain as a primary model system. Specifically, we provide practical details for choosing methods including cell type specific labeling, sample preparation (e.g., tissue clearing), microscopy modalities, image processing, and data analysis (e.g., image registration to standard atlases). We also highlight the need to develop better 3D atlases with standardized anatomical labels and nomenclature across species and developmental time points to extend the mapping to other species including humans and to facilitate data sharing, confederation, and integrative analysis. In summary, this review provides key elements and currently available resources to consider while developing and implementing high-resolution mapping methods.

SARS-CoV-2 Spike Protein Induces Cognitive Deficit and Anxiety-like Behavior in Mouse via Non-cell Autonomous Hippocampal Neuronal Death

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is accompanied by chronic neurological sequelae such as cognitive decline and mood disorder, but the underlying mechanisms have not yet been elucidated. In this study, we explored the possibility that the brain-infiltrating SARS-CoV-2 spike protein contributes to the development of neurological symptoms observed in COVID-19 patients. Our behavioral study showed that administration of SARS-CoV-2 spike protein S1 subunit (S1 protein) to mouse hippocampus induced cognitive deficit and anxiety-like behavior in vivo. These neurological symptoms were accompanied by neuronal cell death in the dorsal and ventral hippocampus as well as glial cell activation. Interestingly, the S1 protein did not directly induce hippocampal cell death in vitro. Rather, it exerted neurotoxicity via glial cell activation, partially through interleukin-1β induction. In conclusion, our data suggest a novel pathogenic mechanism for the COVID-19-associated neurological symptoms that involves glia activation and non-cell autonomous hippocampal neuronal death by the brain-infiltrating S1 protein.

The Roles of IL-22 and Its Receptor in the Regulation of Inflammatory Responses in the Brain

Interleukin (IL)-22 is a potent mediator of inflammatory responses. The IL-22 receptor consists of the IL-22Rα and IL-10Rβ subunits. Previous studies have shown that IL-22Rα expression is restricted to non-hematopoietic cells in the skin, pancreas, intestine, liver, lung, and kidney. Although IL-22 is involved in the development of inflammatory responses, there have been no reports of its role in brain inflammation. Here, we used RT-PCR, Western blotting, flow cytometry, immunohistochemical, and microarray analyses to examine the role of IL-22 and expression of IL-22Rα in the brain, using the microglial cell line, hippocampal neuronal cell line, and inflamed mouse brain tissue. Treatment of BV2 and HT22 cells with recombinant IL-22 increased the expression levels of the pro-inflammatory cytokines IL-6 and TNF-α, as well as cyclooxygenase (COX)-2 and prostaglandin E2. We also found that the JNK and STAT3 signaling pathways play an important role in IL-22-mediated increases in inflammatory mediators. Microarray analyses revealed upregulated expression of inflammation-related genes in IL-22-treated HT22 cells. Finally, we found that IL-22Rα is spontaneously expressed in the brain and is upregulated in inflamed mouse brain. Overall, our results demonstrate that interaction of IL-22 with IL-22Rα plays a role in the development of inflammatory responses in the brain.

Bidirectional Modulation of Neuronal Cells Electrical and Mechanical Properties Through Pristine and Functionalized Graphene Substrates

In recent years, the quest for surface modifications to promote neuronal cell interfacing and modulation has risen. This course is justified by the requirements of emerging technological and medical approaches attempting to effectively interact with central nervous system cells, as in the case of brain-machine interfaces or neuroprosthetic. In that regard, the remarkable cytocompatibility and ease of chemical functionalization characterizing surface-immobilized graphene-based nanomaterials (GBNs) make them increasingly appealing for these purposes. Here, we compared the (morpho)mechanical and functional adaptation of rat primary hippocampal neurons when interfaced with surfaces covered with pristine single-layer graphene (pSLG) and phenylacetic acid-functionalized single-layer graphene (fSLG). Our results confirmed the intrinsic ability of glass-supported single-layer graphene to boost neuronal activity highlighting, conversely, the downturn inducible by the surface insertion of phenylacetic acid moieties. fSLG-interfaced neurons showed a significant reduction in spontaneous postsynaptic currents (PSCs), coupled to reduced cell stiffness and altered focal adhesion organization compared to control samples. Overall, we have here demonstrated that graphene substrates, both pristine and functionalized, could be alternatively used to intrinsically promote or depress neuronal activity in primary hippocampal cultures.

Scalable mapping of myelin and neuron density in the human brain with micrometer resolution

Optical coherence tomography (OCT) is an emerging 3D imaging technique that allows quantification of intrinsic optical properties such as scattering coefficient and back-scattering coefficient, and has proved useful in distinguishing delicate microstructures in the human brain. The origins of scattering in brain tissues are contributed by the myelin content, neuron size and density primarily; however, no quantitative relationships between them have been reported, which hampers the use of OCT in fundamental studies of architectonic areas in the human brain and the pathological evaluations of diseases. Here, we built a generalized linear model based on Mie scattering theory that quantitatively links tissue scattering to myelin content and neuron density in the human brain. We report a strong linear relationship between scattering coefficient and the myelin content that is retained across different regions of the brain. Neuronal cell body turns out to be a secondary contribution to the overall scattering. The optical property of OCT provides a label-free solution for quantifying volumetric myelin content and neuron cells in the human brain.

Two-step screening method to identify α-synuclein aggregation inhibitors for Parkinson’s disease

Parkinson’s disease is a neurodegenerative disease characterized by the formation of neuronal inclusions of α-synuclein in patient brains. As the disease progresses, toxic α-synuclein aggregates transmit throughout the nervous system. No effective disease-modifying therapy has been established, and preventing α-synuclein aggregation is thought to be one of the most promising approaches to ameliorate the disease. In this study, we performed a two-step screening using the thioflavin T assay and a cell-based assay to identify α-synuclein aggregation inhibitors. The first screening, thioflavin T assay, allowed the identification of 30 molecules, among a total of 1262 FDA-approved small compounds, which showed inhibitory effects on α-synuclein fibrilization. In the second screening, a cell-based aggregation assay, seven out of these 30 candidates were found to prevent α-synuclein aggregation without causing substantial toxicity. Of the seven final candidates, tannic acid was the most promising compound. The robustness of our screening method was validated by a primary neuronal cell model and a Caenorhabditis elegans model, which demonstrated the effect of tannic acid against α-synuclein aggregation. In conclusion, our two-step screening system is a powerful method for the identification of α-synuclein aggregation inhibitors, and tannic acid is a promising candidate as a disease-modifying drug for Parkinson’s disease.