Causes, Effects and Strategies for Eradicating Cultism among Students in Tertiary Institutions in Nigeria-A Case Study of Nnamdi Azikiwe University Awka Anambra State, Nigeria

The issue of cultism has in spite of many efforts at reducing it, soared up in the Nigeria’s tertiary institutions. Cultism has cast gloom over the educational sector. It is repeatedly said that the youths are the future leaders but it is a little wonder what the future holds for the youth of this country which has a good proportion of her youth as secret cult member. It therefore became imperative to carefully redress the issue of cultism in our tertiary institution where reason should rule over emotion. Undoubtedly, the issue has assumed horrifying proportion as cultic violence thrives even more. The main purpose of this study was to find out the causes, effects and strategies to stop cultism in tertiary institutions in Nigeria. It was discovered from the study that cultism among the students of tertiary institutions is real and urgent solutions is needed by government and institution at large to curb it. The parents must work closely with the institutions authority to arrive at a lasting solution. Keywords: Cultism, Nigerian, Institutions, Youths and Violence

The Unfolded Protein Response Protects from Tau Neurotoxicity In Vivo

The unfolded protein response is a critical system by which the cell handles excess misfolded protein in the secretory pathway. The role of the system in modulating the effects of aggregation prone cytosolic proteins has received less attention. We use genetic reporters to demonstrate activation of the unfolded protein response in a transgenic Drosophila model of Alzheimer's disease and related tauopathies. We then use loss of function genetic reagents to support a role for the unfolded protein response in protecting from tau neurotoxicity. Our findings suggest that the unfolded protein response can ameliorate the toxicity of tau in vivo

How Cholesterol Constrains Glycolipid Conformation for Optimal Recognition of Alzheimer's β Amyloid Peptide (Aβ1-40)

Membrane lipids play a pivotal role in the pathogenesis of Alzheimer's disease, which is associated with conformational changes, oligomerization and/or aggregation of Alzheimer's β-amyloid (Aβ) peptides. Yet conflicting data have been reported on the respective effect of cholesterol and glycosphingolipids (GSLs) on the supramolecular assembly of Aβ peptides. The aim of the present study was to unravel the molecular mechanisms by which cholesterol modulates the interaction between Aβ1–40 and chemically defined GSLs (GalCer, LacCer, GM1, GM3). Using the Langmuir monolayer technique, we show that Aβ1–40 selectively binds to GSLs containing a 2-OH group in the acyl chain of the ceramide backbone (HFA-GSLs). In contrast, Aβ1–40 did not interact with GSLs containing a nonhydroxylated fatty acid (NFA-GSLs). Cholesterol inhibited the interaction of Aβ1–40 with HFA-GSLs, through dilution of the GSL in the monolayer, but rendered the initially inactive NFA-GSLs competent for Aβ1–40 binding. Both crystallographic data and molecular dynamics simulations suggested that the active conformation of HFA-GSL involves a H-bond network that restricts the orientation of the sugar group of GSLs in a parallel orientation with respect to the membrane. This particular conformation is stabilized by the 2-OH group of the GSL. Correspondingly, the interaction of Aβ1–40 with HFA-GSLs is strongly inhibited by NaF, an efficient competitor of H-bond formation. For NFA-GSLs, this is the OH group of cholesterol that constrains the glycolipid to adopt the active L-shape conformation compatible with sugar-aromatic CH-π stacking interactions involving residue Y10 of Aβ1–40. We conclude that cholesterol can either inhibit or facilitate membrane-Aβ interactions through fine tuning of glycosphingolipid conformation. These data shed some light on the complex molecular interplay between cell surface GSLs, cholesterol and Aβ peptides, and on the influence of this molecular ballet on Aβ-membrane interactions

Tau-tubulin kinase 1 (TTBK1), a neuron-specific tau kinase candidate, is involved in tau phosphorylation and aggregation

Neurofibrillary tangles, which are major pathological hallmarks of Alzheimer’s disease (AD), are composed of paired helical filaments (PHFs) containing hyperphosphorylated tau. Specific kinases regulate tau phosphorylation and are closely linked to the pathogenesis of AD. We have characterized a human tau-tubulin kinase 1 (TTBK1) gene located on chromosome 6p21.1. TTBK1 is a serine/threonine/tyrosine kinase that is conserved among species and belongs to the casein kinase 1 superfamily. It is specifically expressed in the brain, especially in the cytoplasm of cortical and hippocampal neurons. TTBK1 phosphorylates tau proteins in both a Mg2+- and a Mn2+-dependent manner. Phosphopeptide mapping and immunoblotting analysis confirmed a direct tau phosphorylation by TTBK1 at Ser198, Ser199, Ser202 and Ser422, which are also phosphorylated in PHFs. TTBK1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that TTBK1 is a neuron-specific dual kinase involved in tau phosphorylation at AD-related sites and is also associated with tau aggregation

HIV-1gp120 Induces Neuronal Apoptosis through Enhancement of 4-Aminopyridine-Senstive Outward K+ Currents

Human immunodeficiency virus type 1 (HIV-1)-associated dementia (HAD) usually occurs late in the course of HIV-1 infection and the mechanisms underlying HAD pathogenesis are not well understood. Accumulating evidence indicates that neuronal voltage-gated potassium (Kv) channels play an important role in memory processes and acquired neuronal channelopathies in HAD. To examine whether Kv channels are involved in HIV-1-associated neuronal injury, we studied the effects of HIV-1 glycoprotein 120 (gp120) on outward K+ currents in rat cortical neuronal cultures using whole-cell patch techniques. Exposure of cortical neurons to gp120 produced a dose-dependent enhancement of A-type transient outward K+ currents (IA). The gp120-induced increase of IA was attenuated by T140, a specific antagonist for chemokine receptor CXCR4, suggesting gp120 enhancement of neuronal IA via CXCR4. Pretreatment of neuronal cultures with a protein kinase C (PKC) inhibitor, GF109203X, inhibited the gp120-induced increase of IA. Biological significance of gp120 enhancement of IA was demonstrated by experimental results showing that gp120-induced neuronal apoptosis, as detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and caspase-3 staining, was attenuated by either an IA blocker 4-aminopyridine or a specific CXCR4 antagonist T140. Taken together, these results suggest that gp120 may induce caspase-3 dependent neuronal apoptosis by enhancing IA via CXCR4-PKC signaling

Plaque associated microglia hyper-secrete extracellular vesicles and accelerate tau propagation in a humanized APP mouse model

Abstract Background Recent studies suggest that microglia contribute to tau pathology progression in Alzheimer’s disease. Amyloid plaque accumulation transforms microglia, the primary innate immune cells in the brain, into neurodegenerative microglia (MGnD), which exhibit enhanced phagocytosis of plaques, apoptotic neurons and dystrophic neurites containing aggregated and phosphorylated tau (p-tau). It remains unclear how microglia promote disease progression while actively phagocytosing pathological proteins, therefore ameliorating pathology. Methods Adeno-associated virus expressing P301L tau mutant (AAV-P301L-tau) was stereotaxically injected into the medial entorhinal cortex (MEC) in C57BL/6 (WT) and humanized APP mutant knock-in homozygote (AppNL-G-F) mice at 5 months of age. Mice were fed either chow containing a colony stimulating factor-1 receptor inhibitor (PLX5622) or control chow from 4 to 6 months of age to test the effect of microglia depletion. Animals were tested at 6 months of age for immunofluorescence, biochemistry, and FACS of microglia. In order to monitor microglial extracellular vesicle secretion in vivo, a novel lentiviral EV reporter system was engineered to express mEmerald-CD9 (mE-CD9) specifically in microglia, which was injected into the same region of MEC. Results Expressing P301L tau mutant in the MEC induced tau propagation to the granule cell layer of the hippocampal dentate gyrus, which was significantly exacerbated in AppNL-G-F mice compared to WT control mice. Administration of PLX5622 depleted nearly all microglia in mouse brains and dramatically reduced propagation of p-tau in WT and to a greater extent in AppNL-G-F mice, although it increased plaque burden and plaque-associated p-tau+ dystrophic neurites. Plaque-associated MGnD microglia strongly expressed an EV marker, tumor susceptibility gene 101, indicative of heightened synthesis of EVs. Intracortical injection of mE-CD9 lentivirus successfully induced microglia-specific expression of mE-CD9+ EV particles, which were significantly enhanced in Mac2+ MGnD microglia compared to Mac2− homeostatic microglia. Finally, consecutive intracortical injection of mE-CD9 lentivirus and AAV-P301L-tau into AppNL-G-F mice revealed encapsulation of p-tau in microglia-specific mE-CD9+ EVs as determined by super-resolution microscopy and immuno-electron microscopy. Discussion Our findings suggest that MGnD microglia hyper-secrete p-tau+ EVs while compacting Aβ plaques and clearing NP tau, which we propose as a novel mechanistic link between amyloid plaque deposition and exacerbation of tau propagation in AppNL-G-F mice

Correction to: Plaque associated microglia hyper-secrete extracellular vesicles and accelerate tau propagation in a humanized APP mouse model

Correction to: Mol Neurodegeneration 16, 18 (2021) 10.1186/s13024-021-00440-

Using mechanical homogenization to isolate microglia from mouse brain tissue to preserve transcriptomic integrity

Numerous approaches have been developed to isolate microglia from the brain, but procedures using enzymatic dissociation at 37°C can introduce drastic transcriptomic changes and confound results from gene expression assays. Here, we present an optimized protocol for microglia isolation using mechanical homogenization. We use Dounce homogenization to homogenize mouse brain tissue into single-cell suspension. We then isolate microglia through Percoll gradient and flow cytometry. Isolated microglia exhibit a gene expression pattern without the changes induced by heated enzymatic digestion. For complete details on the use and execution of this protocol, please refer to Clayton et al. (2021). © 2022 The Author(s

CCL2 Accelerates Microglia-Mediated Aβ Oligomer Formation and Progression of Neurocognitive Dysfunction

The linkages between neuroinflammation and Alzheimer's disease (AD) pathogenesis are well established. What is not, however, is how specific immune pathways and proteins affect the disease. To this end, we previously demonstrated that transgenic over-expression of CCL2 enhanced microgliosis and induced diffuse amyloid plaque deposition in Tg2576 mice. This rodent model of AD expresses a Swedish beta-amyloid (Abeta) precursor protein mutant.We now report that CCL2 transgene expression accelerates deficits in spatial and working memory and hippocampal synaptic transmission in beta-amyloid precursor protein (APP) mice as early as 2-3 months of age. This is followed by increased numbers of microglia that are seen surrounding Abeta oligomers. CCL2 does not suppress Abeta degradation. Rather, CCL2 and tumor necrosis factor-alpha directly facilitated Abeta uptake, intracellular Abeta oligomerization, and protein secretion.We posit that CCL2 facilitates Abeta oligomer formation in microglia and propose that such events accelerate memory dysfunction by affecting Abeta seeding in the brain

Expression of Caveolin-1 Is Required for the Transport of Caveolin-2 to the Plasma Membrane RETENTION OF CAVEOLIN-2 AT THE LEVEL OF THE GOLGI COMPLEX

Caveolins-1 and -2 are normally co-expressed, and they form a hetero-oligomeric complex in many cell types. These caveolin hetero-oligomers are thought to represent the assembly units that drive caveolae formation in vivo. However, the functional significance of the interaction between caveolins-1 and -2 remains unknown. Here, we show that caveolin-1 co-expression is required for the transport of caveolin-2 from the Golgi complex to the plasma membrane. We identified a human erythroleukemic cell line, K562, that expresses caveolin-2 but fails to express detectable levels of caveolin-1. This allowed us to stringently assess the effects of recombinant caveolin-1 expression on the behavior of endogenous caveolin-2. We show that expression of caveolin-1 in K562 cells is sufficient to reconstitute the de novo formation of caveolae in these cells. In addition, recombinant expression of caveolin-1 allows caveolin-2 to form high molecular mass oligomers that are targeted to caveolae-enriched membrane fractions. In striking contrast, in the absence of caveolin-1 expression, caveolin-2 forms low molecular mass oligomers that are retained at the level of the Golgi complex. Interestingly, we also show that expression of caveolin-1 in K562 cells dramatically up-regulates the expression of endogenous caveolin-2. Northern blot analysis reveals that caveolin-2 mRNA levels remain constant under these conditions, suggesting that the expression of caveolin-1 stabilizes the caveolin-2 protein. Conversely, transient expression of caveolin-2 in CHO cells is sufficient to up-regulate endogenous caveolin-1 expression. Thus, the formation of a hetero-oligomeric complex between caveolins-1 and -2 stabilizes the caveolin-2 protein product and allows caveolin-2 to be transported from the Golgi complex to the plasma membrane