Neuronal Cell Death Research Articles

Translational Research and Therapies for Neuroprotection and Regeneration of the Optic Nerve and Retina: A Narrative Review

Most retinal and optic nerve diseases pose significant threats to vision, primarily due to irreversible retinal neuronal cell death, a permanent change, which is a critical factor in their pathogenesis. Conditions such as glaucoma, retinitis pigmentosa, diabetic retinopathy, and age-related macular degeneration are the top four leading causes of blindness among the elderly in Japan. While standard treatments—including reduction in intraocular pressure, anti-vascular endothelial growth factor therapies, and retinal photocoagulation—can partially delay disease progression, their therapeutic effects remain limited. To address these shortcomings, a range of neuroprotective and regenerative therapies, aimed at preventing retinal neuronal cell loss, have been extensively studied and increasingly integrated into clinical practice over the last two decades. Several of these neuroprotective therapies have achieved on-label usage worldwide. This narrative review introduces several neuroprotective and regenerative therapies for retinal and optic nerve diseases that have been successfully translated into clinical practice, providing foundational knowledge and success stories that serve as valuable references for researchers in the field.

AIBP controls TLR4 inflammarafts and mitochondrial dysfunction in a mouse model of Alzheimer’s disease

Microglia-driven neuroinflammation plays an important role in the development of Alzheimer’s disease. Microglia activation is accompanied by the formation and chronic expression of TLR4 inflammarafts, defined as enlarged and cholesterol-rich lipid rafts serving as an assembly platform for TLR4 dimers and complexes of other inflammatory receptors. The secreted apoA-I binding protein (APOA1BP or AIBP) binds TLR4 and selectively targets cholesterol depletion machinery to TLR4 inflammaraft-expressing inflammatory, but not homeostatic microglia. Here we demonstrated that amyloid-beta (Aβ) induced formation of TLR4 inflammarafts in microglia in vitro and in the brain of APP/PS1 mice. Mitochondria in Apoa1bp−/− APP/PS1 microglia were hyperbranched and cupped, which was accompanied by increased reactive oxygen species and the dilated endoplasmic reticulum. The size and number of Aβ plaques and neuronal cell death were significantly increased, and the animal survival was decreased in Apoa1bp−/−APP/PS1 compared to APP/PS1 female mice. These results suggest that AIBP exerts control of TLR4 inflammarafts and mitochondrial dynamics in microglia and plays a protective role in Alzheimer’s disease associated oxidative stress and neurodegeneration.

Rapamycin Treatment Reduces Brain Pericyte Constriction in Ischemic Stroke.

The contraction and subsequent death of brain pericytes may play a role in microvascular no-reflow following the reopening of an occluded artery during ischemic stroke. Mammalian target of rapamycin (mTOR) inhibition has been shown to reduce motility/contractility of various cancer cell lines and reduce neuronal cell death in stroke. However, the effects of mTOR inhibition on brain pericyte contraction and death during ischemia have not yet been investigated. Cultured pericytes exposed to simulated ischemia for 12 h in vitro contracted after less than 1 h, which was about 7 h prior to cell death. Rapamycin significantly reduced the rate of pericyte contraction during ischemia; however, it did not have a significant effect on pericyte viability at any time point. Rapamycin appeared to reduce pericyte contraction through a mechanism that is independent of changes in intracellular calcium. Using a mouse model of middle cerebral artery occlusion, we showed that rapamycin significantly increased the diameter of capillaries underneath pericytes and increased the number of open capillaries 30 min following recanalisation. Our findings suggest that rapamycin may be a useful adjuvant therapeutic to reduce pericyte contraction and improve cerebral reperfusion post-stroke.

Cdc25A phosphatase is activated and mediates neuronal cell death by PUMA via pRb/E2F1 pathway in a model of Parkinson's disease

Parkinson's disease (PD) is a predominant movement disorder caused mainly due to selective loss of the dopaminergic neurons in the substantia nigra pars compacta of the mid brain. There is currently no cure for PD barring treatments to manage symptoms. The reasons might be due to lack of precise understanding of molecular mechanisms leading to neurodegeneration. Aberrant cell cycle activation has been implicated in neuronal death pathways of various neurodegenerative diseases including PD. This study investigates the role of cell cycle regulator Cell division cycle 25A (Cdc25A) in a PD-relevant neuron death model induced by 6-OHDA treatment. We find Cdc25A is rapidly elevated, activated and is playing a key role in neuron death by regulating Rb phosphorylation and E2F1 activity. Knockdown of Cdc25A via shRNA downregulates the levels of pro-apoptotic PUMA, an E2F1 target and cleaved Caspase-3 levels, suggesting Cdc25A may regulate neuronal apoptosis through these effectors. Our work sheds light on the intricate signaling networks involved in neurodegeneration and highlights Cdc25A as a potential therapeutic target for mitigating aberrant cell cycle re-entry underlying PD pathogenesis. These novel insights into molecular mechanisms provide a foundation for future development of neuroprotective strategies to slow or prevent progression of this debilitating disease.

A Small Molecule Impedes the Aβ1-42 Tetramer Neurotoxicity by Preserving Membrane Integrity: Microsecond Multiscale Simulations.

Amyloid-β (Aβ1-42) peptides aggregated into plaques deposited in the brain are the main hallmark of Alzheimer's disease (AD), a social and economic burden worldwide. In this context, insoluble Aβ1-42 fibrils are the main components of plaques. The recent trials that used approved AD drugs show that they can remove the fibrils from AD patients' brains, but they did not halt the course of the disease. Mounting evidence envisages that the soluble Aβ1-42 oligomers' interactions with the neuronal membrane trigger higher cell death than Aβ1-42 fibril interactions. Developing a compound that can alleviate the oligomer's toxicity is one of the most demanding tasks for curing the disease. We performed two molecular dynamics (MD) simulations in an explicit solvent model. In the first case, 55-μs of multiscale all-atom (AA)/coarse-grained (CG) MD simulations were carried out to decipher the impact of a previously described small anti-Aβ molecule, termed M30 (2-octahydroisoquinolin-2(1H)-ylethanamine), on an Aβ1-42 tetramer structure in close contact with a DMPC bilayer. In the second case, 15-μs AA/CG MD simulations were performed to rationalize the dynamics between Aβ1-42 and Aβ1-42-M30 tetramer complexes embedded in DMPC. On the membrane bilayer, we found that the Aβ1-42 tetramer penetrates the bilayer surface due to unrestricted conformational flexibility and many contacts with the membrane phosphate groups. In contrast, no Aβ1-42-M30 tetramer penetration was observed during the entire course of the simulation. In the case of the membrane-embedded Aβ1-42 tetramer, the integrity of the bottom bilayer leaflet was severely affected by the interactions between the negatively charged phosphate groups and the positively charged residues of the Aβ1-42 tetramer, resulting in a deep tetramer penetration into the bilayer hydrophobic region. These contacts were not observed in the case of the membrane-embedded Aβ1-42-M30 tetramer. It was noted that M30 molecules bind to Aβ1-42 tetramer through hydrogen bonds, resulting in a conformational stable Aβ1-42-M30 complex. The associated complex has reduced conformational changes and an enhanced rigidity that prevents the tetramer dissociation by interfering with the tetramer-membrane contacts. Our findings suggest that the M30 molecules could bind to Aβ1-42 tetramer resulting in a rigid structure, and that such complexes do not significantly perturb the membrane bilayer organization. These observations support the in vitro and in vivo experimental evidence that the M30 molecules prevent synaptotocity, improving AD-affected mice memory.

Targeting ferroptosis with the lipoxygenase inhibitor PTC-041 as a therapeutic strategy for the treatment of Parkinson's disease.

Parkinson's disease is the second most common neurodegenerative disorder, affecting nearly 10 million people worldwide. Ferroptosis, a recently identified form of regulated cell death characterized by 15-lipoxygenase-mediated hydroperoxidation of membrane lipids, has been implicated in neurodegenerative disorders including amyotrophic lateral sclerosis and Parkinson's disease. Pharmacological inhibition of 15 -lipoxygenase to prevent iron- and lipid peroxidation-associated ferroptotic cell death is a rational strategy for the treatment of Parkinson's disease. We report here the characterization of PTC-041 as an anti-ferroptotic reductive lipoxygenase inhibitor developed for the treatment of Parkinson's disease. In these studies, PTC-041 potently protects primary human Parkinson's disease patient-derived fibroblasts from lipid peroxidation and subsequent ferroptotic cell death and prevents ferroptosis-related neuronal loss and astrogliosis in primary rat neuronal cultures. Additionally, PTC-041 prevents ferroptotic-mediated α-synuclein protein aggregation and nitrosylation in vitro, suggesting a potential role for anti-ferroptotic lipoxygenase inhibitors in mitigating pathogenic aspects of synucleinopathies such as Parkinson's disease. We further found that PTC-041 protects against synucleinopathy in vivo, demonstrating that PTC-041 treatment of Line 61 transgenic mice protects against α-synuclein aggregation and phosphorylation as well as prevents associated neuronal and non-neuronal cell death. Finally, we show that. PTC-041 protects against 6-hydroxydopamine-induced motor deficits in a hemiparkinsonian rat model, further validating the potential therapeutic benefits of lipoxygenase inhibitors in the treatment of Parkinson's disease.

Identification of potential biomarkers of cuproptosis in cerebral ischemia.

Cerebral ischemia can cause mild damage to local brain nerves due to hypoxia and even lead to irreversible damage due to neuronal cell death. However, the underlying pathogenesis of this phenomenon remains unclear. This study utilized bioinformatics to explore the role of cuproptosis in cerebral ischemic disease and its associated biomarkers. R software identified the overlap of cerebral ischemia and cuproptosis genes, analyzed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), and explored hub genes. Expressions and localizations of hub genes in brain tissue, cells, and immune cells were analyzed, along with predictions of protein structures, miRNAs, and transcription factors. A network was constructed depicting hub gene co-expression with miRNAs and interactions with transcription factors. Ferredoxin 1 (FDX1) expression was determined using qRT-PCR. Ten cuproptosis-related genes in cerebral ischemia were identified, with GO analysis revealing involvement in acetyl-CoA synthesis, metabolism, mitochondrial function, and iron-sulfur cluster binding. KEGG highlighted processes like the tricarboxylic acid cycle, pyruvate metabolism, and glycolysis/gluconeogenesis. Using the Human Protein Atlas, eight hub genes associated with cuproptosis were verified in brain tissues, hippocampus, and AF22 cells. Lipoyl(octanoyl) transferase 1 (LIPT1), was undetected, while others were found in mitochondria or both nucleus and mitochondria. These genes were differentially expressed in immune cells. FDX1, lipoic acid synthetase (LIAS), dihydrolipoamide S-acetyltransferase (DLAT), pyruvate dehydrogenase E1 component subunit alpha 1 (PDHA1), PDHB, and glutaminase (GLS) were predicted to target 111 miRNAs. PDHA1, FDX1, LIPT1, PDHB, LIAS, DLAT, GLS, and dihydrolipoamide dehydrogenase (DLD) were predicted to interact with 11, 10, 10, 9, 8, 7, 5, and 4 transcription factors, respectively. Finally, FDX1 expression was significantly upregulated in the hippocampus of ovariectomized rats with ischemia. This study revealed an association between cerebral ischemic disease and cuproptosis, identifying eight potential target genes. These findings offer new insights into potential biomarkers for the diagnosis, treatment, and prognosis of cerebral ischemia, and provide avenues for the exploration of new medical intervention targets.

Experimental Validation of the Neurotrophic Factor-α1 Binding Site on the Serotonin Receptor 1E (HTR1E) Responsible for β-Arrestin Activation and Subsequent Neuroprotection.

Stress, such as neuroexcitotoxicity and oxidative stress, as well as traumatic brain injury, will result in neurodegeneration. Deciphering the mechanisms underlying neuronal cell death will facilitate the development of drugs that can promote neuronal survival and repair through neurogenesis. Many growth and trophic factors, including transforming growth factors (TGFs), insulin-like growth factors (IGFs), epidermal growth factor (EGF), fibroblast growth factor 2 (FGF2), and brain-derived neurotrophic factor (BDNF), are known to play a role in neuroprotection and neurogenesis. Neurotrophic factor-α1 (NF-α1), also known as carboxypeptidase E (CPE), has been shown experimentally to have neuroprotective activity, acting extracellularly, independent of its intracellular enzymatic function in prohormone processing. We previously reported experiments and molecular dynamics (MD) simulations showing that a 200 amino acid segment of NF-α1/CPE interacts with the serotonin receptor 1E (HTR1E) to protect human neurons against oxidative and neuroexcitotoxic stress via β-arrestin and extracellular signal-regulated kinase (ERK) signaling. We report here validation of our previously predicted binding site with a series of 16 carboxypeptidase E (CPE) mutants, identifying 3 mutants that substantially decrease the binding to HTR1E. We then carried out pERK studies to show that these 3 mutants also dramatically reduce β-arrestin activation. This was followed by MD simulations of 8 selected mutants, finding that the same 3 most dramatically reduced binding of the mutated CPE to 5-HTR1E. Then, we examined the binding of β-arrestin to these 3 (after phosphorylating the intracellular Ser and Thr) and found that the predicted binding decreased dramatically. Then, we examined the predicted activation of the β-arrestin by these 3 and found a dramatic decrease, just as in the pERK experiments. We consider that these experiments and simulations fully validate the predicted binding site for CPE, identifying the key amino acid residues critical for binding and biological activity. This provides the target for experiments and in silico computational screening to identify small molecules to replace the CPE protein as novel drugs to protect human neurons against oxidative/neuroexcitotoxic stress via β-arrestin/ERK signaling.

Carbon Monoxide: A Pleiotropic Redox Regulator of Life and Death.

Despite recent technological progress, carbon monoxide poisoning is still one of the leading causes of domestic and industrial morbidity and mortality. The brain is particularly vulnerable to CO toxicity, and thus the majority of survivors develop delayed movement and cognitive complications. CO binds to haemoglobin in erythrocytes, preventing oxygen delivery to tissues, and additionally inhibits mitochondrial respiration. This renders the effect of CO to be closely related to hypoxia reperfusion injury. Oxygen deprivation, as well as CO poisoning and re-oxygenation, are shown to be able to activate the production of reactive oxygen species and to induce oxidative stress. Here, we review the role of reactive oxygen species production and oxidative stress in the mechanism of neuronal cell death induced by carbon monoxide and re-oxygenation. We discuss possible protective mechanisms used by brain cells with a specific focus on the inhibition of CO-induced ROS production and oxidative stress.

Changes in Energy Dynamics in Arsenic Exposure Based Neurotoxicity: A Comprehensive Review.

The by-product of naturally occurring rock, soil with different agricultural and industrial processes contaminated groundwater with a toxic metalloid- Arsenic (As3+), which results in different toxicities within the human body and in developing fetus. The present study emphasizes evaluating the presence of oxidative stress and excessive generation of reactive oxygen species (ROS) resulting in mitochondrial dysfunction and caspase activation followed by apoptosis due to arsenic-induced neurotoxicity along with epigenetic modifications at different molecular targets. Published articles available on PubMed and Scopus were studied and summarized. The precise mechanism causing arsenic-induced neurotoxicity at a critical stage of brain development is still unknown, while increased oxidative stress led to mitochondrial dysfunctions which are known to play a prominent role in this. AMPK acts as a metabolic checkpoint and restores ATP levels through a different anabolic pathway in energy starvation. At the same time, arsenic-induced AMPK activation leads to autophagy and neuronal cell death. This review summarized the molecular mechanisms involved in arsenic-induced neurotoxicity, which can help develop suitable future ameliorative and therapeutic strategies.

Role of Mitochondrial Dysfunctions in Neurodegenerative Disorders: Advances in Mitochondrial Biology.

Mitochondria, essential organelles responsible for cellular energy production, emerge as a key factor in the pathogenesis of neurodegenerative disorders. This review explores advancements in mitochondrial biology studies that highlight the pivotal connection between mitochondrial dysfunctions and neurological conditions such as Alzheimer's, Parkinson's, Huntington's, ischemic stroke, and vascular dementia. Mitochondrial DNA mutations, impaired dynamics, and disruptions in the ETC contribute to compromised energy production and heightened oxidative stress. These factors, in turn, lead to neuronal damage and cell death. Recent research has unveiled potential therapeutic strategies targeting mitochondrial dysfunction, including mitochondria targeted therapies and antioxidants. Furthermore, the identification of reliable biomarkers for assessing mitochondrial dysfunction opens new avenues for early diagnosis and monitoring of disease progression. By delving into these advancements, this review underscores the significance of understanding mitochondrial biology in unraveling the mechanisms underlying neurodegenerative disorders. It lays the groundwork for developing targeted treatments to combat these devastating neurological conditions.

Effects of Sildenafil on Cognitive Function Recovery and Neuronal Cell Death Protection after Transient Global Cerebral Ischemia in Gerbils.

Cerebral ischemic stroke is a major cause of death worldwide due to brain cell death resulting from ischemia-reperfusion injury. However, effective treatment approaches for patients with ischemic stroke are still lacking in clinical practice. This study investigated the potential neuroprotective effects of sildenafil, a phosphodiesterase-5 inhibitor, in a gerbil model of global brain ischemia. We investigated the effects of sildenafil on the expression of glial fibrillary acidic protein and aquaporin-4, which are markers related to astrocyte activation and water homeostasis, respectively. Immunofluorescence analysis showed that the number of cells co-expressing these markers, which was elevated in the ischemia-induced group, was significantly reduced in the sildenafil-treated groups. This suggests that sildenafil may have a potential mitigating effect on astrocyte activation induced by ischemia. Additionally, we performed various behavioral tests, including the open-field test, novel object recognition, Barnes maze, Y-maze, and passive avoidance tests, to evaluate sildenafil's effect on cognitive function impaired by ischemia. Overall, the results suggest that sildenafil may serve as a neuroprotective agent, potentially alleviating delayed neuronal cell death and improving cognitive function impaired by ischemia.

Autophagy-lysosomal-associated neuronal death in neurodegenerative disease.

Autophagy, the major lysosomal pathway for degrading damaged or obsolete constituents, protects neurons by eliminating toxic organelles and peptides, restoring nutrient and energy homeostasis, and inhibiting apoptosis. These functions are especially vital in neurons, which are postmitotic and must survive for many decades while confronting mounting challenges of cell aging. Autophagy failure, especially related to the declining lysosomal ("phagy") functions, heightens the neuron's vulnerability to genetic and environmental factors underlying Alzheimer's disease (AD) and other late-age onset neurodegenerative diseases. Components of the global autophagy-lysosomal pathway and the closely integrated endolysosomal system are increasingly implicated as primary targets of these disorders. In AD, an imbalance between heightened autophagy induction and diminished lysosomal function in highly vulnerable pyramidal neuron populations yields an intracellular lysosomal build-up of undegraded substrates, including APP-βCTF, an inhibitor of lysosomal acidification, and membrane-damaging Aβ peptide. In the most compromised of these neurons, β-amyloid accumulates intraneuronally in plaque-like aggregates that become extracellular senile plaques when these neurons die, reflecting an "inside-out" origin of amyloid plaques seen in human AD brain and in mouse models of AD pathology. In this review, the author describes the importance of lysosomal-dependent neuronal cell death in AD associated with uniquely extreme autophagy pathology (PANTHOS) which is described as triggered by lysosomal membrane permeability during the earliest "intraneuronal" stage of AD. Effectors of other cell death cascades, notably calcium-activated calpains and protein kinases, contribute to lysosomal injury that induces leakage of cathepsins and activation of additional death cascades. Subsequent events in AD, such as microglial invasion and neuroinflammation, induce further cytotoxicity. In major neurodegenerative disease models, neuronal death and ensuing neuropathologies are substantially remediable by reversing underlying primary lysosomal deficits, thus implicating lysosomal failure and autophagy dysfunction as primary triggers of lysosomal-dependent cell death and AD pathogenesis and as promising therapeutic targets.

Electroacupuncture reduces inflammatory damage following cerebral ischemia–reperfusion by enhancing ABCA1-mediated efferocytosis in M2 microglia

Ischemic stroke (IS) is a severe cerebrovascular disease with high disability and mortality rates, where the inflammatory response is crucial to its progression and prognosis. Efferocytosis, the prompt removal of dead cells, can reduce excessive inflammation after IS injury. While electroacupuncture (EA) has been shown to decrease inflammation post-ischemia/reperfusion (I/R), its link to efferocytosis is unclear. Our research identified ATP-binding cassette transporter A1 (Abca1) as a key regulator of the engulfment process of efferocytosis after IS by analyzing public datasets and validating findings in a mouse model, revealing its close ties to IS progression. We demonstrated that EA can reduce neuronal cell death and excessive inflammation caused by I/R. Furthermore, EA treatment increased Abca1 expression, prevented microglia activation, promoted M2 microglia polarization, and enhanced their ability to phagocytose injured neurons in I/R mice. This suggests that EA's modulation of efferocytosis could be a potential mechanism for reducing cerebral I/R injury, making regulators of efferocytosis steps a promising therapeutic target for EA benefits.

Neuroprotective effects of pink lotus oil in kainic acid-induced epilepsy

Excitotoxicity-induced oxidative stress results in neuronal cell death. Pink lotus essential oil (PLO) is a concentrated volatile oil from lotus blossoms widely used in traditional medicine. This study aimed to explore the possible therapeutic effects of PLO and its underlying mechanisms on kainic acid (KA)-induced oxidative stress and hippocampal cell death in a mouse model of epilepsy. Mice were treated with 100 mg/kg or 200 mg/kg PLO to ameliorate neurodegeneration and seizure-induced behavior induced by KA injection. Pre- and post-treatment of PLO increased antioxidant activities, reduced the seizure score, prevented oxidative stress by increasing GSH and CAT levels, and reduced MDA (malondialdehyde) levels after KA-induced status epilepticus. KA injection created neuronal cell death in the pyramidal layers of CA1 and CA3 subfields of the hippocampus, and affected interneurons in the hilus of the dentate gyrus. PLO treatment notably diminished KA-induced neuronal cell death in these areas through activation of the Akt signaling pathway, increasing reactive astrogliosis, and up-regulation of GDNF expression. Moreover, caspase-3 expression, and microglia activation were significantly decreased in PLO treatments. Taken together, these results suggest that PLO possesses antiepileptic, anti-apoptosic, and neuroprotective effects on KA-induced epileptogenesis indicating that PLO may serve as a dietary supplement option in the treatment of epilepsy or of other neurodegenerative disorders.

Roles of metabotropic glutamate receptor 5 in low [Mg2+]o-induced interictal epileptiform activity in rat hippocampal slices.

Group I metabotropic glutamate receptors (mGluRs) modulate postsynaptic neuronal excitability and epileptogenesis. We investigated roles of group I mGluRs on low extracellular Mg2+ concentration ([Mg2+]o)-induced epileptiform activity and neuronal cell death in the CA1 regions of isolated rat hippocampal slices without the entorhinal cortex using extracellular recording and propidium iodide staining. Exposure to Mg2+-free artificial cerebrospinal fluid can induce interictal epileptiform activity in the CA1 regions of rat hippocampal slices. MPEP, a mGluR 5 antagonist, significantly inhibited the spike firing of the low [Mg2+]o-induced epileptiform activity, whereas LY367385, a mGluR1 antagonist, did not. DHPG, a group 1 mGluR agonist, significantly increased the spike firing of the epileptiform activity. U73122, a PLC inhibitor, inhibited the spike firing. Thapsigargin, an ER Ca2+-ATPase antagonist, significantly inhibited the spike firing and amplitude of the epileptiform activity. Both the IP3 receptor antagonist 2-APB and the ryanodine receptor antagonist dantrolene significantly inhibited the spike firing. The PKC inhibitors such as chelerythrine and GF109203X, significantly increased the spike firing. Flufenamic acid, a relatively specific TRPC 1, 4, 5 channel antagonist, significantly inhibited the spike firing, whereas SKF96365, a relatively non-specific TRPC channel antagonist, did not. MPEP significantly decreased low [Mg2+]o DMEM-induced neuronal cell death in the CA1 regions, but LY367385 did not. We suggest that mGluR 5 is involved in low [Mg2+]oinduced interictal epileptiform activity in the CA1 regions of rat hippocampal slices through PLC, release of Ca2+ from intracellular stores and PKC and TRPC channels, which could be involved in neuronal cell death.

P09-05 Glyphosate exposure in utero induced social behavior alteration and neuronal cell death, which could be rescued with postnatal butyrate administration

P09-05 Glyphosate exposure in utero induced social behavior alteration and neuronal cell death, which could be rescued with postnatal butyrate administration

LncRNA OIP5-AS1 regulates ferroptosis and mitochondrial dysfunction-mediated apoptosis in spinal cord injury by targeting the miR-128-3p/Nrf2 axis

BackgroundFerroptosis is an important way of neuronal cell death in acute phase and participates in the inflammatory cascade after spinal cord injury (SCI). It is reported that microRNA (miRNA) and long non-coding RNA (lncRNA) are key mediators in the regulation of ferroptosis. This study will explore the inhibitory effect of LncRNA OIP5-AS1 on ferroptosis and mitochondrial dysfunction-mediated apoptosis in SCI. MethodsThe ferric ammonium citrate (FAC)-induced cell model and the SCI rat model were established. The expression of LncRNA OIP5-AS1, miR-128-3p and Nrf2 were transfected to evaluated the effect on the viability and apoptosis of FAC-induced cell. The interaction between LncRNA OIP5-AS1 and miR-128-3p or miR-128-3p and Nrf2 were analyzed. In addition, expressions of markers related to ferroptosis and mitochondrial dysfunction were analyzed in vitro and in vivo. Histopathologic slide staining was used to analyze spinal cord injury in vivo. ResultsLncRNA OIP5-AS1 expression was abnormally down-regulated in FAC-induced SCI cell model and SCI rats. The LncRNA OIP5-AS1 deficiency induced decreased Nrf2 level by less sponging miR-128-3p, thus, aggravating spinal cord injury and inducing more apoptosis, ferroptosis and mitochondrial dysfunction in neural stem cells with SCI. However, overexpression of LncRNA OIP5-AS1 inhibited apoptosis, ferroptosis and mitochondrial dysfunction, thus effectively ameliorating spinal cord injury. ConclusionThis finding demonstrates that LncRNA OIP5-AS1 overexpression could enhance the recovery of spinal cord injury by regulating the miR-128-3p/Nrf2 axis.

Sustained Microglial Activation Promotes Synaptic Loss and Neuronal Dysfunction after Recovery from ZIKV Infection.

Zika virus (ZIKV), transmitted by Aedes mosquitoes, has been a global health concern since 2007. It primarily causes fetal microcephaly and neuronal defects through maternal transmission and induces neurological complications in adults. Recent studies report elevated proinflammatory cytokines and persistent neurological alterations post recovery, but the in vivo mechanisms remain unclear. In our study, viral RNA loads in the brains of mice infected with ZIKV peaked at 7 days post infection and returned to baseline by day 21, indicating recovery. RNA sequencing of the cerebral cortex at 7 and 21 days revealed upregulated genes related to neuroinflammation and microglial activation. Histological analyses indicated neuronal cell death and altered neurite morphology owing to severe neuroinflammation. Additionally, sustained microglial activation was associated with increased phospho-Tau levels, constituting a marker of neurodegeneration. These findings highlight how persistent microglial activation leads to neuronal dysfunction post ZIKV recovery, providing insights into the molecular pathogenesis of ZIKV-induced brain abnormalities.

Chemical regulation of Tau oligomers in phase separation in Alzheimer’s disease

A huge number of patients suffering from certain neurodegenerative disorder, which are collectively called as tauopathies, may exhibit pathological tau protein aggregates in their brains. This category of diseases includes Alzheimer's disease (AD). In AD, post translational modifications such as phos phorylations, glycosylations, truncations, and subsequent aggregation into oligomers, paired helical filaments (PHFs), and neurofibrillary tangles (NFTs) are closely associated with cognitive decline and neurodegeneration. As a result, tau oligomers have emerged as the primary toxic species in AD and tauo pathies. Tau oligomers are soluble, self-assembled tau proteins that are formed prior to fibrils and have been demonstrated to play a pivotal role in neuronal cell death and the induction of neurodegeneration in animal models. In this succinct review, we collate and summarize literature pertaining to tau oligomer formation and its role in Alzheimer's disease. Secondly, we explore the crucial role of zinc ions (Zn²⁺) in tau aggregation, as studies suggest that zinc induces reversible tau oligomerization and can lead to tau hyper phosphorylation. The concentration of zinc is critical, as excessive levels can promote harmful tau aggregation, while normal levels are essential for physiological functions. We also examine natural and chemical compounds that can modulate tau aggregation, and lastly, we discuss how Tau protein can undergo liquid-liquid phase separation (LLPS) in neurons, forming droplets that can later develop into toxic oligomers, which are the primary hallmark of AD. We mention some molecules, such as proteins, nucleic acids, and metal ions, that influence tau LLPS and aggregation.