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The ratio of excitatory to inhibitory neurotransmitters is essential for maintaining the firing patterns of neural networks, and is strictly regulated within individual neurons and brain regions. Excitatory to inhibitory (E/I) imbalance has been shown to participate in the progression of neurodegenerative diseases, including Alzheimer's disease (AD). Glutamate excitotoxicity and GABAergic neuron dysfunction appear to be key components of the neuronal cell death that takes place in AD. Since extracellular vesicles (EVs) are now explored as an important vehicle in transmitting signals between cells, we hypothesized that the function of neuron-derived small EVs (sEVs) might be regulated by the status of neurotransmitter balance and that sEVs might affect amyloid β (Aβ) toxicity on neurons. This study aimed to reveal the effects of sEVs from unbalanced neurotransmitter-stimulated neurons on Aβ-induced toxicity. We demonstrated the opposite effects of the two groups of sEVs isolated from neurons stimulated by glutamate or GABA on Aβ toxicity in vivo and in vitro. The sEVs released from GABA-treated neurons alleviated Aβ-induced damage, while those released from glutamate-treated neurons aggravated Aβ toxicity. Furthermore, we compared the microRNA (miRNA) composition of sEVs isolated from glutamate/GABA/PBS-treated neurons. Our results showed that glutamate and GABA oppositely regulated miR-132 levels in sEVs, resulting in the opposite destiny of recipient cells challenged with Aβ. Our results indicated that manipulating the function of sEVs by different neurotransmitters may reveal the mechanisms underlying the pathogenesis of AD and provide a promising strategy for AD treatment., (© 2021. The Author(s).)

Cognitive dysfunction is one of the complications of diabetes. Unfortunately, there is no effective methods to block its progression currently. One of the pathophysiological mechanisms is synaptic protein damage and neuronal signal disruption because of glucose metabolism disorder. Dystroglycan protein, located in the post-synaptic membrane of neurons, links the intracellular cytoskeleton with extracellular matrix. Abnormal expression of dystroglycan protein affects neuronal biological functions and leads to cognitive impairment. However, there are no relevant studies to observe the changes of β-dystroglycan protein in diabetes rat brain and in primary neurons under high glucose exposure. Our data demonstrated the alterations of cognitive abilities in the diabetic rats; β-dystroglycan protein degradation occurred in hippocampal and cortical tissues in diabetic rat brain. We further explored the mechanisms underlying of this phenomenon. When neurons are exposed to high glucose environment in long-term period, microRNA-132 (miR-132) would be down-regulated in neurons. Matrix Metalloproteinases-9 (MMP-9) mRNA, as a target of miR-132, could be up-regulated; higher expression and overlay activity of MMP-9 protein could increase β-DG protein degradation. In this way, β-DG degradation may affect structure and functions among the synapses, which related to cognition decline. It may provide some theoretical basis for elucidating the molecular mechanism of diabetes-induced cognitive dysfunction., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Accumulation of neuronal α-synuclein is a prominent feature in Parkinson's disease. More recently, such abnormal protein aggregation has been reported to spread from cell to cell and exosomes are considered as important mediators. The focus of such research, however, has been primarily in neurons. Given the increasing recognition of the importance of non-cell autonomous-mediated neurotoxicity, it is critical to investigate the contribution of glia to α-synuclein aggregation and spread. Microglia are the primary phagocytes in the brain and have been well-documented as inducers of neuroinflammation. How and to what extent microglia and their exosomes impact α-synuclein pathology has not been well delineated. We report here that when treated with human α-synuclein preformed fibrils, exosomes containing α-synuclein released by microglia are fully capable of inducing protein aggregation in the recipient neurons. Additionally, when combined with microglial proinflammatory cytokines, these exosomes further increased protein aggregation in neurons. Inhibition of exosome synthesis in microglia reduced α-synuclein transmission. The in vivo significance of these exosomes was demonstrated by stereotaxic injection of exosomes isolated from α-synuclein preformed fibrils treated microglia into the mouse striatum. Phosphorylated α-synuclein was observed in multiple brain regions consistent with their neuronal connectivity. These animals also exhibited neurodegeneration in the nigrostriatal pathway in a time-dependent manner. Depleting microglia in vivo dramatically suppressed the transmission of α-synuclein after stereotaxic injection of preformed fibrils. Mechanistically, we report here that α-synuclein preformed fibrils impaired autophagy flux by upregulating PELI1, which in turn, resulted in degradation of LAMP2 in activated microglia. More importantly, by purifying microglia/macrophage derived exosomes in the CSF of Parkinson's disease patients, we confirmed the presence of α-synuclein oligomer in CD11b+ exosomes, which were able to induce α-synuclein aggregation in neurons, further supporting the translational aspect of this study. Taken together, our study supports the view that microglial exosomes contribute to the progression of α-synuclein pathology and therefore, they may serve as a promising therapeutic target for Parkinson's disease., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Our previous study has shown that PTEN-induced novel kinase 1 (PINK1) knocking down significantly induced mitochondrial fragmentation. Although PINK1 is proved to be associated with autosomal recessive parkinsonism and its function in this chronic pathological process is widely studied, its role in acute energy crisis such as ischemic stroke is poorly known. In this study by employing an oxygen-glucose deprivation (OGD) neuronal model, we explored the function of PINK1 in cerebral ischemia. Human PINK1, two PINK1 mutants W437X and K219M, or Pink1 shRNA were transduced before OGD using lentiviral delivery. Our results showed that over-expression of wild-type PINK1 significantly ameliorated OGD induced cell death and energy disturbance including reduced ATP generation and collapse of mitochondrial membrane potential. PINK1 over-expression also reversed OGD increased mitochondrial fragmentation, and suppressed the translocation of the mitochondrial fission protein dynamin-related protein 1 (Drp1) from the cytosol to the mitochondria. Transduction of the mutant PINK1 failed to provide any protective effect, while knockdown of Pink1 significantly increased the severity of OGD-induced neuronal damage. Importantly, inhibition of Drp1 reversed the effects of knocking down Pink1 on neuronal death and ATP production in response to OGD. This study demonstrates that PINK1 prevents ischemic damage in neurons by attenuating mitochondrial translocation of Drp1, which maintains mitochondrial function and inhibits ischemia-induced mitochondrial fission. These novel findings implicate a pivotal role of PINK1 regulated mitochondrial dynamics in the pathology of ischemic stroke. In this study by employing an oxygen-glucose deprivation (OGD) neuronal model, we explored the function of PINK1 in cerebral ischemia. We indicated that PINK1 significantly ameliorated OGD induced cell death and energy disturbance including reduced ATP generation and collapse of mitochondrial membrane potential by attenuating mitochondrial translocation of Drp1, which maintains mitochondrial function and inhibits ischemia-induced mitochondrial fission., (© 2013 International Society for Neurochemistry.)

Achieving a prolonged neuroprotective state following transient ischemic attacks (TIAs) is likely to effectively reduce the brain damage and neurological dysfunction associated with recurrent stroke. HPC is a phenomenon in which advanced exposure to mild hypoxia reduces the stroke volume produced by a subsequent TIA. However, this neuroprotection is not long-lasting, with the effects reaching a peak after 3 days. Therefore, in this study, we investigated the use of multiple episodes of hypoxic exposure at different time intervals to induce longer-term protection in a mouse stroke model. C57BL/6 mice were subjected to different hypoxic preconditioning protocols: a single episode of HPC or five identical episodes at intervals of 3 days (E3d HPC) or 6 days (E6d HPC). Three days after the last hypoxic exposure, temporary middle cerebral artery occlusion (MCAO) was induced. The effects of these HPC protocols on hypoxia-inducible factor (HIF) regulated gene mRNA expression were measured by quantitative PCR. Changes in extracellular adenosine concentrations, known to exert neuroprotective effects, were also measured using in vivo microdialysis and high pressure liquid chromatography (HPLC). Neuroprotection was provided by E6d HPC but not E3d HPC. HIF-regulated target gene expression increased significantly following all HPC protocols. However, E3d HPC significantly decreased extracellular adenosine and reduced cerebral blood flow in the ischemic region with upregulated expression of the adenosine transporter, equilibrative nucleoside transporter 1 (ENT1). An ENT1 inhibitor, propentofylline increased the cerebral blood flow and re-established neuroprotection in E3d HPC. Adenosine receptor specific antagonists showed that adenosine mainly through A1 receptor mediates HPC induced neuroprotection. Our data indicate that cooperation of HIF-regulated genes and extracellular adenosine is necessary for HPC-induced neuroprotection.

The ketogenic diet (KD) is effective in the treatment of refractory epilepsy, yet the molecular mechanisms underlying its antiepileptic effects have not been determined. There is increasing evidence that neuronal cell death induced by seizures via mitochondrial pathway and seizures can lead to mitochondrial release of cytochrome c, and we have shown previously that translocation of Smac/DIABLO into the cytosol play a role in the brain damage in a model of limbic seizure. In the present study, we explored the neuroprotective effect of KD in C57BL/6 mice with seizures induced by kainic acid (KA). Status epilepticus triggered by intra-amygdaloid microinjection of KA lead to neuronal death in the selective ipsilateral CA3 subfield of the hippocampus and mitochondrial release of Smac/DIABLO and cytochrome c. We found that KD significantly decreased neuronal death in the ipsilateral CA3 at 24h after KA-induced seizures. Furthermore, KD reduced Smac/DIABLO and cytochrome c release from mitochondria, attenuated activation of casepase-9 and caspase-3 following seizures. These results demonstrate that the neuroprotective effect of KD against brain injury induced by limbic seizures, at least partially, is associated with inhibition of mitochondrial release of Smac/DIABLO and cytochrome c., (Copyright © 2012 Elsevier Inc. All rights reserved.)

A high level of plasma homocysteine (Hcy) increases the risk for neurodegenerative diseases. One such disorder is Alzheimer's disease, which involves marked neuronal apoptosis of unknown etiology. This study shows that Hcy inhibits expression of 14-3-3ε and activates calcineurin in rat hippocampal neurons in a dose-dependent manner. Calcineurin-mediated Bad dephosphorylation, which is blocked by calcineurin inhibition and Ca(2+) chelation, causes mitochondrial translocation of Bad and apoptosis; this step in the apoptotic pathway is synergistically blocked by calcineurin inhibition and overexpression of 14-3-3ε. These findings demonstrated that calcineurin activation and downregulation of 14-3-3ε may be one of the mechanisms of Hcy-induced apoptosis of hippocampal neurons.

Accumulation of neuronal α-synuclein is a prominent feature in Parkinson's disease. More recently, such abnormal protein aggregation has been reported to spread from cell to cell and exosomes are considered as important mediators. The focus of such research, however, has been primarily in neurons. Given the increasing recognition of the importance of non-cell autonomous-mediated neurotoxicity, it is critical to investigate the contribution of glia to α-synuclein aggregation and spread. Microglia are the primary phagocytes in the brain and have been well-documented as inducers of neuroinflammation. How and to what extent microglia and their exosomes impact α-synuclein pathology has not been well delineated. We report here that when treated with human α-synuclein preformed fibrils, exosomes containing α-synuclein released by microglia are fully capable of inducing protein aggregation in the recipient neurons. Additionally, when combined with microglial proinflammatory cytokines, these exosomes further increased protein aggregation in neurons. Inhibition of exosome synthesis in microglia reduced α-synuclein transmission. The in vivo significance of these exosomes was demonstrated by stereotaxic injection of exosomes isolated from α-synuclein preformed fibrils treated microglia into the mouse striatum. Phosphorylated α-synuclein was observed in multiple brain regions consistent with their neuronal connectivity. These animals also exhibited neurodegeneration in the nigrostriatal pathway in a time-dependent manner. Depleting microglia in vivo dramatically suppressed the transmission of α-synuclein after stereotaxic injection of preformed fibrils. Mechanistically, we report here that α-synuclein preformed fibrils impaired autophagy flux by upregulating PELI1, which in turn, resulted in degradation of LAMP2 in activated microglia. More importantly, by purifying microglia/macrophage derived exosomes in the CSF of Parkinson's disease patients, we confirmed the presence of α-synuclein oligomer in CD11b+ exosomes, which were able to induce α-synuclein aggregation in neurons, further supporting the translational aspect of this study. Taken together, our study supports the view that microglial exosomes contribute to the progression of α-synuclein pathology and therefore, they may serve as a promising therapeutic target for Parkinson's disease. [ABSTRACT FROM AUTHOR]