Neuroscience
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Recent studies show that overlapping community structure is an important feature of the brain functional network. However, alterations in such overlapping community structure in Alzheimer's disease (AD) patients have not been examined yet. In this study, we investigate the overlapping community structure in AD by using resting-state functional magnetic resonance imaging (rs-fMRI) data. ⋯ In particular, the frontal-parietal and basal ganglia networks exhibit significant differences between the two groups. A machine learning framework proposed in this paper for AD detection achieved an accuracy of 76.7% when using the detected community strengths of the frontal-parietal and basal ganglia networks only as input features. These findings provide novel insights into the understanding of pathological changes in the brain functional network organization of AD and show the potential of the community structure-related features for AD detection.
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A spontaneous mutation of the disrupted in schizophrenia 1 (Disc1) gene is carried by the 129S inbred mouse strain. Truncated DISC1 protein in 129S mouse synapses impairs the scaffolding of excitatory postsynaptic receptors and leads to progressive spine dysgenesis. In contrast, C57BL/6 inbred mice carry the wild-type Disc1 gene and exhibit more typical cognitive performance in spatial exploration and executive behavioral tests. ⋯ Analysis of pyr/int connectivity revealed a significant delay in synaptic transmission for 129S putative pairs. Sampled 129S pyr/int pairs also had lower detectability index scores than B6 putative pairs. Therefore, the spontaneous Disc1 mutation in the 129S strain attenuates the firing of putative pyr CA1 neurons and impairs spike timing fidelity during cognitive tasks.
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Cerebral ischemia/reperfusion (I/R) injury is the continuation and deterioration of ischemic injury, and there are no effective treatment strategies for this condition. It has been reported that microRNAs (miRNAs) are considered as potential targets to protect the brain against I/R injury. Previous studies have shown that miR-489-3p plays a vital role in regulating apoptosis of neurons. miR-489-3p is considered as a potential target to protect the brain against I/R injury-induced neuron apoptosis. ⋯ Silencing of HDAC2 showed a neuroprotective effect against OGD/R injury in vitro. Overexpression of HDAC2 significantly attenuated the protective effects of miR-489-3p mimics on cell injury in vitro. Our results revealed that the upregulation of miR-489-3p attenuated cerebral I/R injury by negatively regulating HDAC2.
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Studies in rodent models of acute and chronic neurodegenerative disorders have uncovered that glutamate-induced excitotoxic cell death is mediated primarily by extrasynaptic N-methyl-d-aspartate receptors (NMDARs). Rodent neurons can also build up in an activity-dependent manner a protective shield against excitotoxicity. This form of acquired neuroprotection is induced by preconditioning with low doses of NMDA or by activation of synaptic NMDARs triggered by bursts of action potentials. ⋯ Moreover, we found that conditions of enhanced synaptic activity increased survival of human iPSC-derived neurons if applied as pre-treatment before toxic NMDA application. These results revealed that both toxic and protective actions of NMDARs are preserved in human neurons. The experimental platform described in this study may prove useful for the validation of neuroprotective gene products and drugs in human neurons.
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Persistent improvement of cognitive deficits in Alzheimer's disease (AD), a common form of dementia, is an unattained therapeutic objective. Gene therapy holds promise for treatment of familial and sporadic forms of AD. p38γ, a member of the p38 mitogen-activated protein (MAP) kinase family, inhibits amyloid-β toxicity through regulation of tau phosphorylation. We recently showed that a gene delivery approach increasing p38γ resulted in markedly better learning and memory performance in mouse models of AD at advanced stages of amyloid-β- and tau-mediated cognitive impairment. ⋯ Moreover, their learning and memory function was markedly impaired compared to control-treated aged APP mice. These results suggest that high neuronal levels of active p38γ emphasize a stress kinase role of p38γ, perturbing circuit function in motivation, navigation, and spatial learning. Overall, this work shows excessive neuronal p38γ levels can aggravate circuit dysfunction and advises adjustable expression systems will be required for sustainable AD gene therapy based on p38γ activity.