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Increase of deposits of amyloid β peptides in the extracellular matrix is landmark during Alzheimer’s Disease (AD) due to the imbalance in the production vs. clearance. This accumulation of amyloid β deposits triggers microglial activation. Microglia plays a dual role in AD, a protective role by clearing the deposits of amyloid β peptides increasing the phagocytic response (CD163, IGF-1 or BDNF) and a cytotoxic role, releasing free radicals (ROS or NO) and proinflammatory cytokines (TNF-α, IL-1β) in response to reactive gliosis activated by the amyloid β aggregates. Microglia activation correlated with an increase K1.3 channels expression, protein levels and current density. Several studies highlight the importance of K1.3 in the activation of inflammatory response and inhibition of neural progenitor cell proliferation and neuronal differentiation. However, little is known about the pathways of this activation in neural stem cells differentiation and proliferation and the role in amyloid β accumulation. In recent studies using in vitro cells derived from mice models, it has been demonstrated that K1.3 blockers inhibit microglia-mediated neurotoxicity in culture reducing the expression and production of the pro-inflammatory cytokines IL-1β and TNF-α through the NF-kB and p38MAPK pathway. Overall, we conclude that K1.3 blockers change the course of AD development, reducing microglial cytotoxic activation and increasing neural stem cell differentiation. However, further investigations are needed to establish the specific pathway and to validate the use of this blocker as therapeutic treatment in Alzheimer patients., This work was supported by a grant from the MICINN (PID2020-118814RB-I00), the Government of the Autonomous Community of the Basque Country (IT1165-19 and KK-2020/00110), and the Spanish Ministry of Science and Innovation (RTI2018-097839-B-100 to AV).

The role of somatic mutations in complex diseases, including neurodevelopmental and neurodegenerative disorders, is becoming increasingly clear. However, to date, no study has shown their relation to Parkinson disease's phenotype. To explore the relevance of embryonic somatic mutations in sporadic Parkinson disease, we performed whole-exome sequencing in blood and four brain regions of ten patients. We identified 59 candidate somatic single nucleotide variants (sSNVs) through sensitive calling and a careful filtering strategy (COSMOS). We validated 27 of them with amplicon-based ultra-deep sequencing, with a 70% validation rate for the highest-confidence variants. The identified sSNVs are in genes with synaptic functions that are co-expressed with genes previously associated with Parkinson disease. Most of the sSNVs were only called in blood but were also found in the brain tissues with ultra-deep amplicon sequencing, demonstrating the strength of multi-tissue sampling designs. This work was supported by the grants from the Spanish MINECO and MICIN (SAF2016-76340R and PID2019-106764RB-C21, Excellence Unit María de Maeztu/Institute of Neurosciences), CIBERNED (ISCIII), and by the “Fundación Reina Sofía” (Exome Project) awarded to ES, by RTI 2018-096824-B-C22 grant from Agencia estatal de Investigación- Spanish Ministry of Science, Innovation and Universities co-financed by FEDER, and by Direcció General de Recerca, Generalitat de Catalunya (2017SGR-702) to FC, MS-M is supported by the Ministerio de Economía y Competitividad, Spain (Maria de Maetzu grant MDM-2014-0370-16-3). PE-C was supported by a Formació de Personal Investigador fellowship from Generalitat de Catalunya (FI_B00122). RR is funded by Cancer Research UK (C66259/A27114).

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, which is causally related to the accumulation of abnormally folded amyloid-β (Aβ) peptide and hyperphosphorylated tau protein aggregates. The dendritic spine regulator Rho protein kinase 2 (Rock2) accumulates in the brain at the earliest stages of AD and remains increased during disease progression. However, the molecular mechanism that upregulates Rock2 in AD, and its role in the disease progression, are unknown. Here, we found that oligomers of the amyloidogenic fragment 25–35 of the Aβ peptide (Aβ25-35) trigger Rock2 accumulation and activation in mouse cortical neurons in primary culture and in mouse hippocampus in vivo. Neuronal apoptotic death and memory impairment caused by Aβ25-35 administration were rescued by genetic and pharmacological inhibition of Rock2 activity. Mechanistically, Aβ25-35 elicited cyclin dependent kinase-5 (Cdk5)-mediated phosphorylation of Cdh1, a cofactor that is essential for the activity of the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C) in neurons. Notably, phosphorylated Cdh1 was disassembled from the APC/C complex, causing its inactivation and subsequent Rock2 protein stabilization and activation. Moreover, Aβ25-35-induced neuronal apoptosis was prevented by expressing a phosphodefective form of Cdh1, but not by a phosphomimetic Cdh1. Finally, Cdh1 inactivation, using both genetic and pharmacological approaches, enhanced Aβ25-35-mediated neuronal death through a mechanism that was prevented by inhibition of Rock2 activity. These results indicate that the Cdk5-Cdh1 signaling pathway accounts for the increased Rock2 activity by amyloidogenic Aβ peptides and that this mechanism may contribute to neurodegeneration and memory loss in AD., The work was funded by The Instituto de Salud Carlos III (to AA, PI21/00727 and RD21/0006/0005); European Regional Development Fund; European Union’s Horizon 2020 Research and Innovation Programme (to AA, grant agreement 686009); and Junta de Castilla y León (to AA and JB, CSI151P20 and CLU201703 P.O.FEDER CyL1420), and the Agencia Estatal de Investigación (to JB, PID 2019-105699RB-I00, MCIN/AEI/10.13039/501100011033 and European Union NextGenerationEU/PRTR). RL, JA and SG-G are funded by Junta de Castilla y León (to RL and JA, CSI151P20; to SG-G, EDU/601/2020).

Sevoflurane (SEVO) is a highly fluorinated methyl isopropyl ether used as an inhalational anesthetic for general anesthesia. Previous studies have shown that SEVO may induce impaired memory and recognition ability and may be associated with neurodegenerative disease, e.g., Alzheimer’s disease (AD). However, the underlying mechanism remains unknown. Here, we used a mouse AD model, APP/PS1, to study the effects of SEVO on neurodegeneration occurring in AD. We found that SEVO exposure significantly impaired the spatial reference memory, sensorimotor, and cognitive function of the mice. Mechanistically, we found that SEVO induced formation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and its downstream caspase 1-mediated production of IL-1β and IL-18, which subsequently deactivated brain-derived neurotrophic factor (BDNF) to promote neurodegeneration. Together, these data suggest that NLRP3 inflammasome is essential for SEVO-induced AD.

It has been reported that several immune cells can release chromatin and granular proteins into extracellular space in response to the stimulation, forming extracellular traps (ETs). The cells involved in the extracellular trap formation are recognized including neutropils, macrophages, basophils, eosinophils, and mast cells. With the development of research related to central nervous system, the role of ETs has been valued in neuroinflammation, blood–brain barrier, and other fields. Meanwhile, it has been found that microglial cells as the resident immune cells of the central nervous system can also release ETs, updating the original understanding. This review aims to clarify the role of the ETs in the central nervous system, especially in neuroinflammation and blood–brain barrier.

Diabetic retinopathy, as one of the common complications of diabetes mellitus, is the leading cause of blindness in the working-age population worldwide. The disease is characterized by damage to retinal vasculature, which is associated with the activation of retina microglial and induces chronic neurodegeneration. Previous studies have identified the effects of activated microglial on the retinal neurons, but the cellular and molecular mechanisms underlying microglial activation is largely unknown. Here, we performed scRNA-seq on the retina of non-human primates with diabetes mellitus, and identified cell-type-specific molecular changes of the six major cell types. By identifying the ligand-receptor expression patterns among different cells, we established the interactome of the whole retina. The data showed that TNF-α signal mediated the activation of microglia through an autocrine manner. And we found TGFβ2, which was upregulated in cone dramatically by hyperglycemia, inhibited microglia activation at the early stage of diabetic retinopathy. In summary, our study is the first to profile cell-specific molecular changes and the cell-cell interactome of retina under diabetes mellitus, paving a way to dissect the cellular and molecular mechanisms underlying early-stage diabetic retinopathy.

BackgroundQuorum sensing peptides (QSPs) are bacterial peptides produced by Gram-positive bacteria to communicate with their peers in a cell-density dependent manner. These peptides do not only act as interbacterial communication signals, but can also have effects on the host. Compelling evidence demonstrates the presence of a gut-brain axis and more specifically, the role of the gut microbiota in microglial functioning. The aim of this study is to investigate microglial activating properties of a selected QSP (PapRIV) which is produced byBacillus cereusspecies.MethodsGastro-intestinal transport of the peptide is investigated using thein vitroCaco-2 model while transport over the blood-brain barrier is investigated in mice using multiple time regression experiments. Microglial activation is assessed using ELISA, fluorometry, immunoblotting, qPCR and phase-contrast microscopy.In vivoplasma detection andex vivometabolization experiments are performed using UHPLC-MS2and UHPLC-UV/MS, respectively.ResultsPapRIV showedin vitroactivating properties of BV-2 microglia cells and was able to cross thein vitroCaco-2 cell model and pass the blood-brain barrierin vivo.In vivopeptide presence was also demonstrated in mouse plasma. The peptide caused induction of IL-6, TNFα and ROS expression and increased the fraction of ameboid BV-2 microglia cells in an NF-κB dependent manner. Different metabolites were identified in serum, of which the main metabolite (DLPFEH) still remained active.ConclusionsPapRIV is thus able to cross the gastro-intestinal tract and the blood-brain barrier and showsin vitroactivating properties in BV-2 microglia cells, hereby indicating a potential role of this quorum sensing peptide in gut-brain interaction.

Most neurological disorders seemingly have heterogenous pathogenesis, with overlapping contribution of neuronal, immune and vascular mechanisms of brain damage. The perivascular space (PVS) in the brain represents a crossroad where those mechanisms interact, as well as a key anatomical component of the recently discovered glymphatic pathway, which is considered to play a crucial role in the clearance of brain waste linked to neurodegenerative diseases. The pathological interplay between neuronal, immune and vascular factors can create an environment that promotes self-perpetration of mechanisms of brain damage across different neurological diseases, including those that are primarily thought of as neurodegenerative, neuroinflammatory or cerebrovascular. PVS changes can be monitored in humans in vivo using magnetic resonance imaging (MRI). In the context of glymphatic clearance, MRI-visible enlarged perivascular spaces (EPVS) are considered to reflect glymphatic stasis secondary to the perivascular accumulation of brain debris, although they may also represent an adaptive mechanism of the glymphatic system to clear them. EPVS are also established correlates of dementia and cerebral small vessel disease (SVD) and are considered to reflect brain inflammatory activity. In this review, we describe the “perivascular unit” as a key anatomical substrate for the interaction between neuronal, immune and vascular mechanisms of brain damage, which are shared across different neurological diseases, including those that are considered primarily neurodegenerative, neuroinflammatory or cerebrovascular. We will describe the main anatomical, physiological and pathological features of the perivascular unit, highlight potential substrates for the interplay between different noxae and summarize MRI studies of EPVS in cerebrovascular, neuroinflammatory and neurodegenerative disorders.

Huntington disease (HD) is a fatal, inherited neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene. While mutant HTT is present ubiquitously throughout life, HD onset typically occurs in mid-life. Oxidative damage accumulates in the aging brain and is a feature of HD. We sought to interrogate the roles and interaction of age and oxidative stress in HD using primary Hu97/18 mouse neurons, neurons differentiated from HD patient induced pluripotent stem cells (iPSCs), and the brains of HD mice. We find that primary neurons must be matured in culture for canonical stress responses to occur. Furthermore, when aging is accelerated in mature HD neurons, mutant HTT accumulates and sensitivity to oxidative stress is selectively enhanced. Furthermore, we observe HD-specific phenotypes in neurons and mouse brains that have undergone accelerated aging, including a selective increase in DNA damage. These findings suggest a role for aging in HD pathogenesis and an interaction between the biological age of HD neurons and sensitivity to exogenous stress.

Background: Odor identification (OI) ability is a suggested early biomarker of Alzheimer’s disease. In this study, we investigated brain activity within the brain’s olfactory network associated with OI in patients with amnestic mild cognitive impairment (aMCI) and mild Alzheimer’s dementia (mAD) to uncover the neuronal basis of this impairment. Materials and Methods: Patients with aMCI (n = 11) or mAD (n = 6) and 28 healthy older adults underwent OI functional MRI (fMRI) at 3T, OI, odor discrimination, and cognitive tests and apolipoprotein-e4 (APOE4) genotyping. Eleven patients had cerebrospinal fluid (CSF) analyzed. Those with aMCI were followed for 2 years to examine conversion to dementia. Results: The aMCI/mAD group performed significantly worse on all OI tests and the odor discrimination test compared to controls. The aMCI/mAD group had reduced activation in the right anterior piriform cortex compared to the controls during OI fMRI [Gaussian random field (GRF) corrected cluster threshold, p < 0.05]. This group difference remained after correcting for age, sex education, and brain parenchymal fraction. This difference in piriform activity was driven primarily by differences in odor discrimination ability and to a lesser extent by OI ability. There was no group by odor discrimination/identification score interaction on brain activity. Across both groups, only odor discrimination score was significantly associated with brain activity located to the right piriform cortex. Brain activity during OI was not associated with Mini Mental Status Examination scores. At the group level, the aMCI/mAD group activated only the anterior insula, while the control group had significant activation within all regions of the olfactory network during OI fMRI. There was no association between brain activity during OI fMRI and total beta-amyloid levels in the CSF in the aMCI/mAD group. Conclusion: The OI impairment in aMCI/mAD patients is associated with significantly reduced activity in the piriform cortex compared to controls. Activation of downstream regions within the olfactory network is also significantly affected in the aMCI/mAD group, except the anterior insula, which is impinged late in the course of Alzheimer’s disease. OI tests thus reflect Alzheimer’s disease pathology in olfactory brain structures. Keywords: smell, olfaction, neurodegenaration, central nervous system (CNS), cognition Copyright © 2021 Kjelvik, Evensmoen, Hummel, Engedal, Selbæk, Saltvedt and Håberg. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Activation of skeletal muscle in response to acetylcholine release from the neuromuscular junction triggered by motor neuron firing forms the basis of all mammalian locomotion. Intricate feedback and control mechanisms, both from within the central nervous system and from sensory organs in the periphery, provide essential inputs that regulate and finetune motor neuron activity. Interestingly, in motor neuron diseases, such as spinal muscular atrophy (SMA), pathological studies in patients have identified alterations in multiple parts of the sensory-motor system. This has stimulated significant research efforts across a range of different animal models of SMA in order to understand these defects and their contribution to disease pathogenesis. Several recent studies have demonstrated that defects in sensory components of the sensory-motor system contribute to dysfunction of motor neurons early in the pathogenic process. In this review, we provide an overview of these findings, with a specific focus on studies that have provided mechanistic insights into the molecular processes that underlie dysfunction of the sensory-motor system in SMA. These findings highlight the role that cell types other than motor neurons play in SMA pathogenesis, and reinforce the need for therapeutic interventions that target and rescue the wide array of defects that occur in SMA.

International audience; Communication between the endoplasmic reticulum (ER) and mitochondria plays a pivotal role in Ca2+ signaling, energy metabolism, and cell survival. Dysfunction in this cross-talk leads to metabolic and neurodegenerative diseases. Wolfram syndrome is a fatal neurodegenerative disease caused by mutations in the ER-resident protein WFS1. Here, we showed that WFS1 formed a complex with neuronal calcium sensor 1 (NCS1) and inositol 1,4,5-trisphosphate receptor (IP3R) to promote Ca2+ transfer between the ER and mitochondria. In addition, we found that NCS1 abundance was reduced in WFS1-null patient fibroblasts, which showed reduced ER-mitochondria interactions and Ca2+ exchange. Moreover, in WFS1-deficient cells, NCS1 overexpression not only restored ER-mitochondria interactions and Ca2+ transfer but also rescued mitochondrial dysfunction. Our results describe a key role of NCS1 in ER-mitochondria cross-talk, uncover a pathogenic mechanism for Wolfram syndrome, and potentially reveal insights into the pathogenesis of other neurodegenerative diseases.