Increasing evidence suggests that infection with Sars-CoV-2 causes neurological deficits in a substantial proportion of affected patients. While these symptoms arise acutely during the course of ...infection, less is known about the possible long-term consequences for the brain. Severely affected COVID-19 cases experience high levels of proinflammatory cytokines and acute respiratory dysfunction and often require assisted ventilation. All these factors have been suggested to cause cognitive decline. Pathogenetically, this may result from direct negative effects of the immune reaction, acceleration or aggravation of pre-existing cognitive deficits, or de novo induction of a neurodegenerative disease. This article summarizes the current understanding of neurological symptoms of COVID-19 and hypothesizes that affected patients may be at higher risk of developing cognitive decline after overcoming the primary COVID-19 infection. A structured prospective evaluation should analyze the likelihood, time course, and severity of cognitive impairment following the COVID-19 pandemic.
Immunotherapy has emerged as a leading new approach to the reduction of amyloid deposits in the brains of Alzheimer patients. At least 4 distinct actions of anti-Abeta antibodies have been proposed ...as contributing to the inhibition of amyloid deposition and its clearance. Critically, each of these proposed mechanisms may be acting simultaneously, and it is feasible that different antibodies may utilize each mechanism to a different extent. One of these proposed mechanisms involves the activation of microglia and the phagocytosis of Abeta peptide. In general this is assumed to proceed through the Fcgamma-receptor binding by antibody opsonized Abeta aggregates, however modifying the microglial phenotype into one with a greater propensity for phagocytosing Abeta is also feasible, as microglia avidly phagocytose Abeta in vitro without antibody present. Evidence is presented supporting arguments that microglial activation does play a role in amyloid removal, particularly compacted amyloid deposits, under certain conditions. In addition to the specific antibody used, other considerations in comparing different reports of antibody action in APP mice include the age of the mice, the extent of pre-existing amyloid when therapy is initiated, the time point when the effects of the therapy are examined and the route of antibody administration. Future questions will consider the source of the activated microglia near the plaques after antibody administration (resident or peripheral) and the extent to which shifts in the microglial phenotype mediate some of the amyloid lowering actions of immunotherapy.
Neuroinflammation in Alzheimer's disease Heneka, Michael T, Prof; Carson, Monica J, Prof; Khoury, Joseph El, Prof ...
Lancet neurology,
04/2015, Letnik:
14, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Summary Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. ...Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease.
The spatially inhomogeneous, small‐scale crustal magnetic fields of Mars influence the escape of planetary atmospheric species and the interaction of the solar wind with the ionosphere. Understanding ...the plasma response to crustal magnetic field regions can therefore provide insight to ionospheric structure and dynamics. To date, several localized spatial structures in ionospheric properties that have been observed over regions of varying magnetic field at Mars have yet to be explained. In this study, a two‐dimensional ionospheric model is used to simulate the effects of field‐aligned plasma transport in regions of strong crustal magnetic fields. Resulting spatial and diurnal plasma distributions are analyzed and found to agree with observations from several spacecraft and offer compelling interpretations for many of the anomalous ionospheric behaviors observed at or near regions of strong crustal magnetic fields on Mars.
Key Points
The Martian ionosphere is sensitive to crustal magnetic field morphology
Ionospheric structure in crustal field regions is simulated in 2‐D
Field aligned transport is a mechanism that explains many observed anomalies
Dietary manipulations are increasingly viewed as possible approaches to treating neurodegenerative diseases. Previous studies suggest that Alzheimer's disease (AD) patients present an energy ...imbalance with brain hypometabolism and mitochondrial deficits. Ketogenic diets (KDs), widely investigated in the treatment and prevention of seizures, have been suggested to bypass metabolic deficits present in AD brain by providing ketone bodies as an alternative fuel to neurons. We investigated the effects of a ketogenic diet in two transgenic mouse lines. Five months old APP/PS1 (a model of amyloid deposition) and Tg4510 (a model of tau deposition) mice were offered either a ketogenic or a control (NIH-31) diet for 3 months. Body weight and food intake were monitored throughout the experiment, and blood was collected at 4 weeks and 4 months for ketone and glucose assessments. Both lines of transgenic mice weighed less than nontransgenic mice, yet, surprisingly, had elevated food intake. The ketogenic diet did not affect these differences in body weight or food consumption. Behavioral testing during the last two weeks of treatment found that mice offered KD performed significantly better on the rotarod compared to mice on the control diet independent of genotype. In the open field test, both transgenic mouse lines presented increased locomotor activity compared to nontransgenic, age-matched controls, and this effect was not influenced by KD. The radial arm water maze identified learning deficits in both transgenic lines with no significant differences between diets. Tissue measures of amyloid, tau, astroglial and microglial markers in transgenic lines showed no differences between animals fed the control or the ketogenic diet. These data suggest that ketogenic diets may play an important role in enhancing motor performance in mice, but have minimal impact on the phenotype of murine models of amyloid or tau deposition.
Inflammation and microglial activation are associated with Alzheimer's disease (AD) pathology. Somewhat surprisingly, injection of a prototypical inflammatory agent, lipopolysaccharide (LPS) into ...brains of amyloid precursor protein (APP) transgenic mice clears some of the pre-existing amyloid deposits. It is less well understood how brain inflammation modulates tau pathology in the absence of Aβ. These studies examined the role of LPS-induced inflammation on tau pathology. We used transgenic rTg4510 mice, which express the P301L mutation (4R0N TauP301L) and initiate tau pathology between 3-5 months of age. First, we found an age-dependent increase in several markers of microglial activation as these rTg4510 mice aged and tau tangles accumulated. LPS injections into the frontal cortex and hippocampus induced significant activation of CD45 and arginase 1 in rTg4510 and non-transgenic mice. In addition, activation of YM1 by LPS was exaggerated in transgenic mice relative to non-transgenic animals. Expression of Ser199/202 and phospho-tau Ser396 was increased in rTg4510 mice that received LPS compared to vehicle injections. However, the numbers of silver-positive neurons, implying presence of more pre- and mature tangles, was not significantly affected by LPS administration. These data suggest that inflammatory stimuli can facilitate tau phosphorylation. Coupled with prior results demonstrating clearance of Aβ by similar LPS injections, these results suggest that brain inflammation may have opposing effects on amyloid and tau pathology, possibly explaining the failures (to date) of anti-inflammatory therapies in AD patients.
Innate immune activation is a major contributor to Alzheimer's Disease (AD) pathophysiology, although the mechanisms involved are poorly understood. Chemokine C-C motif ligand (CCL) 2 is produced by ...neurons and glial cells and is upregulated in the AD brain. Transgene expression of CCL2 in mouse models of amyloidosis produces microglia-induced amyloid β oligomerization, a strong indication of the role of these activation pathways in the amyloidogenic processes of AD. We have previously shown that CCL2 polarizes microglia in wild type mice. However, how CCL2 signaling contributes to tau pathogenesis remains unknown. To address this question, CCL2 was delivered via recombinant adeno-associated virus serotype 9 into both cortex and hippocampus of a mouse model with tau pathology (rTg4510). We report that CCL2 overexpression aggravated tau pathology in rTg4510 as shown by the increase in Gallyas stained neurofibrillary tangles as well as phosphorylated tau-positive inclusions. In addition, biochemical analysis showed a reduction in the levels of detergent-soluble tau species followed by increase in the insoluble fraction, indicating a shift toward larger tau aggregates. Indeed, increased levels of high molecular weight species of phosphorylated tau were found in the mice injected with CCL2. We also report that worsening of tau pathology following CCL2 overexpression was accompanied by a distinct inflammatory response. We report an increase in leukocyte common antigen (CD45) and Cluster of differentiation 68 (CD68) expression in the brain of rTg4510 mice without altering the expression levels of a cell-surface protein Transmembrane Protein 119 (Tmem119) and ionized calcium-binding adaptor molecule 1 (Iba-1) in resident microglia. Furthermore, the analysis of cytokines in brain extract showed a significant increase in interleukin (IL)-6 and CCL3, while CCL5 levels were decreased in CCL2 mice. No changes were observed in IL-1α, IL-1β, TNF-α. IL-4, Vascular endothelial growth factor-VEGF, IL-13 and CCL11. Taken together our data report for the first time that overexpression of CCL2 promotes the increase of pathogenic tau species and is associated with glial neuroinflammatory changes that are deleterious. We propose that these events may contribute to the pathogenesis of Alzheimer's disease and other tauopathies.
The maturation and functional characteristics of human induced pluripotent stem cell (hiPSC)-cortical neurons has not been fully documented. This study developed a phenotypic model of hiPSC-derived ...cortical neurons, characterized their maturation process, and investigated its application for disease modeling with the integration of multi-electrode array (MEA) technology. Immunocytochemistry analysis indicated early-stage neurons (day 21) were simultaneously positive for both excitatory (vesicular glutamate transporter 1 VGlut1) and inhibitory (GABA) markers, while late-stage cultures (day 40) expressed solely VGlut1, indicating a purely excitatory phenotype without containing glial cells. This maturation process was further validated utilizing patch clamp and MEA analysis. Particularly, induced long-term potentiation (LTP) successfully persisted for 1 h in day 40 cultures, but only achieved LTP in the presence of the GABAA receptor antagonist picrotoxin in day 21 cultures. This system was also applied to epilepsy modeling utilizing bicuculline and its correction utilizing the anti-epileptic drug valproic acid.
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•Characterization of human cortical neuronal differentiation to a mature phenotype•Microelectrode evaluation of development from a mixed to pure excitatory population•Utilization of defined culture stage to create an epilepsy model•Manipulation of immaturity with inhibitors for maintaining long-term potentiation
In this article, Hickman and colleagues used controlled hiPSC-cortical neuron maturation to develop models capable of evaluating functional deficits in long-term potentiation, which is the basis for many neurodegenerative diseases. This model has the potential for patient-specific personalized medicine and can be used for both the investigation of pathogenesis and subsequent preclinical assaying of potential drug treatments.
Accumulating evidence increasingly implicates regulation of neuroinflammation as a potential therapeutic target in Alzheimer’s disease and other neurodegenerative disorders
.
Fractalkine (FKN) is a ...unique chemokine that is expressed and secreted by neurons and reduces expression of pro-inflammatory genes. To further demonstrate the utility of agents that increase FKN signaling throughout the central nervous system as possible therapies for AD, we assessed the impact of soluble FKN (sFKN) over expression on cognition in tau depositing rTg450 mice after the onset of cognitive deficits. Using adeno-associated virus serotype 4, we infected cells lining the ventricular system with soluble FKN to increase FKN signaling over a larger fraction of the brain than achieved with intraparenchymal injections. We found that soluble FKN over expression by cells lining the ventricles significantly improved cognitive performance on the novel mouse recognition and radial arm water maze tasks. These benefits were achieved without detectable reductions in tau hyperphosphorylation, hippocampal atrophy, or microglial CD45 expression. Utilizing qPCR, we report a significant increase in
Vegfa
expression, indicating an increase in trophic support and possible neovascularization in AAV-sFKN-injected mice. To our knowledge, this is the first demonstration that FKN over expression can rescue cognitive function in a tau depositing mouse line.
Graphical Abstract
Regulating neuroinflammation is an attractive therapeutic target for Alzheimer’s disease. Microglial activation can not only drive pathology but also accelerate cognitive decline. The chemokine fractalkine regulates the microglial phenotype, increasing trophic support of neurons, and significantly improving cognitive functioning in the rTg4510 mouse model of tauopathy.
The radial arm water maze (RAWM) contains six swim paths (arms) extending out of an open central area, with an escape platform located at the end of one arm (the goal arm). The goal arm location ...remains constant for a given mouse. On day 1, mice are trained for 15 trials (spaced over 3 h), with trials alternating between visible and hidden platform. On day 2, mice are trained for 15 trials with the hidden platform. Entry into an incorrect arm is scored as an error. The RAWM has the spatial complexity and performance measurement simplicity of the dry radial arm maze combined with the rapid learning and strong motivation observed in the Morris water maze without requiring foot shock or food deprivation as motivating factors. With two sessions each day, 16 mice can be tested over 2 days.
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