Neurological and mental health consequences of COVID-19: potential implications for well-being and labour force.

Recent case studies show that the SARS-CoV-2 infectious disease, COVID-19, is associated with accelerated decline of mental health, in particular, cognition in elderly individuals, but also with neurological and neuropsychiatric illness in young people. Recent studies also show a bidirectional link between COVID-19 and mental health in that people with previous history of psychiatric illness have a higher risk for contracting COVID-19 and that COVID-19 patients display a variety of psychiatric illnesses. Risk factors and the response of the central nervous system to the virus show large overlaps with pathophysiological processes associated with Alzheimer's disease, delirium, post-operative cognitive dysfunction and acute disseminated encephalomyelitis, all characterized by cognitive impairment. These similarities lead to the hypothesis that the neurological symptoms could arise from neuroinflammation and immune cell dysfunction both in the periphery as well as in the central nervous system and the assumption that long-term consequences of COVID-19 may lead to cognitive impairment in the well-being of the patient and thus in today's workforce, resulting in large loss of productivity. Therefore, particular attention should be paid to neurological protection during treatment and recovery of COVID-19, while cognitive consequences may require monitoring.

Corrigendum: Effects of Anthocyanin Supplementation on Serum Lipids, Glucose, Markers of Inflammation and Cognition in Adults With Increased Risk of Dementia - A Pilot Study.

[This corrects the article DOI: 10.3389/fgene.2019.00536.].

Detection of Synaptic Proteins in Microglia by Flow Cytometry.

A growing body of evidence indicates that microglia actively remove synapses in vivo, thereby playing a key role in synaptic refinement and modulation of brain connectivity. This phenomenon was mainly investigated in immunofluorescence staining and confocal microscopy. However, a quantification of synaptic material in microglia using these techniques is extremely time-consuming and labor-intensive. To address this issue, we aimed to quantify synaptic proteins in microglia using flow cytometry. With this approach, we first showed that microglia from the healthy adult mouse brain contain a detectable level of VGLUT1 protein. Next, we found more than two-fold increased VGLUT1 immunoreactivity in microglia from the developing brain (P15) as compared to adult microglia. These data indicate that microglia-mediated synaptic pruning mostly occurs during the brain developmental period. We then quantified the VGLUT1 staining in microglia in two transgenic models characterized by pathological microglia-mediated synaptic pruning. In the 5xFAD mouse model of Alzheimer's disease (AD) microglia exhibited a significant increase in VGLUT1 immunoreactivity before the onset of amyloid pathology. Moreover, conditional deletion of TDP-43 in microglia, which causes a hyper-phagocytic phenotype associated with synaptic loss, also resulted in increased VGLUT1 immunoreactivity within microglia. This work provides a quantitative assessment of synaptic proteins in microglia, under homeostasis, and in mouse models of disease.

Emerging Developments in Human Induced Pluripotent Stem Cell-Derived Microglia: Implications for Modelling Psychiatric Disorders With a Neurodevelopmental Origin.

Microglia, the resident tissue macrophages of the brain, are increasingly implicated in the pathophysiology of psychiatric disorders with a neurodevelopmental origin, including schizophrenia. To date, however, our understanding of the potential role for these cells in schizophrenia has been informed by studies of aged post-mortem samples, low resolution in vivo neuroimaging and rodent models. Whilst these have provided important insights, including signs of the heterogeneous nature of microglia, we currently lack a validated human in vitro system to characterize microglia in the context of brain health and disease during neurodevelopment. Primarily, this reflects a lack of access to human primary tissue during developmental stages. In this review, we first describe microglia, including their ontogeny and heterogeneity and consider their role in brain development. We then provide an evaluation of the potential for differentiating microglia from human induced pluripotent stem cells (hiPSCs) as a robust in vitro human model system to study these cells. We find the majority of protocols for hiPSC-derived microglia generate cells characteristically similar to foetal stage microglia when exposed to neuronal environment-like cues. This may represent a robust and relevant model for the study of cellular and molecular mechanisms in schizophrenia. Each protocol however, provides unique benefits as well as shortcomings, highlighting the need for context-dependent protocol choice and cross-lab collaboration and communication to identify the most robust and translatable microglia model.

Exploration of Plasma Lipids in Mild Cognitive Impairment due to Alzheimer's Disease.

BACKGROUND: Lipids have important structural roles in cell membranes and changes to these membrane lipids may influence ß- and γ-secretase activities and thus contribute to Alzheimer's disease (AD) pathology. OBJECTIVE: To explore baseline plasma lipid profiling in participants with mild cognitive impairment (MCI) with and without AD pathology. METHODS: We identified 261 plasma lipids using reversed-phase liquid chromatography/mass spectrometry in cerebrospinal fluid amyloid positive (Aß+) or negative (Aß-) participants with MCI as compared to controls. Additionally, we analyzed the potential associations of plasma lipid profiles with performance on neuropsychological tests at baseline and after two years. RESULTS: Sphingomyelin (SM) concentrations, particularly, SM(d43:2), were lower in MCI Aß+ individuals compared to controls. Further, SM(d43:2) was also nominally reduced in MCI Aß+ individuals compared to MCI Aß-. No plasma lipids were associated with performance on primary neuropsychological tests at baseline or between the two time points after correction for multiple testing. CONCLUSION: Reduced plasma concentrations of SM were associated with AD.

The Wide World of Coacervates: From the Sea to Neurodegeneration.

The formation of immiscible liquid phases or coacervates is a phenomenon widely observed in biology. Marine organisms, for instance, use liquid-liquid phase separation (LLPS) as the precursor phase to form various fibrillar or crustaceous materials that are essential for surface adhesion. More recently, the importance of LLPS has been realized in the compartmentalization of living cells and in obtaining ordered but dynamic partitions that can be reversed according to necessity. Here, we compare the properties, features, and peculiarities of intracellular and extracellular coacervates, drawing parallels and learning from the differences. A more general view of the phenomenon may in the future inform new studies to allow a better comprehension of its laws.

Why does the Aß peptide of Alzheimer share structural similarity with antimicrobial peptides?

The Aß peptides causally associated with Alzheimer disease have been seen as seemingly purposeless species produced by intramembrane cleavage under both physiological and pathological conditions. However, it has been increasingly suggested that they could instead constitute an ancient, highly conserved effector component of our innate immune system, dedicated to protecting the brain against microbial attacks. In this antimicrobial protection hypothesis, Aß aggregation would switch from an abnormal stochastic event to a dysregulated innate immune response. In this perspective, we approach the problem from a different and complementary perspective by comparing the structure and sequence of Aß(1-42) with those of bona fide antimicrobial peptides. We demonstrate that Aß(1-42) bears convincing structural similarities with both viral fusion domains and antimicrobial peptides, as well as sequence similarities with a specific family of bacterial bacteriocins. We suggest a model of the mechanism by which Aß peptides could elicit the immune response against microbes.

Benefits and Harms of Statins in People with Dementia: A Systematic Review and Meta-Analysis.

OBJECTIVES: More people with dementia also fall into the category of high vascular risk, for which a statin is usually prescribed. However, these recommendations are based on studies in people without dementia. We aimed to evaluate the evidence for the long-term effectiveness and harm of statin therapy in patients with dementia. DESIGN: Systematic review of randomized controlled trials and observational research. SETTING: Publications from developed countries indexed in the PubMed, Web of Science, and Cochrane trial database between 2007 and 2019. PARTICIPANTS: Trials including people with all types of dementia with a mean age older than 65 years. INTERVENTION: Treatment with a statin for 6 months or longer. MEASUREMENTS: Major adverse cardiovascular events, dementia progression, and general health at 2 years, or medication adverse events (AEs) at any time. Each article was assessed for bias using the Newcastle-Ottawa or Cochrane Collaboration tools. A narrative synthesis and pooled analyses are reported. RESULTS: Five articles met the inclusion criteria. They reported only on dementia of the Alzheimer's type. There was no evidence regarding cardiovascular events or general health. We made a very low confidence finding that statins reduce dementia progression based on three cohort studies of heterogeneous design. We made a very low confidence finding of no significant difference in AEs based on two randomized controlled trials of 18 months: odds ratios of any AE = 1.21 (95% confidence interval [CI] = .83-1.77), serious AE = 1.03 (95% CI = .76-1.87), and death = 1.69 (95% CI = .79-3.62). CONCLUSION: Evidence was insufficient to fully evaluate the efficacy of statins in people with dementia. We found that statins may have a small benefit delaying progression in Alzheimer's dementia, although this conflicted with previous findings from shorter randomized trials. For safety, the trial data lacked power to show clinically important differences between the groups. We recommend that clinical data be leveraged for further observational studies to inform prescribing decisions. J Am Geriatr Soc 68:650-658, 2020.

Effects of Anthocyanin Supplementation on Serum Lipids, Glucose, Markers of Inflammation and Cognition in Adults With Increased Risk of Dementia - A Pilot Study.

BACKGROUND: Anthocyanins may protect against cardiovascular related cognitive decline and dementia. OBJECTIVE: Open-label study to measure changes in serum lipids, glucose, glycosylated hemoglobin (HbA1c), and markers of inflammation after anthocyanin supplementation in people with increased risk of dementia. As a secondary endpoint we examined potential changes in a battery of cognitive test in the anthocyanin group (AG). A total of 27 individuals with mild cognitive impairment (MCI) (n = 8) or stable non-obstructive coronary artery disease (CAD) (n = 19) consumed two Medox® capsules, each containing 80 mg of natural purified anthocyanins, twice daily for 16 weeks. They provided blood samples and performed a short battery of cognitive tests. Twenty healthy normal controls (NC) (n = 20) provided blood samples, but did not receive any intervention and did not perform cognitive tests. RESULTS: There was a significant difference between groups for CCL-5/RANTES [regulated on activation, normal T-cell expressed and secreted (RANTES)]. In addition, total cholesterol and triglycerides were significantly increased in the AG. Improvements in memory and executive test scores were observed. No adverse effects were reported. CONCLUSION: The results of this pilot study were largely inconclusive with regard to the potential protective effects of anthocyanin supplementation. However, anthocyanins were well tolerated, and compliance was high. Larger, placebo-controlled studies to explore the potential effects of anthocyanins on dementia risk are encouraged. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT02409446.

Concise Review: Modeling Neurodegenerative Diseases with Human Pluripotent Stem Cell-Derived Microglia.

Inflammation of the brain and the consequential immunological responses play pivotal roles in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia (FTD). Microglia, the resident macrophage cells of the brain, have also emerged as key players in neuroinflammation. As primary human microglia from living subjects are normally not accessible to researchers, there is a pressing need for an alternative source of authentic human microglia which allows modeling of neurodegeneration in vitro. Several protocols for induced pluripotent stem cell (iPSC)-derived microglia have recently been developed and provide unlimited access to patient-derived material. In this present study, we give an overview of iPSC-derived microglia models in monoculture and coculture systems, their advantages and limitations, and how they have already been used for disease phenotyping. Furthermore, we outline some of the gene engineering tools to generate isogenic controls, the creation of gene knockout iPSC lines, as well as covering reporter cell lines, which could help to elucidate complex cell interaction mechanisms in the microglia/neuron coculture system, for example, microglia-induced synapse loss. Finally, we deliberate on how said cocultures could aid in personalized drug screening to identify patient-specific therapies against neurodegeneration. Stem Cells 2019;37:724-730.

Cell-to-cell Communication by Extracellular Vesicles: Focus on Microglia.

Extracellular vesicles, including exosomes and microvesicles, are small, nano-to-micrometer vesicles that are released from cells. While initially observed in immune cells and reticulocytes as vesicles meant to remove archaic proteins, now they have been observed in almost all cell types of multicellular organisms. Growing evidence indicates that extracellular vesicles, containing lipids, proteins and RNAs, represent an efficient way to transfer functional cargoes from one cell to another. In the central nervous system, the extensive cross-talk ongoing between neurons and glia, including microglia, the immune cells of the brain, takes advantage of secreted vesicles, which mediate intercellular communication over long range distance. Recent literature supports a critical role for extracellular vesicles in mediating complex and coordinated communication among neurons, astrocytes and microglia, both in the healthy and in the diseased brain. In this review, we focus on the biogenesis and function of microglia-related extracellular vesicles and focus on their putative role in Alzheimer's disease pathology.

The Microglial Innate Immune Receptor TREM2 Is Required for Synapse Elimination and Normal Brain Connectivity.

The triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial innate immune receptor associated with a lethal form of early, progressive dementia, Nasu-Hakola disease, and with an increased risk of Alzheimer's disease. Microglial defects in phagocytosis of toxic aggregates or apoptotic membranes were proposed to be at the origin of the pathological processes in the presence of Trem2 inactivating mutations. Here, we show that TREM2 is essential for microglia-mediated synaptic refinement during the early stages of brain development. The absence of Trem2 resulted in impaired synapse elimination, accompanied by enhanced excitatory neurotransmission and reduced long-range functional connectivity. Trem2-/- mice displayed repetitive behavior and altered sociability. TREM2 protein levels were also negatively correlated with the severity of symptoms in humans affected by autism. These data unveil the role of TREM2 in neuronal circuit sculpting and provide the evidence for the receptor's involvement in neurodevelopmental diseases.

Microglia-Mediated Synapse Loss in Alzheimer's Disease.

Microglia are emerging as key players in neurodegenerative diseases, such as Alzheimer's disease (AD). Thus far, microglia have rather been known as modulator of neurodegeneration with functions limited to neuroinflammation and release of neurotoxic molecules. However, several recent studies have demonstrated a direct role of microglia in "neuro" degeneration observed in AD by promoting phagocytosis of neuronal, in particular, synaptic structures. While some of the studies address the involvement of the ß-amyloid peptides in the process, studies also indicate that this could occur independent of amyloid, further elevating the importance of microglia in AD. Here we review these recent studies and also speculate about the possible cellular mechanisms, and how they could be regulated by risk genes and sleep. Finally, we deliberate on possible avenues for targeting microglia-mediated synapse loss for therapy and prevention.Dual Perspectives Companion Paper: Alzheimer's Disease and Sleep-Wake Disturbances: Amyloid, Astrocytes, and Animal Models by William M. Vanderheyden, Miranda M. Lim, Erik S. Musiek, and Jason R. Gerstner.

TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss.

Microglia coordinate various functions in the central nervous system ranging from removing synaptic connections, to maintaining brain homeostasis by monitoring neuronal function, and clearing protein aggregates across the lifespan. Here we investigated whether increased microglial phagocytic activity that clears amyloid can also cause pathological synapse loss. We identified TDP-43, a DNA-RNA binding protein encoded by the Tardbp gene, as a strong regulator of microglial phagocytosis. Mice lacking TDP-43 in microglia exhibit reduced amyloid load in a model of Alzheimer's disease (AD) but at the same time display drastic synapse loss, even in the absence of amyloid. Clinical examination from TDP-43 pathology cases reveal a considerably reduced prevalence of AD and decreased amyloid pathology compared to age-matched healthy controls, confirming our experimental results. Overall, our data suggest that dysfunctional microglia might play a causative role in the pathogenesis of neurodegenerative disorders, critically modulating the early stages of cognitive decline.

The Alzheimer's Disease γ-Secretase Generates Higher 42:40 Ratios for ß-Amyloid Than for p3 Peptides.

Alzheimer's disease is characterized by intracerebral deposition of ß-amyloid (Aß). While Aß40 is the most abundant form, neurotoxicity is mainly mediated by Aß42. Sequential cleavage of amyloid precursor protein (APP) by ß- and γ-secretases gives rise to full-length Aß (Aß1-x) and N-terminally truncated Aß' (Aß11-x) whereas cleavage by α- and γ-secretases leads to the shorter p3 peptides (Aß17-x). We uncovered significantly higher ratios of 42- versus 40-ending variants for Aß and Aß' than for p3 secreted by mouse neurons and human induced pluripotent stem cell (iPSC)-derived neurons or produced in a cell-free γ-secretase assay with recombinant APP-CTFs. The 42:40 ratio was highest for Aß', followed by Aß and then p3. Mass spectrometry analysis of APP intracellular domains revealed differential processing of APP-C83, APP-C89, and APP-C99 by γ-secretase already at the ε-cleavage stage. This mechanistic insight could aid in developing substrate-targeted modulators of APP-C99 processing to specifically lower the Aß42:Aß40 ratio without compromising γ-secretase function.

Specific Inhibition of ß-Secretase Processing of the Alzheimer Disease Amyloid Precursor Protein.

Development of disease-modifying therapeutics is urgently needed for treating Alzheimer disease (AD). AD is characterized by toxic ß-amyloid (Aß) peptides produced by ß- and γ-secretase-mediated cleavage of the amyloid precursor protein (APP). ß-secretase inhibitors reduce Aß levels, but mechanism-based side effects arise because they also inhibit ß-cleavage of non-amyloid substrates like Neuregulin. We report that ß-secretase has a higher affinity for Neuregulin than it does for APP. Kinetic studies demonstrate that the affinities and catalytic efficiencies of ß-secretase are higher toward non-amyloid substrates than toward APP. We show that non-amyloid substrates are processed by ß-secretase in an endocytosis-independent manner. Exploiting this compartmentalization of substrates, we specifically target the endosomal ß-secretase by an endosomally targeted ß-secretase inhibitor, which blocked cleavage of APP but not non-amyloid substrates in many cell systems, including induced pluripotent stem cell (iPSC)-derived neurons. ß-secretase inhibitors can be designed to specifically inhibit the Alzheimer process, enhancing their potential as AD therapeutics without undesired side effects.

Evidence-Based Clinical Use of Nanoscale Extracellular Vesicles in Nanomedicine.

Recent research has demonstrated that all body fluids assessed contain substantial amounts of vesicles that range in size from 30 to 1000 nm and that are surrounded by phospholipid membranes containing different membrane microdomains such as lipid rafts and caveolae. The most prominent representatives of these so-called extracellular vesicles (EVs) are nanosized exosomes (70-150 nm), which are derivatives of the endosomal system, and microvesicles (100-1000 nm), which are produced by outward budding of the plasma membrane. Nanosized EVs are released by almost all cell types and mediate targeted intercellular communication under physiological and pathophysiological conditions. Containing cell-type-specific signatures, EVs have been proposed as biomarkers in a variety of diseases. Furthermore, according to their physical functions, EVs of selected cell types have been used as therapeutic agents in immune therapy, vaccination trials, regenerative medicine, and drug delivery. Undoubtedly, the rapidly emerging field of basic and applied EV research will significantly influence the biomedicinal landscape in the future. In this Perspective, we, a network of European scientists from clinical, academic, and industry settings collaborating through the H2020 European Cooperation in Science and Technology (COST) program European Network on Microvesicles and Exosomes in Health and Disease (ME-HAD), demonstrate the high potential of nanosized EVs for both diagnostic and therapeutic (i.e., theranostic) areas of nanomedicine.

Emerging roles of extracellular vesicles in the nervous system.

Information exchange executed by extracellular vesicles, including exosomes, is a newly described form of intercellular communication important in the development and physiology of neural systems. These vesicles can be released from cells, are packed with information including signaling proteins and both coding and regulatory RNAs, and can be taken up by target cells, thereby facilitating the transfer of multilevel information. Recent studies demonstrate their critical role in physiological processes, including nerve regeneration, synaptic function, and behavior. These vesicles also have a sinister role in the propagation of toxic amyloid proteins in neurodegenerative conditions, including prion diseases and Alzheimer's and Parkinson's diseases, in inducing neuroinflammation by exchange of information between the neurons and glia, as well as in aiding tumor progression in the brain by subversion of normal cells. This article provides a summary of topics covered in a symposium and is not meant to be a comprehensive review of the subject.

Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects.

The ß-site APP cleaving enzymes 1 and 2 (BACE1 and BACE2) were initially identified as transmembrane aspartyl proteases cleaving the amyloid precursor protein (APP). BACE1 is a major drug target for Alzheimer's disease because BACE1-mediated cleavage of APP is the first step in the generation of the pathogenic amyloid-ß peptides. BACE1, which is highly expressed in the nervous system, is also required for myelination by cleaving neuregulin 1. Several recent proteomic and in vivo studies using BACE1- and BACE2-deficient mice demonstrate a much wider range of physiological substrates and functions for both proteases within and outside of the nervous system. For BACE1 this includes axon guidance, neurogenesis, muscle spindle formation, and neuronal network functions, whereas BACE2 was shown to be involved in pigmentation and pancreatic ß-cell function. This review highlights the recent progress in understanding cell biology, substrates, and functions of BACE proteases and discusses the therapeutic options and potential mechanism-based liabilities, in particular for BACE inhibitors in Alzheimer's disease. The protease BACE1 is a major drug target in Alzheimer disease. Together with its homolog BACE2, both proteases have an increasing number of functions within and outside of the nervous system. This review highlights recent progress in understanding cell biology, substrates, and functions of BACE proteases and discusses the therapeutic options and potential mechanism-based liabilities, in particular for BACE inhibitors in Alzheimer disease.