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.

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.

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.

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.

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.

Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation.

Extracellular vesicles (EVs) are membraneous vesicles released by a variety of cells into their microenvironment. Recent studies have elucidated the role of EVs in intercellular communication, pathogenesis, drug, vaccine and gene-vector delivery, and as possible reservoirs of biomarkers. These findings have generated immense interest, along with an exponential increase in molecular data pertaining to EVs. Here, we describe Vesiclepedia, a manually curated compendium of molecular data (lipid, RNA, and protein) identified in different classes of EVs from more than 300 independent studies published over the past several years. Even though databases are indispensable resources for the scientific community, recent studies have shown that more than 50% of the databases are not regularly updated. In addition, more than 20% of the database links are inactive. To prevent such database and link decay, we have initiated a continuous community annotation project with the active involvement of EV researchers. The EV research community can set a gold standard in data sharing with Vesiclepedia, which could evolve as a primary resource for the field.

Role of genes linked to sporadic Alzheimer's disease risk in the production of ß-amyloid peptides.

Alzheimer's disease (AD) is characterized by the presence of toxic protein aggregates or plaques composed of the amyloid ß (Aß) peptide. Various lengths of Aß peptide are generated by proteolytic cleavages of the amyloid precursor protein (APP). Mutations in many familial AD-associated genes affect the production of the longer Aß42 variant that preferentially accumulates in plaques. In the case of sporadic or late-onset AD, which accounts for greater than 95% of cases, several genes are implicated in increasing the risk, but whether they also cause the disease by altering amyloid levels is currently unknown. Through loss of function studies in a model cell line, here RNAi-mediated silencing of several late onset AD genes affected Aß levels is shown. However, unlike the genes underlying familial AD, late onset AD-susceptibility genes do not specifically alter the Aß42/40 ratios and suggest that these genes probably contribute to AD through distinct mechanisms.

Membrane trafficking pathways in Alzheimer's disease.

Membrane proteins are constantly being trafficked in cells and the relevant proteins in Alzheimer's disease (AD), such as the amyloid precursor protein (APP) and its processing enzymes, are not exempted from that. Molecular cell biologists have been endeavoring to ascertain a roadmap for APP processing and trafficking in various cell types including neurons. This has led to the identification of numerous regulatory sorting mechanisms, protein-protein interactions and lipidic microenvironments that largely define how and where the substrate APP meets its processing enzymes. However, the cell biology of tau, and the formation of neurofibrillary tangles, has long been regarded as a separate field. Nonetheless, recent progress is bringing both worlds together in a new paradigm on how Aß toxicity and tau are physiologically connected. Here, we discuss an update of our current appraisal on how membrane trafficking may play an important role in the pathogenesis of the disease and how this could be exploited for effective therapy.

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.

Order of lipid phases in model and plasma membranes.

Lipid rafts are nanoscopic assemblies of sphingolipids, cholesterol, and specific membrane proteins that contribute to lateral heterogeneity in eukaryotic membranes. Separation of artificial membranes into liquid-ordered (Lo) and liquid-disordered phases is regarded as a common model for this compartmentalization. However, tight lipid packing in Lo phases seems to conflict with efficient partitioning of raft-associated transmembrane (TM) proteins. To assess membrane order as a component of raft organization, we performed fluorescence spectroscopy and microscopy with the membrane probes Laurdan and C-laurdan. First, we assessed lipid packing in model membranes of various compositions and found cholesterol and acyl chain dependence of membrane order. Then we probed cell membranes by using two novel systems that exhibit inducible phase separation: giant plasma membrane vesicles [Baumgart et al. (2007) Proc Natl Acad Sci USA 104:3165-3170] and plasma membrane spheres. Notably, only the latter support selective inclusion of raft TM proteins with the ganglioside GM1 into one phase. We measured comparable small differences in order between the separated phases of both biomembranes. Lateral packing in the ordered phase of giant plasma membrane vesicles resembled the Lo domain of model membranes, whereas the GM1 phase in plasma membrane spheres exhibited considerably lower order, consistent with different partitioning of lipid and TM protein markers. Thus, lipid-mediated coalescence of the GM1 raft domain seems to be distinct from the formation of a Lo phase, suggesting additional interactions between proteins and lipids to be effective.

Retromers in Alzheimer's disease.

Amyloid-ß peptide (Aß), the key pathogenic agent in Alzheimer's disease (AD), is released after sequential proteolytic cleavage of the transmembrane amyloid precursor protein (APP). ß-Site APP-cleaving enzyme 1 (BACE1) cleaves APP in early endosomes, and the cause of increased BACE cleavage of APP in AD is not fully resolved yet. It has been proposed that perturbed intracellular trafficking of APP, which leads to prolonged residence time in early endosomes, influences Aß production and hence the risk for AD. Retromers are a family of proteins that mediate the retrieval of transmembrane proteins from the endosomes to the trans-Golgi network. Misregulation of retromers or retromer-associated proteins influences endosomal localization of APP/BACE1. Here we review the role of retromers in the amyloidogenic processing of APP and their pathogenic role in AD.

Nuclear signaling by the APP intracellular domain occurs predominantly through the amyloidogenic processing pathway.

Proteolytic processing of the amyloid precursor protein (APP) occurs via two alternative pathways, localized to different subcellular compartments, which result in functionally distinct outcomes. Cleavage by a beta-gamma sequence generates the Abeta peptide that plays a central role in Alzheimer's disease. In the case of alpha-gamma cleavage, a secreted neurotrophic molecule is generated and the Abeta peptide cleaved and destroyed. In both cases, a cytosolic APP intracellular domain (AICD) is generated. We have previously shown that coexpression of APP with the APP-binding protein Fe65 and the histone acetyltransferase Tip60 results in the formation of nuclear complexes (termed AFT complexes), which localize to transcription sites. We now show that blocking endocytosis or the pharmacological or genetic inhibition of the endosomal beta-cleavage pathway reduces translocation of AICD to these nuclear AFT complexes. AICD signaling further depends on active transport along microtubules and can be modulated by interference with both anterograde and retrograde transport systems. Nuclear signaling by endogenous AICD in primary neurons could similarly be blocked by inhibiting beta-cleavage but not by alpha-cleavage inhibition. This suggests that amyloidogenic cleavage, despite representing the minor cleavage pathway of APP, is predominantly responsible for AICD-mediated nuclear signaling.

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.].

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.

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.

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.

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.

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.