Strong genetic evidence supports an imbalance between production and clearance of amyloid β-protein (Aβ) in people with Alzheimer disease (AD). Microglia that are potentially involved in alternative ...mechanisms are actually integral to the amyloid cascade. Fluid biomarkers and brain imaging place accumulation of Aβ at the beginning of molecular and clinical changes in the disease. So why have clinical trials of anti-amyloid therapies not provided clear-cut benefits to patients with AD? Can anti-amyloid therapies robustly decrease Aβ in the human brain, and if so, could this lowering be too little, too late? These central questions in research on AD are being urgently addressed.
Although substantial progress has been made in understanding the molecular and pathological bases of neurodegeneration, there have been few successes in the clinic and a number of fundamental ...questions remain unanswered. Is this skepticism misplaced, or do the words of Sir Isaac Newton hold true, that "what we know is a drop, what we don't know is an ocean"?
Alzheimer’s disease (AD) is currently untreatable, and therapeutic strategies aimed to slow cognitive decline have not yet been successful. Many of these approaches have targeted the amyloid cascade, ...indicating that novel treatment strategies are required. Recent genome-wide association studies (GWASs) have identified a number of risk factors in genes expressed in microglia, underscoring their therapeutic potential in neurodegeneration. In this review, we discuss how the recently defined functions of these AD risk genes can be targeted therapeutically to modulate microglial cell state and slow the progression of AD. Antibody-mediated stimulation of the triggering receptor of myeloid cells 2 (TREM2) is on the forefront of these candidate therapeutic approaches based on a combination of compelling human genetics and emerging preclinical data. This and other approaches to modify microglial function are a topic of intensive study and provide an opportunity for innovative AD treatments, which may be applied alone or potentially in combination with classical anti-amyloid therapies.
Identification of genetic risk factors for late-onset Alzheimer’s disease that modulate microglia function provide exciting therapeutic opportunities. In this Review, Lewcock et al. discuss novel targets, including antibody-mediated stimulation of TREM2, a frontrunner among candidate therapeutic approaches.
Stress granules (SGs) are cytoplasmic foci that rapidly form when cells are exposed to stress. They transiently store mRNAs encoding house‐keeping proteins and allow the selective translation of ...stress‐response proteins (e.g. heat shock proteins). Besides mRNA, SGs contain RNA‐binding proteins, such as T cell internal antigen‐1 and poly(A)‐binding protein 1, which can serve as characteristic SG marker proteins. Recently, some of these SG marker proteins were found to label pathological TAR DNA binding protein of 43 kDa (TDP‐43)‐ or fused in sarcoma (FUS)‐positive cytoplasmic inclusions in patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. In addition, protein aggregates in other neurodegenerative diseases (e.g. tau inclusions in Alzheimer's disease) show a co‐localization with T cell internal antigen‐1 as well. Moreover, several RNA‐binding proteins that are commonly found in SGs have been genetically linked to neurodegeneration. This suggests that SGs might play an important role in the pathogenesis of these proteinopathies, either by acting as a seed for pathological inclusions, by mediating translational repression or by trapping essential RNA‐binding proteins, or by a combination of these mechanisms. This minireview gives an overview of the general biology of SGs and highlights the recently identified connection of SGs with TDP‐43, FUS and other proteins involved in neurodegenerative diseases. We propose that pathological inclusions containing RNA‐binding proteins, such as TDP‐43 and FUS, might arise from SGs and discuss how SGs might contribute to neurodegeneration via toxic gain or loss‐of‐function mechanisms.
Stress granules (SGs) are cytoplasmic particles transiently formed in stressed cells. Recently, SG marker proteins were identified to label characteristic TDP‐43‐ or FUS‐positive inclusions found in neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. This review provides an overview about SG biology in general and discusses the possible role of SGs in the pathogenesis of neurodegenerative diseases.
Neurons are critically dependent on mitochondrial integrity based on specific morphological, biochemical, and physiological features. They are characterized by high rates of metabolic activity and ...need to respond promptly to activity‐dependent fluctuations in bioenergetic demand. The dimensions and polarity of neurons require efficient transport of mitochondria to hot spots of energy consumption, such as presynaptic and postsynaptic sites. Moreover, the postmitotic state of neurons in combination with their exposure to intrinsic and extrinsic neuronal stress factors call for a high fidelity of mitochondrial quality control systems. Consequently, it is not surprising that mitochondrial alterations can promote neuronal dysfunction and degeneration. In particular, mitochondrial dysfunction has long been implicated in the etiopathogenesis of Parkinson's disease (PD), based on the observation that mitochondrial toxins can cause parkinsonism in humans and animal models. Substantial progress towards understanding the role of mitochondria in the disease process has been made by the identification and characterization of genes causing familial variants of PD. Studies on the function and dysfunction of these genes revealed that various aspects of mitochondrial biology appear to be affected in PD, comprising mitochondrial biogenesis, bioenergetics, dynamics, transport, and quality control.
Konstanze Winklhofer and colleagues review the various aspects of mitochondrial biology that is affected in Parkinson's disease including mitochondrial biogenesis, bioenergetics, dynamics, transport, and quality control.
Microglial research has advanced considerably in recent decades yet has been constrained by a rolling series of dichotomies such as “resting versus activated” and “M1 versus M2.” This dualistic ...classification of good or bad microglia is inconsistent with the wide repertoire of microglial states and functions in development, plasticity, aging, and diseases that were elucidated in recent years. New designations continuously arising in an attempt to describe the different microglial states, notably defined using transcriptomics and proteomics, may easily lead to a misleading, although unintentional, coupling of categories and functions. To address these issues, we assembled a group of multidisciplinary experts to discuss our current understanding of microglial states as a dynamic concept and the importance of addressing microglial function. Here, we provide a conceptual framework and recommendations on the use of microglial nomenclature for researchers, reviewers, and editors, which will serve as the foundations for a future white paper.
A group of multidisciplinary experts discusses the current understanding of microglial states as a dynamic concept and the importance of addressing microglial function. Conceptual framework and recommendations on microglial nomenclature are provided, serving as foundations for a future white paper.
Microglia play a pivotal role in the maintenance of brain homeostasis but lose homeostatic function during neurodegenerative disorders. We identified a specific apolipoprotein E (APOE)-dependent ...molecular signature in microglia from models of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Alzheimer’s disease (AD) and in microglia surrounding neuritic β-amyloid (Aβ)-plaques in the brains of people with AD. The APOE pathway mediated a switch from a homeostatic to a neurodegenerative microglia phenotype after phagocytosis of apoptotic neurons. TREM2 (triggering receptor expressed on myeloid cells 2) induced APOE signaling, and targeting the TREM2-APOE pathway restored the homeostatic signature of microglia in ALS and AD mouse models and prevented neuronal loss in an acute model of neurodegeneration. APOE-mediated neurodegenerative microglia had lost their tolerogenic function. Our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target that could aid in the restoration of homeostatic microglia.
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•Microglia associated with neuritic Aβ-plaques exhibit a neurodegenerative phenotype•Phagocytosis of apoptotic neurons suppresses homeostatic microglia•The TREM2-APOE pathway regulates neurodegenerative microglial phenotypic switch•Targeting APOE signaling restores homeostatic and tolerogenic microglia
Microglia change their phenotype and function during aging and neurodegeneration, but the underlying molecular mechanisms for this change remain unknown. Krasemann et al. identify the TREM2-APOE pathway as a major regulator of microglia phenotypic change in neurodegenerative diseases and suggest that targeting this pathway could restore homeostatic microglia.
J. Neurochem. (2011) 117, 779–796.
Regulated intramembrane proteolysis (RIP) controls the communication between cells and the extracellular environment. RIP is essential in the nervous system, but ...also in other tissues. In the RIP process, a membrane protein typically undergoes two consecutive cleavages. The first one results in the shedding of its ectodomain. The second one occurs within its transmembrane domain, resulting in secretion of a small peptide and the release of the intracellular domain into the cytosol. The proteolytic cleavage fragments act as versatile signaling molecules or are further degraded. An increasing number of membrane proteins undergo RIP. These include growth factors, cytokines, cell adhesion proteins, receptors, viral proteins and signal peptides. A dysregulation of RIP is found in diseases, such as leukemia and Alzheimer’s disease. One of the first RIP substrates discovered was the amyloid precursor protein (APP). RIP processing of APP controls the generation of the amyloid β‐peptide, which is believed to cause Alzheimer’s disease. Focusing on APP as the best‐studied RIP substrate, this review describes the function and mechanism of the APP RIP proteases with the goal to elucidate cellular mechanisms and common principles of the RIP process in general.
Alzheimer′s disease (AD) is characterized by deposition of amyloid plaques, neurofibrillary tangles, and neuroinflammation. In order to study microglial contribution to amyloid plaque phagocytosis, ...we developed a novel ex vivo model by co‐culturing organotypic brain slices from up to 20‐month‐old, amyloid‐bearing AD mouse model (APPPS1) and young, neonatal wild‐type (WT) mice. Surprisingly, co‐culturing resulted in proliferation, recruitment, and clustering of old microglial cells around amyloid plaques and clearance of the plaque halo. Depletion of either old or young microglial cells prevented amyloid plaque clearance, indicating a synergistic effect of both populations. Exposing old microglial cells to conditioned media of young microglia or addition of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) was sufficient to induce microglial proliferation and reduce amyloid plaque size. Our data suggest that microglial dysfunction in AD may be reversible and their phagocytic ability can be modulated to limit amyloid accumulation. This novel ex vivo model provides a valuable system for identification, screening, and testing of compounds aimed to therapeutically reinforce microglial phagocytosis.
Synopsis
Phagocytic function of aged microglial cells in amyloid plaque‐bearing tissue is not irreversibly impaired, but can be restored through factors secreted by young microglia. Microglia function in Aβ clearance and reducing the amyloid burden highlights the need for development of therapeutic approaches modulating microglial activity.
A novel ex vivo co‐culture model for amyloid plaque clearance by microglia is established.
Enhanced amyloid clearance and reduced plaque size occurs upon co‐culturing young WT and old APPPS1 brain slices or exposure of old microglia to conditioned media of young microglia or GM‐CSF.
Factors secreted by young microglia stimulate proliferation of old microglia, which is a pre‐requisite for enhanced clearance of the plaque halo.
Impaired phagocytic function of aged microglia can be rescued via GM‐CSF secretion from co‐cultured young microglia in amyloid‐bearing organotypic tissue.
Coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with late-onset Alzheimer's disease (AD). We demonstrate that amyloid plaque seeding is increased in the ...absence of functional Trem2. Increased seeding is accompanied by decreased microglial clustering around newly seeded plaques and reduced plaque-associated apolipoprotein E (ApoE). Reduced ApoE deposition in plaques is also observed in brains of AD patients carrying TREM2 coding variants. Proteomic analyses and microglia depletion experiments revealed microglia as one origin of plaque-associated ApoE. Longitudinal amyloid small animal positron emission tomography demonstrates accelerated amyloidogenesis in Trem2 loss-of-function mutants at early stages, which progressed at a lower rate with aging. These findings suggest that in the absence of functional Trem2, early amyloidogenesis is accelerated due to reduced phagocytic clearance of amyloid seeds despite reduced plaque-associated ApoE.
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