The Essential Role of Astrocytes in Neurodegeneration and Neuroprotection.

Astrocytes are glial cells that perform several fundamental physiological functions within the brain. They can control neuronal activity and levels of ions and neurotransmitters, and release several factors that modulate the brain environment. Over the past few decades, our knowledge of astrocytes and their functions has rapidly evolved. Neurodegenerative diseases are characterized by selective degeneration of neurons, increased glial activation, and glial dysfunction. Given the significant role played by astrocytes, there is growing interest in their potential therapeutic role. However, defining their contribution to neurodegeneration is more complex than was previously thought. This review summarizes the main functions of astrocytes and their involvement in neurodegenerative diseases, highlighting their neurotoxic and neuroprotective ability.

Genomic Mosaicism of the Brain: Origin, Impact, and Utility.

Genomic mosaicism describes the phenomenon where some but not all cells within a tissue harbor unique genetic mutations. Traditionally, research focused on the impact of genomic mosaicism on clinical phenotype-motivated by its involvement in cancers and overgrowth syndromes. More recently, we increasingly shifted towards the plethora of neutral mosaic variants that can act as recorders of cellular lineage and environmental exposures. Here, we summarize the current state of the field of genomic mosaicism research with a special emphasis on our current understanding of this phenomenon in brain development and homeostasis. Although the field of genomic mosaicism has a rich history, technological advances in the last decade have changed our approaches and greatly improved our knowledge. We will provide current definitions and an overview of contemporary detection approaches for genomic mosaicism. Finally, we will discuss the impact and utility of genomic mosaicism.

Nano-Plumber Reshapes Glymphatic-Lymphatic System to Sustain Microenvironment Homeostasis and Improve Long-Term Prognosis after Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Long-term changes in the microenvironment of the brain contribute to the degeneration of neurological function following TBI. However, current research focuses primarily on short-term modulation during the early phases of TBI, not on the critical significance of long-term homeostasis in the brain microenvironment. Notably, dysfunction of the glymphatic-lymphatic system results in the accumulation of danger/damage-associated molecular patterns (DAMPs) in the brain, which is regarded as the leading cause of long-term microenvironmental disturbances following TBI. Here, a nanostructure, Nano-plumber, that co-encapsulates the microenvironment regulator pro-DHA and the lymphatic-specific growth factor VEGF-C is developed, allowing for a sustainable and orderly regulation of the microenvironment to promote long-term neurological recovery. Nano-plumber reverses the injury microenvironment by suppressing microglia and astrocytes activation and maintaining reduced activation via enhanced glymphatic-lymphatic drainage, and significantly improves the neurological function of rodents with TBI. This study demonstrates that glymphatic-lymphatic system reconstruction is essential for enhancing long-term prognosis following TBI, and that the Nano-plumber developed here may serve as a clinically translatable treatment option for TBI.

Emerging non-proinflammatory roles of microglia in healthy and diseased brains.

Microglia, the resident myeloid cells of the central nervous system, are the first line of defense against foreign pathogens, thereby confining the extent of brain injury. However, the role of microglia is not limited to macrophage-like functions. In addition to proinflammatory response mediation, microglia are involved in neurodevelopmental remodeling and homeostatic maintenance in the absence of disease. An increasing number of studies have also elucidated microglia-mediated regulation of tumor growth and neural repair in diseased brains. Here, we review the non-proinflammatory roles of microglia, with the aim of promoting a deeper understanding of the functions of microglia in healthy and diseased brains and contributing to the development of novel therapeutics that target microglia in neurological disorders.

Sirtuins promote brain homeostasis, preventing Alzheimer's disease through targeting neuroinflammation.

Both basic pathomechanisms underlying Alzheimer's disease and some premises for stipulating a possible preventive role of some sirtuins, especially SIRT1 and SIRT3, protective against Alzheimer's disease-related pathology, are discussed in this article. Sirtuins can inhibit some processes that underlie Alzheimer's disease-related molecular pathology (e.g., neuroinflammation, neuroinflammation-related oxidative stress, Aß aggregate deposition, and neurofibrillary tangle formation), thus preventing many of those pathologic alterations at relatively early stages of their development. Subsequently, the authors discuss in details which mechanisms of sirtuin action may prevent the development of Alzheimer's disease, thus promoting brain homeostasis in the course of aging. In addition, a rationale for boosting sirtuin activity, both with allosteric activators and with NAD+ precursors, has been presented.

The synaptic lipidome in health and disease.

Adequate homeostasis of lipid, protein and carbohydrate metabolism is essential for cells to perform highly specific tasks in our organism, and the brain, with its uniquely high energetic requirements, posesses singular characteristics. Some of these are related to its extraordinary dotation of synapses, the specialized subcelluar structures where signal transmission between neurons occurs in the central nervous system. The post-synaptic compartment of excitatory synapses, the dendritic spine, harbors key molecules involved in neurotransmission tightly packed within a minute volume of a few femtoliters. The spine is further compartmentalized into nanodomains that facilitate the execution of temporo-spatially separate functions in the synapse. Lipids play important roles in this structural and functional compartmentalization and in mechanisms that impact on synaptic transmission. This review analyzes the structural and dynamic processes involving lipids at the synapse, highlighting the importance of their homeostatic balance for the physiology of this complex and highly specialized structure, and underscoring the pathologies associated with disbalances of lipid metabolism, particularly in the perinatal and late adulthood periods of life. Although small variations of the lipid profile in the brain take place throughout the adult lifespan, the pathophysiological consequences are clinically manifested mostly during late adulthood. Disturbances in lipid homeostasis in the perinatal period leads to alterations during nervous system development, while in late adulthood they favor the occurrence of neurodegenerative diseases.

Dynamic expression of homeostatic ion channels in differentiated cortical astrocytes in vitro.

The capacity of astrocytes to adapt their biochemical and functional features upon physiological and pathological stimuli is a fundamental property at the basis of their ability to regulate the homeostasis of the central nervous system (CNS). It is well known that in primary cultured astrocytes, the expression of plasma membrane ion channels and transporters involved in homeostatic tasks does not closely reflect the pattern observed in vivo. The individuation of culture conditions that promote the expression of the ion channel array found in vivo is crucial when aiming at investigating the mechanisms underlying their dynamics upon various physiological and pathological stimuli. A chemically defined medium containing growth factors and hormones (G5) was previously shown to induce the growth, differentiation, and maturation of primary cultured astrocytes. Here we report that under these culture conditions, rat cortical astrocytes undergo robust morphological changes acquiring a multi-branched phenotype, which develops gradually during the 2-week period of culturing. The shape changes were paralleled by variations in passive membrane properties and background conductance owing to the differential temporal development of inwardly rectifying chloride (Cl-) and potassium (K+) currents. Confocal and immunoblot analyses showed that morphologically differentiated astrocytes displayed a large increase in the expression of the inward rectifier Cl- and K+ channels ClC-2 and Kir4.1, respectively, which are relevant ion channels in vivo. Finally, they exhibited a large diminution of the intermediate filaments glial fibrillary acidic protein (GFAP) and vimentin which are upregulated in reactive astrocytes in vivo. Taken together the data indicate that long-term culturing of cortical astrocytes in this chemical-defined medium promotes a quiescent functional phenotype. This culture model could aid to address the regulation of ion channel expression involved in CNS homeostasis in response to physiological and pathological challenges.

Transcriptional and epigenetic regulation of microglia in maintenance of brain homeostasis and neurodegeneration.

The emerging role of microglia in brain homeostasis, neurodegeneration, and neurodevelopmental disorders has attracted considerable interest. In addition, recent developments in microglial functions and associated pathways have shed new light on their fundamental role in the immunological surveillance of the brain. Understanding the interconnections between microglia, neurons, and non-neuronal cells have opened up additional avenues for research in this evolving field. Furthermore, the study of microglia at the transcriptional and epigenetic levels has enhanced our knowledge of these native brain immune cells. Moreover, exploring various facets of microglia biology will facilitate the early detection, treatment, and management of neurological disorders. Consequently, the present review aimed to provide comprehensive insight on microglia biology and its influence on brain development, homeostasis, management of disease, and highlights microglia as potential therapeutic targets in neurodegenerative and neurodevelopmental diseases.

Single Cell Transcriptomics of Ependymal Cells Across Age, Region and Species Reveals Cilia-Related and Metal Ion Regulatory Roles as Major Conserved Ependymal Cell Functions.

Ependymal cells are ciliated-epithelial glial cells that develop from radial glia along the surface of the ventricles of the brain and the spinal canal. They play a critical role in cerebrospinal fluid (CSF) homeostasis, brain metabolism, and the clearance of waste from the brain. These cells have been implicated in disease across the lifespan including developmental disorders, cancer, and neurodegenerative disease. Despite this, ependymal cells remain largely understudied. Using single-cell RNA sequencing data extracted from publicly available datasets, we make key findings regarding the remarkable conservation of ependymal cell gene signatures across age, region, and species. Through this unbiased analysis, we have discovered that one of the most overrepresented ependymal cell functions that we observed relates to a critically understudied role in metal ion homeostasis. Our analysis also revealed distinct subtypes and states of ependymal cells across regions and ages of the nervous system. For example, neonatal ependymal cells maintained a gene signature consistent with developmental processes such as determination of left/right symmetry; while adult ventricular ependymal cells, not spinal canal ependymal cells, appeared to express genes involved in regulating cellular transport and inflammation. Together, these findings highlight underappreciated functions of ependymal cells, which will be important to investigate in order to better understand these cells in health and disease.

Functional Weight of Somatic and Cognitive Networks and Asymmetry of Compensatory Mechanisms: Collaboration or Divergency among Hemispheres after Cerebrovascular Accident?

The human brain holds highly sophisticated compensatory mechanisms relying on neuroplasticity. Neuronal degeneracy, redundancy, and brain network organization make the human nervous system more robust and evolvable to continuously guarantee an optimal environmental-related homeostasis. Nevertheless, after injury, restitution processes appear dissimilar, depending on the pathology. Following a cerebrovascular accident, asymmetry, within- and across-network compensation and interhemispheric inhibition are key features to functional recovery. In moderate-to-severe stroke, neurological outcome is often poor, and little is known about the paths that enable either an efficient collaboration among hemispheres or, on the contrary, an antagonism of adaptative responses. In this review, we aim to decipher key issues of ipsilesional and contralesional hemispheric functioning allowing the foundations of effective neurorehabilitation strategies.

TREM2, microglia, and Alzheimer's disease.

Triggering receptor expressed on myeloid cells 2 (TREM2) has been suggested to play a crucial role in Alzheimer's disease (AD) pathogenesis, as revealed by genome-wide association studies (GWAS). Since then, rapidly increasing literature related to TREM2 has focused on elucidating its role in AD pathology. In this review, we summarize our understanding of TREM2 biology, explore TREM2 functions in microglia, address the multiple mechanisms of TREM2 in AD, and raise key questions for further investigations to elucidate the detailed roles and molecular mechanisms of TREM2 in microglial responses. A major breakthrough in our understanding of TREM2 is based on our hypothesis suggesting that TREM2 may act as a multifaceted player in microglial functions in AD brain homeostasis. We conclude that TREM2 can not only influence microglial functions in amyloid and tau pathologies but also participate in inflammatory responses and metabolism, acting alone or with other molecules, such as apolipoprotein E (APOE). This review provides novel insight into the broad role of TREM2 in microglial function in AD and enables us to develop new strategies aimed at the immune system to treat AD pathogenesis.

Plasma biomarkers of astrocytic and neuronal dysfunction in early- and late-onset Alzheimer's disease.

INTRODUCTION: We investigated plasma proteomic markers of astrocytopathy, brain degeneration, plasticity, and inflammation in sporadic early-onset versus late-onset Alzheimer's disease (EOAD and LOAD). METHODS: Plasma was analyzed using ultra-sensitive immuno-based assays from 33 EOAD, 30 LOAD, and 36 functionally normal older adults. RESULTS: Principle component analyses identified 3 factors: trophic (BDNF, VEGF, TGFß), degenerative (GFAP, NfL), and inflammatory (TNFα, IL-6, IP-10, IL-10). Trophic factor was elevated in both AD groups and associated with cognition and gray matter volumes. Degenerative factor was elevated in EOAD, with higher levels associated with worse functioning in this group. Biomarkers of inflammation were not significantly different between groups and were only associated with age. DISUCSSION: Plasma proteomic biomarkers provide novel means of investigating molecular processes in vivo and their contributions to clinical outcomes. We present initial investigations of several of these fluid biomarkers, capturing aspects of astrocytopathy, neuronal injury, cellular plasticity, and inflammation in EOAD versus LOAD.

AGO CLIP Reveals an Activated Network for Acute Regulation of Brain Glutamate Homeostasis in Ischemic Stroke.

Post-transcriptional regulation by microRNAs (miRNAs) is essential for complex molecular responses to physiological insult and disease. Although many disease-associated miRNAs are known, their global targets and culminating network effects on pathophysiology remain poorly understood. We applied Argonaute (AGO) crosslinking immunoprecipitation (CLIP) to systematically elucidate altered miRNA-target interactions in brain following ischemia and reperfusion (I/R) injury. Among 1,190 interactions identified, the most prominent was the cumulative loss of target regulation by miR-29 family members. Integration of translational and time-course RNA profiles revealed a dynamic mode of miR-29 target de-regulation, led by acute translational activation and a later increase in RNA levels, allowing rapid proteomic changes to take effect. These functional regulatory events rely on canonical and non-canonical miR-29 binding and engage glutamate reuptake signals, such as glial glutamate transporter (GLT-1), to control local glutamate levels. These results uncover a miRNA target network that acts acutely to maintain brain homeostasis after ischemic stroke.

Glutathione Conjugation at the Blood-CSF Barrier Efficiently Prevents Exposure of the Developing Brain Fluid Environment to Blood-Borne Reactive Electrophilic Substances.

Exposure of the developing brain to toxins, drugs, or deleterious endogenous compounds during the perinatal period can trigger alterations in cell division, migration, differentiation, and synaptogenesis, leading to lifelong neurological impairment. The brain is protected by cellular barriers acting through multiple mechanisms, some of which are still poorly explored. We used a combination of enzymatic assays, live tissue fluorescence microscopy, and an in vitro cellular model of the blood-CSF barrier to investigate an enzymatic detoxification pathway in the developing male and female rat brain. We show that during the early postnatal period the choroid plexus epithelium forming the blood-CSF barrier and the ependymal cell layer bordering the ventricles harbor a high detoxifying capacity that involves glutathione S-transferases. Using a functional knock-down rat model for choroidal glutathione conjugation, we demonstrate that already in neonates, this metabolic pathway efficiently prevents the penetration of blood-borne reactive compounds into CSF. The versatility of the protective mechanism results from the multiplicity of the glutathione S-transferase isoenzymes, which are differently expressed between the choroidal epithelium and the ependyma. The various isoenzymes display differential substrate specificities, which greatly widen the spectrum of molecules that can be inactivated by this pathway. In conclusion, the blood-CSF barrier and the ependyma are identified as key cellular structures in the CNS to protect the brain fluid environment from different chemical classes of potentially toxic compounds during the postnatal period. This metabolic neuroprotective function of brain interfaces ought to compensate for the liver postnatal immaturity.SIGNIFICANCE STATEMENT Brain homeostasis requires a stable and controlled internal environment. Defective brain protection during the perinatal period can lead to lifelong neurological impairment. We demonstrate that the choroid plexus forming the blood-CSF barrier is a key player in the protection of the developing brain. Glutathione-dependent enzymatic metabolism in the choroidal epithelium inactivates a broad spectrum of noxious compounds, efficiently preventing their penetration into the CSF. A second line of detoxification is located in the ependyma separating the CSF from brain tissue. Our study reveals a novel facet of the mechanisms by which the brain is protected at a period of high vulnerability, at a time when the astrocytic network is still immature and liver xenobiotic metabolism is limited.

Impact of Metabolic Syndrome on Neuroinflammation and the Blood-Brain Barrier.

Metabolic syndrome, which includes diabetes and obesity, is one of the most widespread medical conditions. It induces systemic inflammation, causing far reaching effects on the body that are still being uncovered. Neuropathologies triggered by metabolic syndrome often result from increased permeability of the blood-brain-barrier (BBB). The BBB, a system designed to restrict entry of toxins, immune cells, and pathogens to the brain, is vital for proper neuronal function. Local and systemic inflammation induced by obesity or type 2 diabetes mellitus can cause BBB breakdown, decreased removal of waste, and increased infiltration of immune cells. This leads to disruption of glial and neuronal cells, causing hormonal dysregulation, increased immune sensitivity, or cognitive impairment depending on the affected brain region. Inflammatory effects of metabolic syndrome have been linked to neurodegenerative diseases. In this review, we discuss the effects of obesity and diabetes-induced inflammation on the BBB, the roles played by leptin and insulin resistance, as well as BBB changes occurring at the molecular level. We explore signaling pathways including VEGF, HIFs, PKC, Rho/ROCK, eNOS, and miRNAs. Finally, we discuss the broader implications of neural inflammation, including its connection to Alzheimer's disease, multiple sclerosis, and the gut microbiome.

In vivo Differential Brain Clearance and Catabolism of Monomeric and Oligomeric Alzheimer's Aß protein.

Amyloid ß (Aß) is the major constituent of the brain deposits found in parenchymal plaques and cerebral blood vessels of patients with Alzheimer's disease (AD). Several lines of investigation support the notion that synaptic pathology, one of the strongest correlates to cognitive impairment, is related to the progressive accumulation of neurotoxic Aß oligomers. Since the process of oligomerization/fibrillization is concentration-dependent, it is highly reliant on the homeostatic mechanisms that regulate the steady state levels of Aß influencing the delicate balance between rate of synthesis, dynamics of aggregation, and clearance kinetics. Emerging new data suggest that reduced Aß clearance, particularly in the aging brain, plays a critical role in the process of amyloid formation and AD pathogenesis. Using well-defined monomeric and low molecular mass oligomeric Aß1-40 species stereotaxically injected into the brain of C57BL/6 wild-type mice in combination with biochemical and mass spectrometric analyses in CSF, our data clearly demonstrate that Aß physiologic removal is extremely fast and involves local proteolytic degradation leading to the generation of heterogeneous C-terminally cleaved proteolytic products, while providing clear indication of the detrimental role of oligomerization for brain Aß efflux. Immunofluorescence confocal microscopy studies provide insight into the cellular pathways involved in the brain removal and cellular uptake of Aß. The findings indicate that clearance from brain interstitial fluid follows local and systemic paths and that in addition to the blood-brain barrier, local enzymatic degradation and the bulk flow transport through the choroid plexus into the CSF play significant roles. Our studies highlight the diverse factors influencing brain clearance and the participation of various routes of elimination opening up new research opportunities for the understanding of altered mechanisms triggering AD pathology and for the potential design of combined therapeutic strategies.

Corrigendum: Versatility of the complement system in neuroinflammation, neurodegeneration, and brain homeostasis.

[This corrects the article on p. 380 in vol. 8, PMID: 25426028.].

Versatility of the complement system in neuroinflammation, neurodegeneration and brain homeostasis.

The immune response after brain injury is highly complex and involves both local and systemic events at the cellular and molecular level. It is associated to a dramatic over-activation of enzyme systems, the expression of proinflammatory genes and the activation/recruitment of immune cells. The complement system represents a powerful component of the innate immunity and is highly involved in the inflammatory response. Complement components are synthesized predominantly by the liver and circulate in the bloodstream primed for activation. Moreover, brain cells can produce complement proteins and receptors. After acute brain injury, the rapid and uncontrolled activation of the complement leads to massive release of inflammatory anaphylatoxins, recruitment of cells to the injury site, phagocytosis and induction of blood brain barrier (BBB) damage. Brain endothelial cells are particularly susceptible to complement-mediated effects, since they are exposed to both circulating and locally synthesized complement proteins. Conversely, during neurodegenerative disorders, complement factors play distinct roles depending on the stage and degree of neuropathology. In addition to the deleterious role of the complement, increasing evidence suggest that it may also play a role in normal nervous system development (wiring the brain) and adulthood (either maintaining brain homeostasis or supporting regeneration after brain injury). This article represents a compendium of the current knowledge on the complement role in the brain, prompting a novel view that complement activation can result in either protective or detrimental effects in brain conditions that depend exquisitely on the nature, the timing and the degree of the stimuli that induce its activation. A deeper understanding of the acute, subacute and chronic consequences of complement activation is needed and may lead to new therapeutic strategies, including the ability of targeting selective step in the complement cascade.