scholarly journals The Role of Complement in Synaptic Pruning and Neurodegeneration

2021 ◽  
Vol Volume 10 ◽  
pp. 373-386
Author(s):  
Angela Gomez-Arboledas ◽  
Munjal M Acharya ◽  
Andrea J Tenner
Keyword(s):  
Synaptic Pruning

scholarly journals Loss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xin Ding ◽  
Jin Wang ◽  
Miaoxin Huang ◽  
Zhangpeng Chen ◽  
Jing Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Knock Out ◽  
Classical Complement Pathway ◽  
Synaptic Remodeling ◽  
The Central Nervous System ◽  
System Activation ◽  
Knock Out Mice ◽  
Synaptic Pruning

AbstractMicroglia play a key role in regulating synaptic remodeling in the central nervous system. Activation of classical complement pathway promotes microglia-mediated synaptic pruning during development and disease. CD47 protects synapses from excessive pruning during development, implicating microglial SIRPα, a CD47 receptor, in synaptic remodeling. However, the role of microglial SIRPα in synaptic pruning in disease remains unclear. Here, using conditional knock-out mice, we show that microglia-specific deletion of SIRPα results in decreased synaptic density. In human tissue, we observe that microglial SIRPα expression declines alongside the progression of Alzheimer’s disease. To investigate the role of SIRPα in neurodegeneration, we modulate the expression of microglial SIRPα in mouse models of Alzheimer’s disease. Loss of microglial SIRPα results in increased synaptic loss mediated by microglia engulfment and enhanced cognitive impairment. Together, these results suggest that microglial SIRPα regulates synaptic pruning in neurodegeneration.

scholarly journals Synaptic Elimination in Neurological Disorders

2019 ◽  
Vol 17 (11) ◽  
pp. 1071-1095 ◽  
Author(s):  
Pablo L. Cardozo ◽  
Izabella B. Q. de Lima ◽  
Esther M.A. Maciel ◽  
Nathália C. Silva ◽  
Tomas Dobransky ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Animal Models ◽  
Neurological Disorders ◽  
Brain Regions ◽  
Complement Cascade ◽  
Complement Proteins ◽  
Complement Component 3 ◽  
Synaptic Pruning ◽  
Classical Complement

Synapses are well known as the main structures responsible for transmitting information through the release and recognition of neurotransmitters by pre- and post-synaptic neurons. These structures are widely formed and eliminated throughout the whole lifespan via processes termed synaptogenesis and synaptic pruning, respectively. Whilst the first process is needed for ensuring proper connectivity between brain regions and also with the periphery, the second phenomenon is important for their refinement by eliminating weaker and unnecessary synapses and, at the same time, maintaining and favoring the stronger ones, thus ensuring proper synaptic transmission. It is well-known that synaptic elimination is modulated by neuronal activity. However, only recently the role of the classical complement cascade in promoting this phenomenon has been demonstrated. Specifically, microglial cells recognize activated complement component 3 (C3) bound to synapses targeted for elimination, triggering their engulfment. As this is a highly relevant process for adequate neuronal functioning, disruptions or exacerbations in synaptic pruning could lead to severe circuitry alterations that could underlie neuropathological alterations typical of neurological and neuropsychiatric disorders. In this review, we focus on discussing the possible involvement of excessive synaptic elimination in Alzheimer’s disease, as it has already been reported dendritic spine loss in post-synaptic neurons, increased association of complement proteins with its synapses and, hence, augmented microglia-mediated pruning in animal models of this disorder. In addition, we briefly discuss how this phenomenon could be related to other neurological disorders, including multiple sclerosis and schizophrenia.

scholarly journals Microglial Dysregulation in OCD, Tourette Syndrome, and PANDAS

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Luciana Frick ◽  
Christopher Pittenger
Keyword(s):  
Tourette Syndrome ◽  
Potential Role ◽  
Neuronal Damage ◽  
Immune Dysregulation ◽  
Streptococcal Infections ◽  
Obsessive Compulsive ◽  
Compulsive Disorder ◽  
Inflammatory Activation ◽  
Synaptic Pruning

There is accumulating evidence that immune dysregulation contributes to the pathophysiology of obsessive-compulsive disorder (OCD), Tourette syndrome, and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). The mechanistic details of this pathophysiology, however, remain unclear. Here we focus on one particular component of the immune system: microglia, the brain’s resident immune cells. The role of microglia in neurodegenerative diseases has been understood in terms of classic, inflammatory activation, which may be both a consequence and a cause of neuronal damage. In OCD and Tourette syndrome, which are not characterized by frank neural degeneration, the potential role of microglial dysregulation is much less clear. Here we review the evidence for a neuroinflammatory etiology and microglial dysregulation in OCD, Tourette syndrome, and PANDAS. We also explore new hypotheses as to the potential contributions of microglial abnormalities to pathophysiology, beyond neuroinflammation, including failures in neuroprotection, lack of support for neuronal survival, and abnormalities in synaptic pruning. Recent advances in neuroimaging and animal model work are creating new opportunities to elucidate these issues.

Microglia in development: linking brain wiring to brain environment

2011 ◽  
Vol 7 (1) ◽  
pp. 77-83 ◽  
Author(s):  
Rosa C. Paolicelli ◽  
Cornelius T. Gross
Keyword(s):  
Resting State ◽  
Brain Connectivity ◽  
Neuronal Cells ◽  
Imaging Studies ◽  
The Brain ◽  
Synaptic Pruning

Microglia are enigmatic non-neuronal cells that infiltrate and take up residence in the brain during development and are thought to perform a surveillance function. An established literature has documented how microglia are activated by pathogenic stimuli and how they contribute to and resolve injuries to the brain. However, much less work has been aimed at understanding their function in the uninjured brain. A series of recent in vivo imaging studies shows that microglia in their resting state are highly motile and actively survey their neuronal surroundings. Furthermore, new data suggest that microglia in their resting state are able to phagocytose unwanted synapses and in this way contribute to synaptic pruning and maturation during development. Coupled with their exquisite sensitivity to pathogenic stimuli, these data suggest that microglia form a link that couples changes in brain environment to changes in brain wiring. Here we discuss this hypothesis and propose a model for the role of microglia during development in sculpting brain connectivity.

scholarly journals Novel Monoclonal Antibodies Against Mouse C1q: Characterisation and Development of a Quantitative ELISA for Mouse C1q

2021 ◽  
Author(s):  
Robert A. J. Byrne ◽  
Megan Torvell ◽  
Nikoleta Daskoulidou ◽  
Dina Fathalla ◽  
Eirini Kokkali ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Biological Fluids ◽  
Rodent Models ◽  
Wild Type ◽  
Disease Biomarker ◽  
Tissue Extracts ◽  
Deficient Mice ◽  
Synaptic Pruning ◽  
Detection And Quantification

AbstractRecent studies have identified roles for complement in synaptic pruning, both physiological during development and pathological in Alzheimer’s disease (AD). These reports suggest that C1q initiates complement activation on synapses and C3 fragments then tag them for removal by microglia. There is an urgent need to characterise these processes in rodent AD models; this requires the development of reagents and methods for detection and quantification of rodent C1q in fluids and pathological tissues. These will enable better evaluation of the role of C1q in disease and its value as disease biomarker. We describe the generation in C1q-deficient mice of novel monoclonal antibodies against mouse and rat C1q that enabled development of a sensitive, specific, and quantitative ELISA for mouse and rat C1q capable of measuring C1q in biological fluids and tissue extracts. Serum C1q levels were measured in wild-type (WT), C1q knockout (KO), C3 KO, C7 KO, Crry KO, and 3xTg and APPNL-G-F AD model mice through ageing. C1q levels significantly decreased in WT, APPNL-G-F, and C7 KO mice with ageing. C1q levels were reduced in APPNL-G-F compared to WT at all ages and in 3xTg at 12 months; C3 KO and C7 KO, but not Crry KO mice, also demonstrated significantly lower C1q levels compared to matched WT. In brain homogenates, C1q levels increased with age in both WT and APPNL-G-F mice. This robust and adaptable assay for quantification of mouse and rat C1q provides a vital tool for investigating the expression of C1q in rodent models of AD and other complement-driven pathologies.

scholarly journals Synaptic Pruning in Alzheimer’s Disease: Role of the Complement System

2020 ◽  
pp. 1-20
Author(s):  
Frederic H. Brucato ◽  
Daniel E. Benjamin
Keyword(s):  
Health Care ◽  
Health Care Systems ◽  
Symptomatic Treatment ◽  
Human Beings ◽  
The World ◽  
Care Systems ◽  
The Complement System ◽  
Primary Risk Factor ◽  
Synaptic Pruning

Alz heimer’s disease (AD) continues to threaten aged individuals and health care systems around the world. Human beings have been trying to postpone, reduce, or eliminate the primary risk factor for AD, aging, throughout history. Despite this, there is currently only symptomatic treatment for AD and this treatment is limited to only a handful of FDA approved AD drugs.

scholarly journals Critical Role of TLR4 on the Microglia Activation Induced by Maternal LPS Exposure Leading to ASD-Like Behavior of Offspring

2021 ◽  
Vol 9 ◽  
Author(s):  
Lu Xiao ◽  
Junyan Yan ◽  
Di Feng ◽  
Shasha Ye ◽  
Ting Yang ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Frontal Cortex ◽  
Litter Size ◽  
Fetal Brain ◽  
Spine Density ◽  
Dendritic Length ◽  
Related Proteins ◽  
Lps Treatment ◽  
Synaptic Pruning

Objective: To investigate the role of TLR4 on the microglia activation in the pre-frontal cortex, which leads to autism-like behavior of the offspring induced by maternal lipopolysaccharide (LPS) exposure.Methods: Pregnant TLR4−/− (knockout, KO) and WT (wild type, WT) dams were intraperitoneally injected with LPS or PBS, respectively. The levels of TNFα, IL-1β, and IL-6 in the maternal serum and fetal brain were assessed with ELISA following LPS exposure. The gestation period, litter size and weight of the offspring were evaluated. Three-chamber sociability test, open field test and olfactory habituation/dishabituation test were used to assess the offspring's autism-like behavior at 7 weeks of age. Western blotting was performed to examine the levels of TLR4, Phospho-NFκB p65, IKKα, IBA-1, iNOS, Arg-1, C3, CR3A, NMDAR2A, and Syn-1 expression in the pre-frontal cortex. The morphological changes in the microglia, the distribution and expression of TLR4 were observed by immunofluorescence staining. Golgi-Cox staining was conducted to evaluate the dendritic length and spine density of the neurons in 2-week-old offspring.Results: Maternal LPS stimulation increased serum TNFα and IL-6, as well as fetal brain TNFα in the WT mice. The litter size and the weight of the WT offspring were significantly reduced following maternal LPS treatment. LPS-treated WT offspring had lower social and self-exploration behavior, and greater anxiety and repetitive behaviors. The protein expression levels of TLR4 signaling pathways, including TLR4, Phospho-NFκB p65, IKKα, and IBA-1, iNOS expression were increased in the LPS-treated WT offspring, whereas Arg-1 was decreased. Maternal LPS treatment resulted in the significant reduction in the levels of the synaptic pruning-related proteins, C3 and CR3A. Moreover, the neuronal dendritic length and spine density, as well as the expression levels of the synaptic plasticity-related proteins, NMDAR2A and Syn-1 were reduced in the WT offspring; however, gestational LPS exposure had no effect on the TLR4−/− offspring.Conclusion: Activation of TLR4 signaling pathway following maternal LPS exposure induced the abnormal activation of microglia, which in turn was involved in excessive synaptic pruning to decrease synaptic plasticity in the offspring. This may be one of the reasons for the autism-like behavior in the offspring mice.

scholarly journals The role of polypeptide compounds in mechanism of CNS plasticity in patients with hereditary pathology of peripheral motor neuron

2017 ◽  
Vol 63 (5) ◽  
pp. 453-456 ◽  
Author(s):  
M.G. Sokolova ◽  
S.V. Lobzin ◽  
V.A. Penniyaynen ◽  
A.V. Kipenko ◽  
E.V. Lopatina ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Physiological Mechanism ◽  
Axon Growth ◽  
Nerve Tissue ◽  
Tissue Cultures ◽  
Inhibition Effect ◽  
Peripheral Motor ◽  
Organotypic Tissue ◽  
Synaptic Pruning

Synaptic pruning is a physiological mechanism of neuroplasticity, which is regulated through synthesis of growth polypeptides, neurotrophins. The role of neurotrophins in the mechanism of synaptic pruning in patients with hereditary pathology of peripheral motor neuron was studied in a clinical experimental trial. It was found that patients had elevated levels of regulatory growth polypeptides, which led to the axon growth inhibition effect in organotypic tissue cultures. Thus, neurotrophin overexpression can be considered as a factor preventing synaptic pruning and contributing to further process of neurological degeneration in nerve tissue in patients with hereditary pathology of peripheral motor neuron.

scholarly journals Microglia complement signaling promotes neuronal elimination and normal brain functional connectivity

2021 ◽  
Author(s):  
Senthilkumar Deivasigamani ◽  
Mariya Timotey Miteva ◽  
Silvia Natale ◽  
Daniel Gutierrez-Barragan ◽  
Bernadette Basilico ◽  
...  
Keyword(s):  
Functional Connectivity ◽  
Cortical Thickness ◽  
Complement Receptor ◽  
Normal Brain ◽  
Synaptic Remodeling ◽  
Mouse Cortex ◽  
Brain Functional Connectivity ◽  
The Brain ◽  
Synaptic Pruning

Complement signaling is thought to serve as an opsonization signal to promote the phagocytosis of synapses by microglia. However, while its role in synaptic remodeling has been demonstrated in the retino-thalamic system, it remains unclear whether complement signaling mediates synaptic pruning in the brain more generally. Here we show that mice lacking the complement 3 receptor (C3r), the major microglia complement receptor, fail to show a deficit in either synaptic pruning or axon elimination in the developing mouse cortex. Instead, mice lacking C3r show a deficit in the perinatal elimination of neurons, both in the retina as well as in the cortex, a deficit that is associated with increased cortical thickness and enhanced functional connectivity in these regions in adulthood. These data demonstrate a preferential role for complement in promoting neuronal elimination in the developing brain and argue for a reconsideration of the role of complement in synaptic pruning.

scholarly journals Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia

2020 ◽  
Author(s):  
Nicole Scott-Hewitt ◽  
Fabio Perrucci ◽  
Raffaella Morini ◽  
Marco Erreni ◽  
Matthew Mahoney ◽  
...  
Keyword(s):  
Synapse Formation ◽  
Annexin V ◽  
Brain Structures ◽  
Synapse Elimination ◽  
Developmentally Regulated ◽  
Molecular Components ◽  
Established Role ◽  
Synaptic Pruning

AbstractNeuronal circuits assembly requires the fine equilibrium between synapse formation and elimination. Microglia, through the elimination of supernumerary synapses, have an established role in this process. While the microglial receptor TREM2 and the soluble complement proteins C1q and C3 are recognized key players in this process, the neuronal molecular components that tag synapses to be eliminated are still undefined. Here we show that exposed phosphatidylserine (PS) represents a neuronal ‘eat-me’ signal enabling microglial-mediated synapse pruning. In hippocampal neuron and microglia co-cultures, synapse elimination can be prevented by blocking accessibility of exposed PS using Annexin V or through microglial loss of TREM2. In vivo, exposed PS is detectable at both hippocampal and retinogeniculate synapses, where exposure coincides with the onset of synapse elimination and increased PS engulfment by microglia. Mice deficient in C1q, which fail to properly refine retinogeniculate connections, display elevated exposed PS and reduced PS engulfment by microglia. These data provide mechanistic insight into microglial-mediated synapse pruning and identify a novel role of developmentally regulated PS exposure that is common among developing brain structures.

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