The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within ...

The Microbiota-Gut-Brain Axis

Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and frontotemporal lobar dementia are among the most pressing problems of developed societies with aging populations. Neurons carry out essential functions such as signal transmission and network integration in the central nervous system and are the main targets of neurodegenerative disease. In this Review, I address how the neuron’s environment also contributes to neurodegeneration. Maintaining an optimal milieu for neuronal function rests with supportive cells termed glia and the blood-brain barrier. Accumulating evidence suggests that neurodegeneration occurs in part because the environment is affected during disease in a cascade of processes collectively termed neuroinflammation. These observations indicate that therapies targeting glial cells might provide benefit for those afflicted by neurodegenerative disorders.

https://science.sciencemag.org/content/sci/353/6301/777.full.pdf

How neuroinflammation contributes to neurodegeneration.

Microglia and non-parenchymal macrophages in the brain are mononuclear phagocytes that are increasingly recognized to be essential players in the development, homeostasis and diseases of the central nervous system. With the availability of new genetic, molecular and pharmacological tools, considerable advances have been made towards our understanding of the embryonic origins, developmental programmes and functions of these cells. These exciting discoveries, some of which are still controversial, also raise many new questions, which makes brain macrophage biology a fast-growing field at the intersection of neuroscience and immunology. Here, we review the current knowledge of how and where brain macrophages are generated, with a focus on parenchymal microglia. We also discuss their normal functions during development and homeostasis, the disturbance of which may lead to various neurodegenerative and neuropsychiatric diseases.

Microglia and macrophages in brain homeostasis and disease

Proliferation and activation of microglia in the brain, concentrated around amyloid plaques, is a prominent feature of Alzheimer’s disease (AD). Human genetics data point to a key role for microglia in the pathogenesis of AD. The majority of risk genes for AD are highly expressed (and many are selectively expressed) by microglia in the brain. There is mounting evidence that microglia protect against the incidence of AD, as impaired microglial activities and altered microglial responses to β-amyloid are associated with increased AD risk. On the other hand, there is also abundant evidence that activated microglia can be harmful to neurons. Microglia can mediate synapse loss by engulfment of synapses, likely via a complement-dependent mechanism; they can also exacerbate tau pathology and secrete inflammatory factors that can injure neurons directly or via activation of neurotoxic astrocytes. Gene expression profiles indicate multiple states of microglial activation in neurodegenerative disease settings, which might explain the disparate roles of microglia in the development and progression of AD pathology.

/pdf/microglia-in-alzheimer-s-disease-4edri8sjir.pdf

Microglia in Alzheimer's disease.

There has been an explosion of new findings recently giving us insights into the involvement of microglia in central nervous system (CNS) disorders. A host of new molecular tools and mouse models of disease are increasingly implicating this enigmatic type of nervous system cell as a key player in conditions ranging from neurodevelopmental disorders such as autism to neurodegenerative disorders such as Alzheimer's disease and chronic pain. Contemporaneously, diverse roles are emerging for microglia in the healthy brain, from sculpting developing neuronal circuits to guiding learning-associated plasticity. Understanding the physiological functions of these cells is crucial to determining their roles in disease. Here we focus on recent developments in our rapidly expanding understanding of the function, as well as the dysfunction, of microglia in disorders of the CNS.

Microglia emerge as central players in brain disease.

https://escholarship.org/content/qt7vs838vd/qt7vs838vd.pdf

Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation.

Autosomal dominant mutations of the RNA/DNA binding protein FUS are linked to familial amyotrophic lateral sclerosis (FALS); however, it is not clear how FUS mutations cause neurodegeneration. Using transgenic mice expressing a common FALS-associated FUS mutation (FUS-R521C mice), we found that mutant FUS proteins formed a stable complex with WT FUS proteins and interfered with the normal interactions between FUS and histone deacetylase 1 (HDAC1). Consequently, FUS-R521C mice exhibited evidence of DNA damage as well as profound dendritic and synaptic phenotypes in brain and spinal cord. To provide insights into these defects, we screened neural genes for nucleotide oxidation and identified brain-derived neurotrophic factor (Bdnf) as a target of FUS-R521C–associated DNA damage and RNA splicing defects in mice. Compared with WT FUS, mutant FUS-R521C proteins formed a more stable complex with Bdnf RNA in electrophoretic mobility shift assays. Stabilization of the FUS/Bdnf RNA complex contributed to Bdnf splicing defects and impaired BDNF signaling through receptor TrkB. Exogenous BDNF only partially restored dendrite phenotype in FUS-R521C neurons, suggesting that BDNF-independent mechanisms may contribute to the defects in these neurons. Indeed, RNA-seq analyses of FUS-R521C spinal cords revealed additional transcription and splicing defects in genes that regulate dendritic growth and synaptic functions. Together, our results provide insight into how gain-of-function FUS mutations affect critical neuronal functions.

/pdf/als-associated-mutation-fus-r521c-causes-dna-damage-and-rna-w7xjsi9p8n.pdf

ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects

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Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation.

ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects