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.

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.

A microglial cell is both a glial cell of the central nervous system and a mononuclear phagocyte, which belongs to the haematopoietic system and is involved in inflammatory and immune responses. As such, microglia face a challenging task. The neurons of the central nervous system cannot divide and be replenished, and therefore need to be protected against pathogens, which is a key role of the immune system, but without collateral damage. In addition, after physical injury, neural cells need restorative support, which is provided by inflammatory responses. Excessive or chronic inflammatory responses can, however, be harmful. How microglia balance these demands, and how their behaviour can be modified to ameliorate disorders of the central nervous system, is becoming clear.

The myeloid cells of the central nervous system parenchyma.

Microglia are the resident brain macrophages and they have been traditionally studied as orchestrators of the brain inflammatory response during infections and disease In addition, microglia has a more benign, less explored role as the brain professional phagocytes Phagocytosis is a term coined from the Greek to describe the receptor-mediated engulfment and degradation of dead cells and microbes In addition, microglia phagocytoses brain-specific cargo, such as axonal and myelin debris in spinal cord injury or multiple sclerosis, amyloid-β deposits in Alzheimer's disease, and supernumerary synapses in postnatal development Common mechanisms of recognition, engulfment, and degradation of the different types of cargo are assumed, but very little is known about the shared and specific molecules involved in the phagocytosis of each target by microglia More importantly, the functional consequences of microglial phagocytosis remain largely unexplored Overall, phagocytosis is considered a beneficial phenomenon, since it eliminates dead cells and induces an anti-inflammatory response However, phagocytosis can also activate the respiratory burst, which produces toxic reactive oxygen species (ROS) Phagocytosis has been traditionally studied in pathological conditions, leading to the assumption that microglia have to be activated in order to become efficient phagocytes Recent data, however, has shown that unchallenged microglia phagocytose apoptotic cells during development and in adult neurogenic niches, suggesting an overlooked role in brain remodeling throughout the normal lifespan The present review will summarize the current state of the literature regarding the role of microglial phagocytosis in maintaining tissue homeostasis in health as in disease

/pdf/janus-faced-microglia-beneficial-and-detrimental-id6ywmrpl7.pdf

Janus-faced microglia: beneficial and detrimental consequences of microglial phagocytosis

Objective To identify new genes and risk factors associated with frontotemporal dementia (FTD). Several genes and loci have been associated with different forms of FTD, but a large number of families with dementia do not harbor mutations in these genes. Design Whole-exome sequencing and whole-genome genotyping were performed in all patients. Genetic variants obtained from whole-exome sequencing were integrated with the data obtained from whole-genome genotyping. Setting Database of the Behavioral Neurology Outpatient Clinic of the Department of Neurology, Istanbul Faculty of Medicine, Istanbul, Turkey. Patients Forty-four Turkish patients with an FTD-like clinical diagnosis were included in the study. Relatives were screened when appropriate. Main Outcome Measure Mutations in the triggering receptor expressed on myeloid cells 2 gene (TREM2). Results In 3 probands with FTD-like disease, we identified different homozygous mutations in TREM2 that had previously been associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). None of these 3 patients had a typical clinical presentation of PLOSL: they presented with behavioral change and subsequent cognitive impairment and motor features but without any bone cysts or bone-associated phenotypes. Imaging showed white matter abnormalities as well as frontal atrophy in all 3 patients. Conclusions Our results show that TREM2 is responsible for an unexpectedly high number of dementia cases in our cohort, suggesting that this gene should be taken into account when mutations in other dementia genes are excluded. Even for complex syndromes such as dementia, exome sequencing has proven to be a rapid and cost-effective tool to identify genetic mutations, allowing for the association of clinical phenotypes with unexpected molecular underpinnings.

https://jamanetwork.com/journals/jamaneurology/articlepdf/1557588/noc120026_78_84.pdf

Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement.

The authors review the clinical, radiological, electrophysiological, pathological, and molecular aspects of Nasu–Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy or PLOSL). Nasu-Hakola disease is a unique disease characterized by multiple bone cysts associated with a peculiar form of neurodegeneration that leads to dementia and precocious death usually during the fifth decade of life. The diagnosis can be established on the basis of clinical and radiological findings. Recently, molecular analysis of affected families revealed mutations in the DAP12 (TYROBP) or TREM2 genes, providing an interesting example how mutations in two different subunits of a multi-subunit receptor complex result in an identical human disease phenotype. The association of PLOSL with mutations in the DAP12 or TREM2 genes has led to improved diagnosis of affected individuals. Also, the possible roles of the DAP12/TREM2 signaling pathway in microglia and osteoclasts in humans are just beginning to be elucidated. Some aspects of this peculiar signaling pathway are discussed here.

Nasu-Hakola Disease (Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy—PLOSL): A Dementia Associated with Bone Cystic Lesions. From Clinical to Genetic and Molecular Aspects

da Silva Júnior Jp

Papers

Nasu-Hakola Disease (Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy—PLOSL): A Dementia Associated with Bone Cystic Lesions. From Clinical to Genetic and Molecular Aspects