TMEM119 (transmembrane protein 119) and Microglia

TMEM119 is a type I transmembrane protein that serves as a marker for resting homeostatic microglia in the central nervous system.

TMEM119 helps distinguish microglia from circulating macrophages, facilitating the study of microglial roles in neurodegenerative diseases.

P2RY12 serves as a specific marker for homeostatic microglia, along with TMEM119. It plays a crucial role in mediating chemotaxis and the extension of microglial processes toward sites of injury. Both P2RY12 and TMEM119 are exclusively expressed in microglia, distinguishing them from Iba1, CD11b, CX3CR1, and F4/80, which are also found in blood-derived macrophages.

TMEM119 is being studied for its role in binding to and clearing amyloid-beta (Aβ), a protein associated with pathology in AD.

TMEM119 enhances microglial phagocytosis of Aβ by recruiting the low-density lipoprotein receptor 1 (LRP1), promoting uptake and subsequent lysosomal degradation.

TMEM119 expression is, in general, reduced in disease-associated microglia (DAM), indicating a transition from homeostatic to reactive states. This expression has been observed in multiple sclerosis (MS), traumatic brain injury, and stroke.

TMEM119 may have pro-tumorigenic functions, as its expression is elevated in various cancers, such as osteosarcoma, ovarian cancer, and breast cancer.

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Acute Lesion: an area of brain tissue that shows damage from injury or disease. During an acute MS lesion, the active demyelination driven by inflammation is visible on T1-weighted MR images.

Alzheimer's Disease: a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral changes. It is associated with the accumulation of amyloid-beta plaques and tau tangles in the brain, and loss of neurons and synapses in the cerebral cortex and subcortical regions.

Amyloid-Beta (Aβ): a peptide derived from the amyloid precursor protein (APP) that can aggregate to form plaques.

Biomarker: a measurable indicator of a biological state or condition. Biomarkers are often used in medicine and research to detect or monitor the presence, progress, or severity of a disease, as well as to assess the effectiveness of a treatment.

Blood-Brain Barrier (BBB) Permeability: BBB is a highly selective semipermeable layer of endothelial cells between the circulatory system and the brain. This layer forms a barrier that protects the brain from harmful or unwanted substances in the blood. Increased BBB permeability can result from neurological diseases and traumatic injuries and can be visible with gadolinium scans. Increased BBB permeability is a key factor in MS lesion formation, allowing immune cells to enter the brain and cause inflammation.

Cerebrospinal Fluid (CSF): an ultrafiltrate of plasma contained within the ventricles of the brain and the subarachnoid spaces of the brain and spinal cord.

Cognitive Impairment: a decline in cognitive function, including memory, thinking, and reasoning skills.

Disease-Associated Microglia (DAM): a subset of microglia with a specific transcriptional signature – conserved in human and mice – thought to play an important role in neurodegenerative disorders. Originally discovered in AD, but also appear to be present in other neurodegenerative diseases (Deczkowska, 2018). Whether they are more accurately described as one signature across diseases or distinct signatures in distinct diseases is still under investigation (Paolicelli, 2022).

Experimental Autoimmune Encephalomyelitis (EAE): a commonly used autoimmune-mediated model of multiple sclerosis (MS) induced by CD4+ T cells specific for myelin-derived antigens, and characterized by paralysis resulting from inflammation, demyelination, axonal injury, and neurodegeneration in the central nervous system (CNS).

Immunofluorescence (IF): a method similar to immunohistochemistry that uses fluorescently-labeled antibodies to detect specific antigens in tissue samples.

Immunohistochemistry (IHC): a laboratory technique to rapidly identify specific proteins in cells and tissues. IHC capitalizes on the ability of antibodies to target specific proteins, and then utilizes a sandwich of secondary antibodies and detection reagents to identify and localize the protein of interest in tissue sections at the microscopic level.

Lysosome: a membrane-bound degradative organelle in eukaryotic cells, responsible for digesting lipids, proteins, and other macromolecules.

Microglia: one of the neuroglial cell types present in the brain and spinal cord. Constituting approximately 10-15% of the total cellular population in the brain, microglial cells function as the primary immune cells of the central nervous system. These cells are essential for maintaining homeostasis, clearing cellular debris, and providing critical support functions within the brain.

Multiple Sclerosis (MS): the most commonly demyelinating disease of the central nervous system (CNS); MS is an immune-mediated disease, involving T cell, B cells, microglia, and macrophages, and characterized by inflammation, demyelination, axonal injury, and neurodegeneration.

Neurodegeneration: a complex, multifactorial process resulting in the loss of neurons.

Neuroinflammation: an inflammatory response within the central nervous system (CNS), primarily involving the activation of microglia and astrocytes. This process can be triggered by various factors, including infections, traumatic brain injury, toxic metabolites, and autoimmune diseases.  

Oligodendrocyte: one of the neuroglial cell types present in the brain and spinal cord. Constituting approximately 20-40% of all glial cells, oligodendrocytes represent approximately 10-20% of all brain cells. Oligodendrocytes are the cells that produce and maintenance the myelin sheath. A single oligodendrocyte will extend its processes to multiple axons, and ensheathing multiple segments with the protective myelin layers.

Reactive Microglia: microglia that are responding to or reacting to a particular condition. The name was proposed by Paolicelli et al. (Paolicelli, 2022) in lieu of the discouraged term “activated” microglia, emphasizing that microglia can have many different “reactive states” in health and disease.

Transmembrane Protein 119 (TMEM119): a type I transmembrane protein recognized as a marker of resting homeostatic microglia in the CNS. TMEM119 helps distinguish microglia from circulating macrophages, facilitating the study of microglial roles in neurodegenerative diseases.

Triggering Receptor Expressed on Myeloid Cells 2 (TREM2): a type-I transmembrane glycoprotein and innate immune receptor found on microglia in the central nervous system and other myeloid cells like dendritic cells and granulocytes. It is part of the TREM superfamily and is encoded by the TREM2 gene.