TREM2, Microglia and Neuroinflammation

Triggering receptor expressed on myeloid cells 2 (TREM2) is a type-I transmembrane glycoprotein that acts as an innate immune receptor primarily found on microglia (in the CNS) and other myeloid cells.

TREM2 is involved in sensing damage, promoting microglial survival and proliferation, facilitating phagocytosis, regulating inflammation, and modulating the transition to disease-associated microglia (DAM).

TREM2 functions as a sensor for a variety of ligands, including components derived from bacteria, phospholipids, glycolipids, APOE, APOJ, amyloid-beta oligomers, and TDP-43.

sTREM2 is a form of TREM2 released into the extracellular space via proteolytic cleavage or alternative splicing and serves as a biomarker for microglial activation and neuroinflammation.

A biallelic mutation in the TREM2 gene can lead to Nasu-Hakola disease, which is a rare autosomal recessive disease characterized by bone cysts, early-onset dementia and significant neurological decline.

Various types of heterozygous mutations in TREM2 (such as R47H, R62H, and H157Y) are associated with an increased risk of late-onset AD by impairing microglial activation and dysregulating the inflammatory response.

Preclinical studies have shown that TREM2 agonist antibodies can increase microglial proliferation, improve plaque compaction, and enhance brain glucose metabolism. Clinical studies using TREM2 agonists on patients with AD are currently ongoing.

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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.

Amyotrophic Lateral Sclerosis (ALS): also known as Lou Gehrig's disease, it is the most common form of motor neuron disease and affects the upper and lower motor neurons. This fatal neuromuscular disease is characterized by progressive weakness of the muscles required to move, speak, eat, and breathe.

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.

Cytokine: a protein that serves as a signaling molecule among immune system cells. Cytokines are classified into interleukins, interferons, tumour necrosis factors (TNF), chemokines, colony-stimulating factors, and transforming growth factors. Depending on their role in the immune response, cytokines can be categorized as pro-inflammatory or anti-inflammatory.

Demyelination: a destructive process that causes damage to the myelin sheath that surrounds axons. In the central nervous system, the myelin sheath protects nerves in the brain, spinal cord and optic nerves. When this myelin sheath is damaged, the ability of the nerve to conduct electrical impulses slow or even stop.

Diffuse Plaque: a subtype of amyloid-beta plaque that lack a compact fibrillar structure and are often associated with cases without cognitive impairment.

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).

Frontotemporal Dementia (FTD): a group of neurodegenerative disorders characterized by progressive damage to the frontal and/or temporal lobes of the brain. This damage leads to a variety of symptoms that can include changes in personality, behavior, and language abilities. FTD is distinct from other types of dementia, such as Alzheimer's disease, in that it often affects younger individuals (typically between the ages of 45 and 65) and presents with early and prominent changes in social behavior, executive function, and language, rather than memory loss. The three main subtypes of FTD are behavioral variant FTD (bvFTD), non-fluent variant primary progressive aphasia (nfvPPA), and semantic variant primary progressive aphasia (svPPA).

Genetic Risk: the likelihood that an individual carries a particular disease-associated mutation or is affected by a specific genetic disorder.

Immune-mediated Inflammation: describes the condition where the inflammatory pathways of the immune system drive inflammation. Within the brain, immune-mediated inflammation includes cellular infiltration (T cells, B cells, and macrophages) as well as activation of proinflammatory cytokines. In MS, the immune-mediated inflammation targets myelin, contributing to lesion formation.

Lewy Bodies: large deposits of alpha-synuclein that accumulate within neurons. These clumps are hallmark of Parkinson’s disease.

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.

Myelin: a mixture of phospholipids and proteins that forms a concentric wrapped structure to ensheath an axon. Its primary function is to insulate the axon and enhance the speed and efficiency of electrical signal transmission.

Neuritic Plaque: an amyloid plaque containing dystrophic neurites (degenerating axons and dendrites).

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

Neurofibrillary Tangles: abnormal accumulations of tau inside neurons. In healthy neurons, tau proteins help stabilize the structure of microtubules, in certain neurodegenerative conditions, such as Alzheimer's disease, tau proteins become hyperphosphorylated, causing them to clump together and form twisted, thread-like structures known as tangles. 

Parkinson's Disease (PD): a neurodegenerative disease that is characterized by: (a) movement-related (motor) symptoms, including resting tremor, bradykinesia, rigidity, and postural instability, related to the loss of dopaminergic neurons in the substantia nigra; and (b) non-motor symptoms including anxiety, depression, apathy, hallucinations, constipation, orthostatic hypotension, sleep disorders, hyposmia/anosmia, and cognitive impairment.

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.

Synapse: a junction allowing communication between neurons or neurons and muscles.

Tau: a protein that plays a crucial role in maintaining the stability and function of neurons in the brain. It is predominantly found in neurons, where it stabilizes microtubules, which are part of the cell's cytoskeleton. Microtubules are essential for maintaining cell shape, enabling intracellular transport, and facilitating cellular division. Hyperphosphorylation of tau is evident in various neurodegenerative diseases, where the abnormally phosphorylated molecules lead to the detachment of tau from the microtubules. These detached tau proteins can aggregate to form insoluble fibrils, known as neurofibrillary tangles. Diseases impacted by tau aggregation are called tauopathies, and include Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia (FTD), and corticobasal degeneration.

Transactive response DNA binding Protein of 43 kDa (TDP-43): a highly conserved nuclear RNA/DNA-binding protein encoded by the TARDBP gene involved in the regulation of RNA processing.

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.

Tyrosine: an amino acid that can be obtained through the diet or produced in the body from phenylalanine.