Translational regulation and protein-coding capacity of the 5' untranslated region of human TREM2.

TREM2 is a transmembrane receptor expressed in microglia and macrophages. Elevated TREM2 levels in these cells are associated with age-related pathological conditions, including Alzheimer's disease. However, the regulatory mechanism underlying the protein expression of TREM2 remains unclear.

Alzheimer's Disease-Associated Alternative Splicing of Is Regulated by the HNRNPA Family Proteins.

Genetic variations of have been implicated as a susceptibility factor of Alzheimer's disease (AD). A polymorphism on exon 2 of , rs12459419, affects the alternative splicing of this exon. The minor allele is associated with a reduced risk of AD and promotes the skipping of exon 2 to produce a shorter CD33 isoform lacking the extracellular ligand-binding domain, leading to decreased suppressive signaling on microglial activity.

Reactive astrocytes express Aggregatin () in the brains of Alzheimer's disease and Nasu-Hakola disease.

By combining genomic data and brain imaging data, a recent study has identified a novel gene named that participates in the formation of amyloid-β (Aβ) plaques and brain atrophy in Alzheimer's disease (AD). encodes a 47-kDa protein designated Aggregatin that accumulates in the center of amyloid plaques and physically interacts with Aβ to facilitate Aβ aggregation. Aggregatin is expressed predominantly in the central nervous system (CNS) and its levels are increased in brains of the patients with AD and in mouse models of AD.

CELF2 regulates the species-specific alternative splicing of TREM2.

Genetic variations of TREM2 have been implicated as a risk factor of Alzheimer's disease (AD). Recent studies suggest that the loss of TREM2 function compromises microglial responses to the accumulation of amyloid beta. Previously, we found that exon 3 of TREM2 is an alternative exon whose skipping leads to a reduction in full-length TREM2 protein by inducing nonsense-mediated mRNA decay.

Microglia express TMEM119 in the brains of Nasu-Hakola disease.

We previously identified an evolutionarily conserved protein named transmembrane protein 119 (TMEM119) as the most reliable maker for human microglia. Recent studies showed that under homeostatic conditions, microglia intensely express TMEM119, whereas the expression levels are greatly reduced in disease-associated microglia (DAM) activated at the site of neurodegeneration. Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder, pathologically characterized by leukoencephalopathy, astrogliosis, axonal spheroids, and accumulation of microglia.

Microglia express GPNMB in the brains of Alzheimer's disease and Nasu-Hakola disease.

Glycoprotein non-metastatic melanoma protein B (GPNMB) is a type I transmembrane glycoprotein first identified in low-metastatic human melanoma cell lines as a regulator of tumor growth. GPNMB is widely expressed in various tissues, where it is involved in cell differentiation, migration, inflammation/anti-inflammation, tissue regeneration, and neuroprotection. GPNMB is identified in microglia of adult rat brains, neurons and astrocytes of GPNMB transgenic (Tg) mouse brains, and motor neurons of amyotrophic lateral sclerosis (ALS) patients.

Microglia express gamma-interferon-inducible lysosomal thiol reductase in the brains of Alzheimer's disease and Nasu-Hakola disease.

Gamma-interferon-inducible lysosomal thiol reductase (GILT), expressed in antigen-presenting cells (APCs), facilitates the reduction of disulfide bonds of endocytosed proteins in the endocytic pathway and they are further processed for presentation of immunogenic peptides loaded on major histocompatibility complex (MHC) class II. Although the constitutive and IFNγ-inducible expression of GILT was observed in various APCs, such as dendritic cells, monocytes/macrophages, and B cells, GILT-expressing cell types remain unknown in the human central nervous system (CNS). Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder characterized by sclerosing leukoencephalopathy and multifocal bone cysts, caused by a loss-of-function mutation of either () or , both of which are expressed on microglia.

Small nuclear RNA-mediated modulation of splicing reveals a therapeutic strategy for a TREM2 mutation and its post-transcriptional regulation.

Loss-of-function mutations in TREM2 cause Nasu-Hakola disease (NHD), a rare genetic disease characterized by early-onset dementia with leukoencephalopathy and bone cysts. An NHD-associated mutation, c.482 + 2 T > C, disrupts the splice donor site of intron 3 and causes aberrant skipping of exon 3, resulting in the loss of full-length TREM2 protein.

Alzheimer's disease pathology in Nasu-Hakola disease brains.

Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder, characterized by progressive presenile dementia and formation of multifocal bone cysts, caused by genetic mutations of either triggering receptor expressed on myeloid cells 2 () or TYRO protein tyrosine kinase binding protein (), alternatively named DNAX-activation protein 12 (), both of which are expressed on microglia in the brain and form the receptor-adaptor complex that chiefly recognizes anionic lipids. TREM2 transmits the signals involved in microglial survival, proliferation, chemotaxis, and phagocytosis. A recent study indicated that a loss of TREM2 function causes greater amounts of amyloid-β (Aβ) deposition in the hippocampus of a mouse model of Alzheimer's disease (AD) owing to a dysfunctional response of microglia to amyloid plaques, suggesting that TREM2 facilitates Aβ clearance by microglia.

Microglia express ABI3 in the brains of Alzheimer's disease and Nasu-Hakola disease.

Nasu-Hakola disease (NHD) is a rare autosomal recessive leukoencephalopathy caused by a loss-of-function mutation of either () or expressed in microglia. A rare variant of the gene encoding p.Arg47His causes a 3-fold increase in the risk for late-onset Alzheimer's disease (LOAD).

Expression of GPR17, a regulator of oligodendrocyte differentiation and maturation, in Nasu-Hakola disease brains.

The G protein-coupled receptor 17 (GPR17), a Gi-coupled GPCR, acts as an intrinsic timer of oligodendrocyte differentiation and myelination. The expression of GPR17 is upregulated during differentiation of oligodendrocyte precursor cells (OPCs) into premyelinating oligodendrocytes (preoligodendrocytes), whereas it is markedly downregulated during terminal maturation of myelinating oligodendrocytes. Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder caused by a loss-of-function mutation of either () or .

Expression of gp91phox and p22phox, catalytic subunits of NADPH oxidase, on microglia in Nasu-Hakola disease brains.

The superoxide-producing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex of phagocytes (phox) plays a key role in production of reactive oxygen species (ROS) by microglia. The catalytic subunits of the NADPH oxidase are composed of p22phox and gp91phox. Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder caused by a loss-of-function mutation of either () or .

Targeted sequencing approach to identify genetic mutations in Nasu-Hakola disease.

Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder characterized by sclerosing leukoencephalopathy and multifocal bone cysts, caused by a loss-of-function mutation of either or . TREM2 and DAP12 constitute a receptor/adaptor signaling complex expressed exclusively on osteoclasts, dendritic cells, macrophages, and microglia. Premortem molecular diagnosis of NHD requires genetic analysis of both and , in which 20 distinct NHD-causing mutations have been reported.