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The Role of TREM2 in Alzheimer's Disease and Other Neurological Disorders.

Yaghmoor F, Noorsaeed A, Alsaggaf S, Aljohani W, Scholtzova H, Boutajangout A, Wisniewski T - J Alzheimers Dis Parkinsonism (2014)

Bottom Line: Several risk factors have been discovered that are associated with AD, with advancing age being the most prominent.Recently, rare variants of TREM2 have been reported as a significant risk factor for LOAD, comparable to inheritance of apoE4.In this review we will focus on the role(s) of TREM2 in AD as well as in other neurodegenerative disorders.

View Article: PubMed Central - PubMed

Affiliation: Departments of Neurology, New York University School of Medicine, Alexandria ERSP, 450 East 29th Street, New York, NY 10016, USA.

ABSTRACT

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Late-onset AD (LOAD), is the most common form of Alzheimer's disease, representing about >95% of cases and early-onset AD represents <5% of cases. Several risk factors have been discovered that are associated with AD, with advancing age being the most prominent. Other environmental risk factors include diabetes mellitus, level of physical activity, educational status, hypertension and head injury. The most well known genetic risk factor for LOAD is inheritance of the apolipoprotein (apo) E4 allele. Recently, rare variants of TREM2 have been reported as a significant risk factor for LOAD, comparable to inheritance of apoE4. In this review we will focus on the role(s) of TREM2 in AD as well as in other neurodegenerative disorders.

No MeSH data available.


Related in: MedlinePlus

Normal and disease associated pathways of TREM2 activation.
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Figure 1: Normal and disease associated pathways of TREM2 activation.

Mentions: TREM2 is an innate immune receptor expressed on the cell surface of microglia, macrophages, osteoclasts and immature dendritic cells [12–14]. TREM2 has also been found on bronchial epithelial cells, fibroblasts, and lung adenocarcinoma cells. The TREM2 gene encodes 5 exons that code for a 693 pb DNA, located on chromosome 6p21.1, which is translated into 230 amino-acids [15–17]. The receptor is a variably glycosylated, single-pass type I membrane glycoprotein made up of an extracellular immunoglobulin-like domain, a transmembrane domain and a cytoplasmic tail, which associates with tyrosine kinase-binding protein (TYROBP, also known as DAP12), forming a receptor-signaling complex[18,19] (Figure 1). TREM2 is one of the highest expressed cell surface receptors on microglia and is >300 fold enriched in microglia versus astrocytes [20]. Microglia plays a key role in the immune response in the central nervous system (CNS) and is the resident innate immune cells responsible for the early control of infections. In the human brain, TREM2 is found at high concentrations in white matter, the hippocampus and the neocortex, but at very low concentrations in the cerebellum. These regions are consistent with the distribution of pathology in AD [14,18,21]. TREM2 was initially identified as a phagocytic receptor of bacteria [22]. TREM2 recognizes anionic lipopolysaccharide (LPS) in the cell wall of bacteria. When the bacteria bind to TREM2 on macrophages, activation of the signaling pathway triggers the phagocytic uptake of the bacteria and the release of reactive oxygen species [23]. Heat shock protein 60 (Hsp60) is a mitochondrial chaperone that has also been shown to be a TREM2 agonist when expressed on the surface of neuroblastoma cells or astrocytes [24]. The formation of amyloid plaques in an AD model has been shown to induce expression of TREM2, in particular among microglia in the outer zone of plaques, correlating with partial amyloid phagocytosis [25]. TREM2 expression also correlated positively with microglia being able to stimulate CD4+ T-cell proliferation, tumor necrosis factor, but not interferon γ; hence, potentially promoting neuroprotective “wound repair responses” [25]. TREM2 has also been shown to be involved in phagocytosis of apoptotic neurons, since down regulation of TREM2 or DAP12 in microglia reduces such phagocytosis, while over expression of TREM2 has the opposite effect [26]. Other pattern recognition receptors which have been shown to play an important part in macrophage/microglial function and have a role in AD related pathology are the Toll-like receptors (TLRs) [12,27–29]. TLRs interact with the TREM2/DAP12 on multiple levels; these interactions appear to be tissue and receptor specific [30,31].


The Role of TREM2 in Alzheimer's Disease and Other Neurological Disorders.

Yaghmoor F, Noorsaeed A, Alsaggaf S, Aljohani W, Scholtzova H, Boutajangout A, Wisniewski T - J Alzheimers Dis Parkinsonism (2014)

Normal and disease associated pathways of TREM2 activation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317331&req=5

Figure 1: Normal and disease associated pathways of TREM2 activation.
Mentions: TREM2 is an innate immune receptor expressed on the cell surface of microglia, macrophages, osteoclasts and immature dendritic cells [12–14]. TREM2 has also been found on bronchial epithelial cells, fibroblasts, and lung adenocarcinoma cells. The TREM2 gene encodes 5 exons that code for a 693 pb DNA, located on chromosome 6p21.1, which is translated into 230 amino-acids [15–17]. The receptor is a variably glycosylated, single-pass type I membrane glycoprotein made up of an extracellular immunoglobulin-like domain, a transmembrane domain and a cytoplasmic tail, which associates with tyrosine kinase-binding protein (TYROBP, also known as DAP12), forming a receptor-signaling complex[18,19] (Figure 1). TREM2 is one of the highest expressed cell surface receptors on microglia and is >300 fold enriched in microglia versus astrocytes [20]. Microglia plays a key role in the immune response in the central nervous system (CNS) and is the resident innate immune cells responsible for the early control of infections. In the human brain, TREM2 is found at high concentrations in white matter, the hippocampus and the neocortex, but at very low concentrations in the cerebellum. These regions are consistent with the distribution of pathology in AD [14,18,21]. TREM2 was initially identified as a phagocytic receptor of bacteria [22]. TREM2 recognizes anionic lipopolysaccharide (LPS) in the cell wall of bacteria. When the bacteria bind to TREM2 on macrophages, activation of the signaling pathway triggers the phagocytic uptake of the bacteria and the release of reactive oxygen species [23]. Heat shock protein 60 (Hsp60) is a mitochondrial chaperone that has also been shown to be a TREM2 agonist when expressed on the surface of neuroblastoma cells or astrocytes [24]. The formation of amyloid plaques in an AD model has been shown to induce expression of TREM2, in particular among microglia in the outer zone of plaques, correlating with partial amyloid phagocytosis [25]. TREM2 expression also correlated positively with microglia being able to stimulate CD4+ T-cell proliferation, tumor necrosis factor, but not interferon γ; hence, potentially promoting neuroprotective “wound repair responses” [25]. TREM2 has also been shown to be involved in phagocytosis of apoptotic neurons, since down regulation of TREM2 or DAP12 in microglia reduces such phagocytosis, while over expression of TREM2 has the opposite effect [26]. Other pattern recognition receptors which have been shown to play an important part in macrophage/microglial function and have a role in AD related pathology are the Toll-like receptors (TLRs) [12,27–29]. TLRs interact with the TREM2/DAP12 on multiple levels; these interactions appear to be tissue and receptor specific [30,31].

Bottom Line: Several risk factors have been discovered that are associated with AD, with advancing age being the most prominent.Recently, rare variants of TREM2 have been reported as a significant risk factor for LOAD, comparable to inheritance of apoE4.In this review we will focus on the role(s) of TREM2 in AD as well as in other neurodegenerative disorders.

View Article: PubMed Central - PubMed

Affiliation: Departments of Neurology, New York University School of Medicine, Alexandria ERSP, 450 East 29th Street, New York, NY 10016, USA.

ABSTRACT

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Late-onset AD (LOAD), is the most common form of Alzheimer's disease, representing about >95% of cases and early-onset AD represents <5% of cases. Several risk factors have been discovered that are associated with AD, with advancing age being the most prominent. Other environmental risk factors include diabetes mellitus, level of physical activity, educational status, hypertension and head injury. The most well known genetic risk factor for LOAD is inheritance of the apolipoprotein (apo) E4 allele. Recently, rare variants of TREM2 have been reported as a significant risk factor for LOAD, comparable to inheritance of apoE4. In this review we will focus on the role(s) of TREM2 in AD as well as in other neurodegenerative disorders.

No MeSH data available.


Related in: MedlinePlus