TREM2
   HOME

TheInfoList



OR:

Triggering receptor expressed on myeloid cells 2 (TREM2) is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''TREM2''
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. TREM2 is expressed on macrophages, immature monocyte-derived dendritic cells, osteoclasts, and microglia, which are immune cells in the central nervous system. In the
liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
, TREM2 is expressed by several cell types, including macrophages, that respond to injury. In the intestine, TREM2 is expressed by myeloid-derived dendritic cells and macrophage. TREM2 is overexpressed in many tumor types and has anti-inflammatory activities. It might therefore be a good therapeutic target.


Gene

The
TREM2
' gene lies on the sixth chromosome in humans, specifically in location 6p21.1. The gene has 5 coding
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...
regions.
Alternative splicing Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...
of the ''TREM2''
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...
transcript leads to different
isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
of the protein being produced upon translation. Specifically, ''TREM2'' mRNA has 3 different isoforms containing 3 consistent exons, and 2 that vary between the isoforms. ''TREM2'' mRNA is most highly expressed in brain, lungs,
adrenal gland The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex which ...
s,
placenta The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mater ...
,
gall bladder In vertebrates, the gallbladder, also known as the cholecyst, is a small hollow organ where bile is stored and concentrated before it is released into the small intestine. In humans, the pear-shaped gallbladder lies beneath the liver, althoug ...
, and colon. The functions of TREM2 have been studied in mice with disruption or mutation of the mouse ortholog,
Trem2
'
''TREM2'' orthologs
are also present in rat, dog, Rhesus monkey, macaque, chimpanzee, and other animals.


Protein

The TREM2 receptor is a
transmembrane protein A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
that is made up of an extracellular region (also referred to as the ectodomain), the membrane-traversing segment, and an intracellular component. The extracellular component of TREM2 can bind different anionic ligands, specifically
glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
s and lipids. This ectodomain component includes an
Ig-like V-type domain The immunoglobulin superfamily (IgSF) is a large protein superfamily of cell surface and soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. Molecules are categorized as members of this superfamily ...
, where ligands bind the receptor. The TREM2 ectodomain is modified after protein translation; these modifications affect is affinity for different ligands. The intracellular component of TREM2 does not have any signaling ability on its own; rather, it signals via the DNAX activator proteins 10 and 12 (
DAP10 Hematopoietic cell signal transducer is a protein that in humans is encoded by the ''HCST'' gene. This gene encodes a transmembrane signaling adaptor that contains a YxxM motif in its cytoplasmic domain. The encoded protein may form part of the i ...
and
DAP12 TYRO protein tyrosine kinase-binding protein is an adapter protein that in humans is encoded by the ''TYROBP'' gene. Function This gene encodes a transmembrane signaling polypeptide which contains an immunoreceptor tyrosine-based activation mo ...
). A single TREM2 molecule can interact with DAP10 and DAP12 at the same time. Part of the ectodomain of TREM2 can be processed by enzymes (
ADAM10 A Disintegrin and metalloproteinase domain-containing protein 10, also known as ADAM10 or CDw156 or CD156c is a protein that in humans is encoded by the ''ADAM10'' gene. Function Members of the ADAM family are cell surface proteins with a uni ...
,
ADAM17 A disintegrin and metalloprotease 17 (ADAM17), also called TACE (''tumor necrosis factor-α-converting enzyme''), is a 70-kDa enzyme that belongs to the ADAM protein family of disintegrins and metalloproteases. Chemical characteristics ADAM17 ...
) and released as a soluble version, called soluble TREM2 (sTREM2). This protein fragment is released into the sera and cerebral spinal fluid ( CSF), and might serve as a biomarker for neurodegenerative and other disorders, but further studies are needed.


Function

The TREM2 protein is found in immune cells termed
myeloid cells A myelocyte is a young cell of the granulocytic series, occurring normally in bone marrow (can be found in circulating blood when caused by certain diseases). Structure When stained with the usual dyes, the cytoplasm is distinctly basophilic ...
, which include
macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
,
granulocyte Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear. They ha ...
s, monocytes, and dendritic cells. Monocyte-, macrophage-, and neutrophil-mediated inflammatory responses can be stimulated through
G protein G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their act ...
-linked 7-transmembrane receptors (e.g.,
FPR1 Formyl peptide receptor 1 (FPR1, FPR1 receptor, fMet-Leu-Phe receptor 1, FMLP receptor 1, or N-formylmethionyl-leucyl-phenylalanine receptor 1) is a cell surface receptor protein that in humans is encoded by the ''formyl peptide receptor 1'' (''F ...
), Fc receptors,
CD14 CD14 (cluster of differentiation 14) is a human protein made mostly by macrophages as part of the innate immune system. It helps to detect bacteria in the body by binding lipopolysaccharide (LPS), a pathogen-associated molecular pattern (PAMP). C ...
,
toll like receptor Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-pass membrane-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize s ...
s (such as
TLR4 Toll-like receptor 4 is a protein that in humans is encoded by the ''TLR4'' gene. TLR4 is a transmembrane protein, member of the toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. Its activation leads to an ...
), and cytokine receptors (e.g.,
IFNGR1 Interferon gamma receptor 1 (IFNGR1) also known as CD119 (Cluster of Differentiation 119), is a protein that in humans is encoded by the ''IFNGR1'' gene. Function The gene ''IFNGR1'' encodes IFN-γR1, which is the ligand-binding chain (alpha) o ...
). Engagement of these receptors can also prime myeloid cells to respond to other stimuli. Myeloid cells express receptors belonging to the immunoglobulin (Ig) superfamily, such as TREM2, or to the
C-type lectin A C-type lectin (CLEC) is a type of carbohydrate-binding protein known as a lectin. The C-type designation is from their requirement for calcium for binding. Proteins that contain C-type lectin domains have a diverse range of functions including ...
superfamily. On myeloid cells, TREM2 binds anionic molecules, free and bound to plasma membrane, including bacterial products, DNA, lipoproteins, phospholipids, glycoproteins, DNA, and bacterial fragments. TREM2 binding of ligand results in phosphorylation at 2 tyrosines in the
immunoreceptor tyrosine-based activation motif An immunoreceptor tyrosine-based activation motif (ITAM) is a conserved sequence of four amino acids that is repeated twice in the cytoplasmic tails of non-catalytic tyrosine-phosphorylated receptors, cell-surface proteins found mainly on immune cel ...
(ITAM) of DAP12 by SRC tyrosine kinases. Spleen tyrosine kinase (
Syk Tyrosine-protein kinase SYK, also known as spleen tyrosine kinase, is an enzyme which in humans is encoded by the ''SYK'' gene. Function SYK, along with ZAP70, is a member of the Syk family of tyrosine kinases. These cytoplasmic non-receptor t ...
) interacts with these phosphorylation sites and activates the phosphatidylinositol-3 kinase (
PI3K Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
) signaling pathway, as well as other signaling molecules such as
mTOR The mammalian target of sirolimus, rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''MT ...
,
MAPK A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
, and ERK. Association of TREM2 with DAP10 also activates the PI3K signaling pathway, leading to expression of transcription factors that include AP1,
NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
, and
NFAT Nuclear factor of activated T-cells (NFAT) is a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the developme ...
. The PI3K signaling pathway also increases intracellular calcium content, which activates calcium-dependent kinases. TREM2 activation also affects expression of GAL1, GAL3, IL1RN, and progranulin, which modulate the immune response. TREM2 is expressed by microglia and osteoclasts, and is involved in development and/or maintenance of brain and bone. In mice, TREM2 is involved in synaptic pruning, a process of shaping neuronal circuitry by microglia- and astrocyte-mediated removal of excessive synapses via phagocytosis. In brain, the highest levels of TREM2 are found in
hippocampus The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, a ...
,
white matter White matter refers to areas of the central nervous system (CNS) that are mainly made up of myelinated axons, also called tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distribution ...
, and the
spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spi ...
, and levels of TREM2 increase with age in humans and mice. TREM2 is also expressed by macrophages of adipose tissue, adrenal gland, and placenta. Immunosuppressive tumor-associated macrophages ( TAMs) have been characterized by expression of TREM2. TREM2 signaling leads to downregulated transcription of genes that promote inflammation (''Tnf, Il1b,'' and ''Nos2''), as well as release of cytokines that prevent activation of anti-tumor CD8+ T cells. TREM2+ immunosuppressive TAMs correlate with the level of exhausted
T cells A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell re ...
in the human
tumor microenvironment The tumor microenvironment (TME) is the environment around a tumor, including the surrounding blood vessels, immune cells, fibroblasts, signaling molecules and the extracellular matrix (ECM). The tumor and the surrounding microenvironment are cl ...
( TME). A TREM2+ TAM-rich TME therefore appears to be immune suppressive and might promote resistance to cancer therapies, such as checkpoint inhibitors. TREM2 signaling can antagonize TLR expression and signaling, resulting in reduced production of inflammatory cytokines by cultured mouse macrophages. Conversely, TREM2 expression is reduced following inflammatory signaling induction by
lipopolysaccharide Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer m ...
(a TLR4 ligand) or interferon gamma
IFNG
. The neuroprotective effects of TREM2 involve not only production of anti-inflammatory cytokines, but also clearance of abnormal proteins and phagocytosis of apoptotic neurons. In contrast to anti-inflammatory effects in brain and cancer, TREM2 signaling has been reported to contribute to intestinal inflammation and development of inflammatory bowel diseases (IBD). sTREM2 is believed to negatively regulate TREM2 signaling by acting as decoy receptors. sTREM might therefore have pro-inflammatory effects. sTREM2 has been indicated in activating signaling pathways such as PI3K and ERK through an unidentified receptor. Levels of sTREM2 are increased in CSF of patients with
Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
, and correlate with the CSF levels of disease biomarkers, such as t-tau and p-tau.


Association with diseases

TREM2 signaling has been associated with pathogenesis of several diseases. Variants of in the ''DAP12 (TYROBP)'' or ''TREM2'' genes have been associated with
polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy Nasu–Hakola disease also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy is a rare disease characterised by early-onset dementia and multifocal bone cysts. It is caused by autosomal recessive loss of functi ...
(PLOSL or Nasu–Hakola disease).


Alzheimer's disease

Variants of ''TREM2'' have been associated with neurodegenerative disorders, including
Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
. TREM2 is involved in the microglial response to the
amyloid plaque Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of micr ...
s that are characteristic of AD. Loss of TREM2 function reduces the responses of microglia to plaques, which then appear to take on a more toxic state. Expression of TREM2 is associated with that of
CD33 CD33 or Siglec-3 (sialic acid binding Ig-like lectin 3, SIGLEC3, SIGLEC-3, gp67, p67) is a transmembrane receptor expressed on cells of myeloid lineage. It is usually considered myeloid-specific, but it can also be found on some lymphoid cells. ...
. Zhong et al reported that, in mice, stereotactic injection of sTREM2 or adeno-associated virus-mediated activation of sTREM2 reduced the amyloid plaque load and reduced functional memory deficits. Moreover, sTREM2 stimulated microglial proliferation and homing toward amyloid plaques where amyloid-β uptake and degradation was increased. Interestingly, these effects were specifically mediated by microglia. Level of sTREM2 in the CSF might be a biomarker for Alzheimer's disease and the associated inflammatory response.


Cancer

Although TREM2 expression is low in most normal tissues, it is overexpressed in many human tumor types. An analysis of levels of ''TREM2'' mRNA in 33 cancer tissues from
The Cancer Genome Atlas ''The'' () is a grammatical article in English, denoting persons or things already mentioned, under discussion, implied or otherwise presumed familiar to listeners, readers, or speakers. It is the definite article in English. ''The'' is the m ...
(TCGA) indicate higher levels of expression in tumor vs normal tissues in 18 cancer types, including head and neck squamous cell carcinoma, colon adenocarcinoma, and
glioblastoma Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ch ...
, as well as gynecologic, liver, gastric, kidney, breast, bladder, and esophageal cancers. High expression of TREM2 was associated with shorter survival times of patients with
ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different c ...
,
gastric cancer Stomach cancer, also known as gastric cancer, is a cancer that develops from the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes, including gastric adenocarcinomas. Lymph ...
, lower-grade
glioma A glioma is a type of tumor that starts in the glial cells of the brain or the spine. Gliomas comprise about 30 percent of all brain tumors and central nervous system tumours, and 80 percent of all malignant brain tumours. Signs and symptoms ...
,
hepatocellular carcinoma Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide. It occurs in t ...
, o
renal clear cell carcinoma
Tumor infiltration by TREM2+, APOE+, C1Q+ macrophage was reported to be a biomarker for recurrence o
clear-cell renal carcinoma
TREM2+ macrophages from human tumors also express
CD68 CD68 ( Cluster of Differentiation 68) is a protein highly expressed by cells in the monocyte lineage (e.g., monocytic phagocytes, osteoclasts), by circulating macrophages, and by tissue macrophages (e.g., Kupffer cells, microglia). Structure a ...
,
CD163 CD163 (Cluster of Differentiation 163) is a protein that in humans is encoded by the CD163 gene. CD163 is the high affinity scavenger receptor for the hemoglobin-haptoglobin complex and in the absence of haptoglobin - with lower affinity - for hem ...
,
CSF1R Colony stimulating factor 1 receptor (CSF1R), also known as macrophage colony-stimulating factor receptor (M-CSFR), and CD115 (Cluster of Differentiation 115), is a cell-surface protein encoded by the human ''CSF1R'' gene (known also as c-FMS). CS ...
, and nuclear
MAFB Transcription factor MafB also known as V-maf musculoaponeurotic fibrosarcoma oncogene homolog B is a protein that in humans is encoded by the ''MAFB'' gene. This gene maps to chromosome 20q11.2-q13.1, consists of a single exon and spans around 3 ...
.


IBD

TREM2 expressed by human monocyte dendritic cells in the intestine. Expression of TREM2 is limited to inflamed sections of intestine and contribute to IBD development. TREM2 is associated with increased production of inflammatory cytokines and changes in the gut microbiota.


Liver disease

One feature of liver disease is the initiation of an inflammatory process, leading to
fibrosis Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...
and
steatohepatitis Steatohepatitis is a type of fatty liver disease, characterized by inflammation of the liver with concurrent fat accumulation in liver. Mere deposition of fat in the liver is termed steatosis, and together these constitute fatty liver changes. T ...
. In mouse models of
nonalcoholic steatohepatitis Non-alcoholic fatty liver disease (NAFLD), also known as metabolic (dysfunction) associated fatty liver disease (MAFLD), is excessive fat build-up in the liver without another clear cause such as alcohol use. There are two types; non-alcoholic ...
(NASH), disease development was associated with liver infiltration by monocyte-derived macrophages and increased expression of ''Trem2'' an
''Cd9''
Mice with disruption of ''Trem2'' had more severe liver damage following administration of carbon tetrachloride or acetaminophen, compared to mice without gene disruption. The authors of this study found that TREM2 is expressed by Kupfer cells and
hepatic stellate cells The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it is ...
, indicating that TREM2 might downregulate inflammation. Expression was also increased in liver tissues from patients with cirrhosis. Compared with non-tumor liver tissue, TREM2 expression was increased in tumors from mice and patients with
hepatocellular carcinoma Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide. It occurs in t ...
(HCC). This study also showed that disruption of ''Trem2'' promoted tumor development and exacerbated liver damage and inflammation. In liver tumors, TREM2 was expressed b
tumor-infiltrating macrophages
(TAMs). TREM2 might therefore promote the resolution of inflammation during hepatic injury, ultimately preventing parenchymal cell death.


PLOSL or Nasu–Hakola disease

PLOSL or Nasu–Hakola disease is a neurodegenerative disorder characterized by bone cysts, dementia, and early death and is associated with variants in the ''TYROBP'' gene (encodes DAP12 protein) and ''TREM2'' gene. Bone cysts in patients with PLOSL contain fat in lieu of bone marrow. In this disease, the main cell type in the brain that is affected is the microglia, where TREM2 is expressed. Several recessive, inactivating mutations in ''TREM2'' and ''TYROBP'' (encodes DAP12 protein) have been identified that can cause PLOSL. The mutations prevent association between TREM2 and DAP12 or expression of shorter, non-functional forms of TREM2. Loss of function of TREM2 signaling increases the inflammatory responses of microglia, reducing clearance of dead neurons and promoting inflammation and even formation of amyloid plaques.


Stroke

During
ischemic stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
, microglia respond to the area of insult. TREM2 appears to reduce the inflammatory response induced by TLR signaling and promote microglial migration, survival, and regeneration.


Other diseases

TREM2 has also been linked to additional disorders such as
ALS Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most com ...
,
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
, and more dementia related conditions.


Therapeutic targeting of TREM2

TREM2 is a good therapeutic target for several diseases, including cancer and liver and neurodegenerative diseases. Several companies are developing agents to target TREM2. However, TREM2 is likely to have distinct roles in the pathogenesis of these disorders, so therapeutic agents in development employ different approaches to modify TREM2 activity.


Neurodegenerative diseases

In the brain, TREM2 is expressed on microglia that regulate clearance of neuronal debris. Binding of apolipoproteins, such as ApoE, to TREM2 promotes phagocytosis of apoptotic neurons or the uptake of amyloid beta by microglia. Variants of ''TREM2'' that encode proteins with reduced affinity for ligands have been associated with Alzheimer’s disease.


Targeting sTREM2

A potential mechanism of intervention could be targeting the enzymes that cleave the ectodomain, adjusting the rate at which sTREM2 is released. In rodents, a potential therapeutic using this mechanism was used against AD pathology, and the rodents had smaller plaques than controls.


References

{{Reflist Alzheimer's disease