TREM2, Microglia, and Neurodegenerative Diseases

A recent discovery has shown that the R47H variant of TREM2 enhances the risk of AD by about threefold – similar to the risk conferred by APOE4. This finding has focused the attention of the field on microglia, the resident macrophages of the brain. In mouse AD models, TREM2 deficiency reduces the microglial response to Aβ plaque pathology: there is reduced number of microglial cells surrounding plaques and impaired activation of microglial gene expression. Evidence suggests that microglia participate in amyloid plaque compaction via a TREM2-dependent mechanism, forming a protective barrier that attenuates toxicity towards nearby neurons. Phospholipids and lipoproteins (including APOE and CLU) have been identified as ligands for TREM2. The R47H variant of TREM2 impairs TREM2 ligand binding, phagocytosis by microglia, and downstream transcriptional responses. The genetic associations of TREM2 loss-of-function variants with AD and other forms of dementia highlight the essential role of microglia in maintaining a healthy brain and suggest that enhancing microglial function may have therapeutic benefit. Alzheimer’s disease (AD) is the most common form of dementia and the 6th leading cause of death in the US. The neuropathological hallmarks of the disease are extracellular amyloid-β (Aβ) plaques and intraneuronal hyperphosphorylated tau aggregates. Genetic variants of TREM2 (triggering receptor expressed on myeloid cells 2), a cell-surface receptor expressed selectively in myeloid cells, greatly increase the risk of AD, implicating microglia and the innate immune system as pivotal factors in AD pathogenesis. Recent studies have advanced our understanding of TREM2 biology and microglial activities in aging and neurodegenerative brains, providing new insights into TREM2 functions in amyloid plaque maintenance, microglial envelopment of plaque, microglia viability, and the identification of novel TREM2 ligands. Our increased understanding of TREM2 and microglia has opened new avenues for therapeutic intervention to delay or prevent the progression of AD. Alzheimer’s disease (AD) is the most common form of dementia and the 6th leading cause of death in the US. The neuropathological hallmarks of the disease are extracellular amyloid-β (Aβ) plaques and intraneuronal hyperphosphorylated tau aggregates. Genetic variants of TREM2 (triggering receptor expressed on myeloid cells 2), a cell-surface receptor expressed selectively in myeloid cells, greatly increase the risk of AD, implicating microglia and the innate immune system as pivotal factors in AD pathogenesis. Recent studies have advanced our understanding of TREM2 biology and microglial activities in aging and neurodegenerative brains, providing new insights into TREM2 functions in amyloid plaque maintenance, microglial envelopment of plaque, microglia viability, and the identification of novel TREM2 ligands. Our increased understanding of TREM2 and microglia has opened new avenues for therapeutic intervention to delay or prevent the progression of AD. AD mouse model combining the Swedish KM670/671NL, Florida I716 V, and London V717I mutations in the human APP transgene, and the M146L and L286V mutations in the human PSEN1 transgene, with both genes under the control of the Thy1 promoter. aggregated α-synuclein is a major constituent of Lewy bodies, the hallmark pathology found in Parkinson’s disease, dementia with Lewy bodies, and multiple systems atrophy. In the healthy brain its function is thought to involve clustering synaptic vesicles at the presynaptic terminal. a defining pathological feature of AD, plaques are extracellular accumulations of aggregated fibrillar Aβ peptide. Aβ can also exist in a soluble form. The peptide is generated from amyloid precursor protein through sequential cleavage by β and γ secretases. progressive disease where degeneration of upper and lower motor neurons leads to weakness and paralysis of voluntary muscles, resulting in respiratory failure and death, usually within 5 years after onset of symptoms. Also known as Lou Gehrig’s disease or motor neuron disease. exists in three polymorphic forms differing at two amino acids APOE-ε2 (cys112, cys158), APOE-ε3 (cys112, arg158), and APOE-ε4 (arg112, arg158). The ε4 allele increases AD risk ∼threefold while ε2 reduces risk ∼0.6 fold. The major apolipoprotein in brain, APOE is produced mainly by astrocytes and is found in high-density lipoprotein (HDL)-like particles. AD mouse model containing the Swedish APP KM670/671NL human transgene under the control of the thymus cell antigen-1 (Thy1) promoter. an AD mouse model (also known as APPPS1) containing the Swedish APP KM670/671NL and PSEN1 L166P human transgenes under the control of the Thy1 promoter. an AD mouse model (also known as APP/PS1) containing the Swedish APP KM670/671NL and PSEN1 deltaE9 human transgenes under the control of the mouse Prnp promoter. specialized form of extracellular matrix that acts to divide the epithelium from the underlying tissue. layer of capillaries adjacent to the Bruch’s membrane in the choroid, the vascular layer of the eye. also known as apolipoprotein J (APOJ), CLU is processed into an α and β chain, resulting in a disulfide-linked, heterodimeric protein mainly produced by astrocytes in the CNS and is found in HDL-like particles; CLU variants are genetically linked to AD. a component of innate immunity, the complement system comprises a set of proteins that work together to enhance the ability of antibodies and phagocytic cells to kill infected cells, clear pathogens and dying cells, and promote inflammation to fight infection. an AD mouse model (also known as APPswe/ind) that expresses a human APP transgene containing the Swedish KM670/671NL and Indiana V717F mutations under the control of the hamster Prnp promoter. model of demyelination where mice are fed a diet containing cuprizone, a copper chelator, which selectively causes oligodendrocyte cell death, resulting in demyelination within a few weeks. Remyelination can be studied after withdrawal of the toxin. destruction of the myelin sheath that normally insulates nerve fibers. accumulations of yellow or white extracellular material appearing between retinal pigment epithelial cells and endothelial cells of the choriocapillaris. pathological swelling and distortion of axons, the long neuronal processes conducting impulses away from the cell body. a model of inflammatory demyelinating disease generated by injecting mice with myelin proteins or peptides together with an adjuvant, giving rise to T cell-mediated autoimmunity and progressive weakness/paralysis. characterized by progressive neuronal loss especially in the frontal and temporal lobes. Often presents with personality and behavior changes. population-based studies that determine whether specific genetic variants are associated with a disease or any trait of interest. an AD mouse model expressing a human APP transgene containing the Swedish KM670/671NL and Indiana V717F mutations under the control of the human PDGFB promoter. specialized tissue-resident macrophages found in the liver that constantly sample the environment for microbial products. one of six main layers in the cerebral cortex containing large pyramidal neurons whose axons often project long distances to other parts of the CNS. agonists of Toll-like receptors TLR4, TLR9, and TLR2, respectively; often used to stimulate acute proinflammatory antimicrobial responses in innate immune cells while maintaining a sterile environment. lipid-laden particles consisting of a phospholipid shell (with embedded apolipoproteins) and a lipid/cholesterol-filled interior. Lipoproteins are present in blood and other body fluids; they help to transport lipids, cholesterol, and other molecules within the body. autoimmune disease where the myelin sheath of nerve cells is damaged, causing a range of symptoms including visual loss, sensory disturbance, paralysis, and cognitive dysfunction. a sheath containing lipids and proteins that surrounds axons; electrically insulates the nerve fiber and increases the speed of nerve impulses. also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, a disease characterized by bone cysts, white matter degeneration, and progressive dementia. aggregates of hyperphosphorylated tau found within neurons. A hallmark of AD, this pathology is also found in other neurodegenerative diseases, and these are collectively known as tauopathies. the ratio of odds of a disease for individuals having a specific allele to the odds of disease for individuals who do not have that same allele. When the allele frequency in AD patients is higher than in the control group, the odds ratio is greater than 1, and the genetic variant is associated with increased risk of disease. surgical joining of two individual animals, in particular, via the circulatory system. PET imaging uses a radioactive tracer to measure the function of internal organs or the distribution of pathology such as amyloid plaques. an AD mouse model containing the Swedish KM670/671NL APP mutant and the PSEN2 N141I mutant in which the transgenes are under the control of the Thy1 or Prnp promoters, respectively. a pigmented cell layer that helps to maintain the photoreceptors of the eye and acts as a component of the blood–retina barrier. a technique in which next-generation sequencing technology is used to measure the quantity of specific RNAs in an unbiased genome-wide fashion (the transcriptome). a mouse model of ALS expressing the G93A mutant of human SOD1 (superoxide dismutase), a cause of familial ALS, under the control of the human SOD1 promoter. process of synapse elimination that occurs during brain development. receptors primarily expressed in innate immune cells (such as microglia, macrophages, and dendritic cells) that recognize highly conserved structural motifs derived from pathogens or from dying cells.