TY - JOUR
T1 - TREM2-dependent effects on microglia in Alzheimer's Disease
AU - Zhou, Yingyue
AU - Ulland, Tyler K.
AU - Colonna, Marco
PY - 2018/7/9
Y1 - 2018/7/9
N2 - Alzheimer's disease (AD) is a late-onset dementia characterized by the deposition of amyloid plaques and formation of neurofibrillary tangles (NFTs) which lead to neuronal loss and cognitive deficits. Abnormal protein aggregates in the AD brain are also associated with reactive microglia and astrocytes. Whether this glial response is beneficial or detrimental in AD pathology is under debate. Microglia are the resident innate immune cells in the central nervous system (CNS) that survey the surrounding environment. Genome-wide association studies (GWAS) have identified the R47H variant of triggering receptor expressed on myeloid cell 2 (TREM2) as a risk factor for late-onset AD (LOAD) with an odds ratio of 4.5. TREM2 is an immunoreceptor primarily present on microglia in the CNS that binds to polyanionic molecules. The transmembrane domain of TREM2 signals through DAP12, an adaptor protein that contains an immunoreceptor tyrosine-based activation motif (ITAM), which mediates TREM2 signaling and promotes microglial activation and survival. In mouse models of AD, Trem2 haplodeficiency and deficiency lead to reduced microglial clustering around amyloid β (Aβ) plaques, suggesting TREM2 is required for plaque-associated microglial responses. Recently, TREM2 has been shown to enhance microglial metabolism through the mammalian target of rapamycin (mTOR) pathway. Although aberrant metabolism has long been associated with AD, not much was known regarding how metabolism in microglia might affect disease progression. In this review, we discuss the role of TREM2 and metabolism in AD pathology, highlighting how TREM2-mediated microglial metabolism modulates AD pathogenesis.
AB - Alzheimer's disease (AD) is a late-onset dementia characterized by the deposition of amyloid plaques and formation of neurofibrillary tangles (NFTs) which lead to neuronal loss and cognitive deficits. Abnormal protein aggregates in the AD brain are also associated with reactive microglia and astrocytes. Whether this glial response is beneficial or detrimental in AD pathology is under debate. Microglia are the resident innate immune cells in the central nervous system (CNS) that survey the surrounding environment. Genome-wide association studies (GWAS) have identified the R47H variant of triggering receptor expressed on myeloid cell 2 (TREM2) as a risk factor for late-onset AD (LOAD) with an odds ratio of 4.5. TREM2 is an immunoreceptor primarily present on microglia in the CNS that binds to polyanionic molecules. The transmembrane domain of TREM2 signals through DAP12, an adaptor protein that contains an immunoreceptor tyrosine-based activation motif (ITAM), which mediates TREM2 signaling and promotes microglial activation and survival. In mouse models of AD, Trem2 haplodeficiency and deficiency lead to reduced microglial clustering around amyloid β (Aβ) plaques, suggesting TREM2 is required for plaque-associated microglial responses. Recently, TREM2 has been shown to enhance microglial metabolism through the mammalian target of rapamycin (mTOR) pathway. Although aberrant metabolism has long been associated with AD, not much was known regarding how metabolism in microglia might affect disease progression. In this review, we discuss the role of TREM2 and metabolism in AD pathology, highlighting how TREM2-mediated microglial metabolism modulates AD pathogenesis.
KW - Alzheimer's disease
KW - Autophagy
KW - Metabolism
KW - Microglia
KW - TREM2
UR - http://www.scopus.com/inward/record.url?scp=85050273292&partnerID=8YFLogxK
U2 - 10.3389/fnagi.2018.00202
DO - 10.3389/fnagi.2018.00202
M3 - Short survey
C2 - 30038567
AN - SCOPUS:85050273292
VL - 10
JO - Frontiers in Aging Neuroscience
JF - Frontiers in Aging Neuroscience
SN - 1663-4365
IS - JUL
M1 - 202
ER -