Abstract
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.
Highlights
Reviewed by: Eloise Hudry, Harvard NeuroDiscovery Center, Harvard Medical School, United States Marc Suárez-Calvet, BarcelonaBeta Brain Research Center, Spain
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
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
Summary
Microglia are the resident innate immune cells in the central nervous system (CNS) that account for ∼10%–15% of cells. The number of plaque-associated microglia is significantly reduced in Trem deficient AD mice, and the effect is Trem gene dose-dependent (Jay et al, 2015; Wang et al, 2015) In both transgenic mice expressing the human TREM2 R47H or patients with the R47H variant, a similar reduction in microgliosis is observed (Yuan et al, 2016; Song et al, 2018), supporting that R47H is a loss-offunction mutation. Whether the increased neuritic dystrophy in Trem deficient mice is due to impaired clearance of damaged neurites by Trem2−/− microglia or the result of elevated damage by loosely compacted plaques remains unclear These studies indicate that TREM2 signaling promotes microglial responses to Aβ in AD. Increased autophagy is detected in Trem2-deficient microglia and in AD patients carrying one allele of the R47H or R62H variant of TREM2, suggesting microglia attempt to compensate the mTOR defects with autophagy as a survival mechanism
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