Down-regulated mRNAs include those encoding complement factor-H (CFH), an SH3-proline-rich multi-domain-scaffolding protein of the postsynaptic density (SHANK3), and the triggering receptor expressed in myeloid/microglial cells (TREM2), as is observed in sporadic AD brain.
TREM2 variants associated with Alzheimer's disease induce partial loss of function of the TREM2 protein and alter the behaviour of microglial cells, including their response to amyloid plaques.
Moreover, the rare TREM2 variant (p.Arg47His), which was considered to be a risk factor for Alzheimer's disease in European descent populations, was not detected in our cohort.
The triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial innate immune receptor associated with a lethal form of early, progressive dementia, Nasu-Hakola disease, and with an increased risk of Alzheimer's disease.
Glial expression of TREM2/TYROBP exacerbated tau-mediated neurodegeneration and synergistically affected pathways underlying late-onset AD pathology, while neuronal Aβ42 and glial TREM2/TYROBP synergistically altered expression of the genes in synaptic function and immune modules in AD.
We demonstrate that this protocol successfully decreases the expression of two key genes associated with AD, the triggering receptor expressed in myeloid cells 2 (TREM2) and CD33, in primary microglia cell cultures.
Recent studies have found an association between functional variants in TREM2 and PLD3 and Alzheimer's disease (AD), but their effect on cognitive function is unknown.
These data suggest that the AD-associated TREM2R47H variant increases risk for AD by conferring a loss of TREM2 function and enhancing neuritic dystrophy around plaques.
A comprehensive understanding of TREM2 function in the pathogenesis of AD offers a unique opportunity to explore the potential of this microglial receptor as an alternative target in AD therapy.
Partial loss-of-function variants in the TREM2 immune receptor are associated with increased risk for Alzheimer's disease (AD) and other forms of neurodegenerative disease, but the molecular bases for these connections are unknown.
Two DS cases had the AD-associated TREM2-R47H mutation, which manifested a morphologically extreme phenotype of megakaryocytes and erythrocytes in addition to impaired trafficking of TREM2 to the erythroid membrane.
Emerging evidence from protein binding assays suggests that APOE binds to TREM2 and APOE-containing lipoproteins in the brain as well as periphery, and are putative ligands for TREM2, thus raising the possibility of an APOE-TREM2 interaction modulating different aspects of AD pathology, potentially in an isoform-specific manner.
Taken together, these findings uncover the underlying mechanisms by which TREM2 protects against tau pathology and highlight TREM2 as a potential therapeutic target for AD.
In addition, studies of triggering receptor expressed on myeloid cells 2-deficiency in AD mice revealed heterogeneous microglial reactions at different disease stages, complicating the therapeutic strategy for AD.
Triggering receptor expressed on myeloid cells 2 (TREM2) activates the innate immune system, promotes phagocytosis by microglia, and is associated with Alzheimer's disease (AD).
In mouse models of AD, <i>Trem2</i> haplodeficiency and deficiency lead to reduced microglial clustering around amyloid β (Aβ) plaques, suggesting TREM2 is required for plaque-associated microglial responses.
Here, we review the rapidly growing literature on the role of disease-associated microglia, TREM2 and APOE in the pathogenesis of Alzheimer disease and present an integrated view of innate immune function in Alzheimer disease.