Coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with late onset Alzheimer’s disease (AD). We demonstrate that amyloid plaque seeding is increased in the absence of functional Trem2. Increased seeding is accompanied by decreased microglial clustering around newly seeded plaques and reduced plaque associated Apolipoprotein E (ApoE). Reduced ApoE deposition in plaques is also observed in brains of AD patients carrying TREM2 coding variants. Proteomic analyses and microglia depletion experiments revealed microglia as one origin of plaque associated ApoE. Longitudinal amyloid small animal positron emission tomography demonstrates accelerated amyloidogenesis in Trem2 loss of function mutants at early stages, which progressed at a lower rate with aging. These findings suggest that in the absence of functional Trem2 early amyloidogenesis is accelerated due to reduced phagocytic clearance of amyloid seeds despite reduced plaque associated ApoE.

Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk for several neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia (FTD). Homozygous TREM2 missense mutations, such as p.T66M, lead to the FTD-like syndrome, but how they cause pathology is unknown. Using CRISPR/Cas9 genome editing, we generated a knock-in mouse model for the disease-associated Trem2 p.T66M mutation. Consistent with a loss-of-function mutation, we observe an intracellular accumulation of immature mutant Trem2 and reduced generation of soluble Trem2 similar to patients with the homozygous p.T66M mutation. Trem2 p.T66M knock-in mice show delayed resolution of inflammation upon lipopolysaccharide stimulation and cultured macrophages display significantly reduced phagocytic activity. Immunohistochemistry together with TSPO small animal positron emission tomography (μPET) demonstrates an age-dependent reduction in microglial activity. Surprisingly, perfusion magnetic resonance imaging and FDG-μPET imaging reveal a significant reduction in cerebral blood flow and brain glucose metabolism. Thus, we demonstrate that a TREM2 loss-of-function mutation causes brain-wide metabolic alterations pointing toward a possible function of microglia in regulating brain glucose metabolism.

FDG-PET shows that microglial activation might drive cerebral glucose uptake in mice and patients with AD.

Microglia adopt numerous fates with homeostatic microglia ( HM ) and a microglial neurodegenerative phenotype ( MG nD) representing two opposite ends. A number of variants in genes selectively expressed in microglia are associated with an increased risk for neurodegenerative diseases such as Alzheimer's disease ( AD ) and frontotemporal lobar degeneration ( FTLD ). Among these genes are progranulin ( GRN ) and the triggering receptor expressed on myeloid cells 2 ( TREM 2 ). Both cause neurodegeneration by mechanisms involving loss of function. We have now isolated microglia from Grn −/− mice and compared their transcriptomes to those of Trem2 −/− mice . Surprisingly, while loss of Trem2 enhances the expression of genes associated with a homeostatic state, microglia derived from Grn −/− mice showed a reciprocal activation of the MG nD molecular signature and suppression of gene characteristic for HM . The opposite mRNA expression profiles are associated with divergent functional phenotypes. Although loss of TREM 2 and progranulin resulted in opposite activation states and functional phenotypes of microglia, FDG (fluoro‐2‐deoxy‐ d ‐glucose)‐μ PET of brain revealed reduced glucose metabolism in both conditions, suggesting that opposite microglial phenotypes result in similar wide spread brain dysfunction.

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