TREM2 receptor protects against complement-mediated synaptic loss by binding to complement C1q during neurodegeneration.

Triggering receptor expressed on myeloid cells 2 (TREM2) is strongly linked to Alzheimer's disease (AD) risk, but its functions are not fully understood. Here, we found that TREM2 specifically attenuated the activation of classical complement cascade via high-affinity binding to its initiator C1q. In the human AD brains, the formation of TREM2-C1q complexes was detected, and the increased density of the complexes was associated with lower deposition of C3 but higher amounts of synaptic proteins. In mice expressing mutant human tau, Trem2 haploinsufficiency increased complement-mediated microglial engulfment of synapses and accelerated synaptic loss. Administration of a 41-amino-acid TREM2 peptide, which we identified to be responsible for TREM2 binding to C1q, rescued synaptic impairments in AD mouse models. We thus demonstrate a critical role for microglial TREM2 in restricting complement-mediated synaptic elimination during neurodegeneration, providing mechanistic insights into the protective roles of TREM2 against AD pathogenesis.

Identification of the minimal active soluble TREM2 sequence for modulating microglial phenotypes and amyloid pathology.

BACKGROUND: TREM2 is a microglial receptor genetically linked to the risk for Alzheimer's disease (AD). The cerebrospinal fluid (CSF) levels of soluble TREM2 (sTREM2) have emerged as a valuable biomarker for the disease progression in AD and higher CSF levels of sTREM2 are linked to slower cognitive decline. Increasing sTREM2 in mouse models of amyloidosis reduces amyloid-related pathology through modulating microglial functions, suggesting a beneficial role of sTREM2 in microglia biology and AD pathology. METHODS: In the current study, we performed serial C- and N-terminal truncations of sTREM2 protein to define the minimal sequence requirement for sTREM2 function. We initially assessed the impacts of sTREM2 mutants on microglial functions by measuring cell viability and inflammatory responses. The binding of the sTREM2 mutants to oligomeric Aß was determined by solid-phase protein binding assay and dot blot assay. We further evaluated the impacts of sTREM2 mutants on amyloid-related pathology by direct stereotaxic injection of sTREM2 proteins into the brain of 5xFAD mice. RESULTS: We found that both sTREM2 fragments 41-81 and 51-81 enhance cell viability and inflammatory responses in primary microglia. However, the fragment 51-81 exhibited impaired affinity to oligomeric Aß. When administrated to the 5xFAD mice brain, the sTREM2 fragment 41-81, but not 51-81, increased the number of plaque-associated microglia and reduced the plaque deposition. Interestingly, the fragment 41-81 was more efficient than the physiological form of sTREM2 in ameliorating Aß-related pathology. CONCLUSIONS: Our results indicate that the interaction of sTREM2 truncated variants with Aß is essential for enhancing microglial recruitment to the vicinity of an amyloid plaque and reducing the plaque load. Importantly, we identified a 41-amino acid sequence of sTREM2 that is sufficient for modulating microglial functions and more potent than the full-length sTREM2 in reducing the plaque load and the plaque-associated neurotoxicity. Taken together, our data provide more insights into the mechanisms underlying sTREM2 function and the minimal active sTREM2 sequence represents a promising candidate for AD therapy.

Association of ß-Amyloid, Microglial Activation, Cortical Thickness, and Metabolism in Older Adults Without Dementia.

BACKGROUND AND OBJECTIVES: Plasma ß-amyloid42 (Aß42)/Aß40 levels have shown promise in identifying Aß-PET positive individuals. This study explored the concordance and discordance of plasma Aß42/Aß40 positivity (Plasma±) with CSF Aß42/Aß40 positivity (CSF±) and Aß-PET positivity (PET±) in older adults without dementia. Associations of Aß deposition, cortical thickness, glucose metabolism, and microglial activation were also investigated. METHODS: We selected participants without dementia who had concurrent plasma Aß42/Aß40 and Aß-PET scans from the Alzheimer's Disease Neuroimaging Initiative cohort. Participants were categorized into Plasma±/PET± based on thresholds of composite 18F-florbetapir (FBP) standardized uptake value ratio (SUVR) ≥1.11 and plasma Aß42/Aß40 ≤0.1218. Aß-PET-negative individuals were further divided into Plasma±/CSF± (CSF Aß42/Aß40 ≤0.138), and the concordance and discordance of Aß42/Aß40 in the plasma and CSF were investigated. Baseline and slopes of regional FBP SUVR were compared among Plasma±/PET± groups, and associations of regional FBP SUVR, FDG SUVR, cortical thickness, and CSF soluble Triggering Receptor Expressed on Myeloid Cell 2 (sTREM2) levels were analyzed. RESULTS: One hundred eighty participants (mean age 72.7 years, 51.4% female, 96 cognitively unimpaired, and 84 with mild cognitive impairment) were included. We found that the proportion of Plasma+/PET- individuals was 6.14 times higher (odds ratio (OR) = 6.143, 95% confidence interval (CI) 2.740-16.185, p < 0.001) than that of Plasma-/PET+ individuals, and Plasma+/CSF- individuals showed 8.5 times larger percentage (OR = 8.5, 95% CI: 3.031-32.974, p < 0.001) than Plasma-/CSF+ individuals in Aß-PET-negative individuals. Besides, Plasma+/PET- individuals exhibited faster (p < 0.05) Aß accumulation predominantly in bilateral banks of superior temporal sulcus (BANKSSTS) and supramarginal, and superior parietal cortices compared with Plasma-/PET- individuals, despite no difference in baseline FBP SUVRs. In Plasma+/PET+ individuals, higher CSF sTREM2 levels correlated with slower BANKSSTS Aß accumulation (standardized ß (ßstd) = -0.418, 95% CI -0.681 to -0.154, p = 0.002). Conversely, thicker cortical thickness and higher glucose metabolism in supramarginal and superior parietal cortices were associated with faster (p < 0.05) CSF sTREM2 increase in Plasma+/PET- individuals rather than in Plasma+/PET+ individuals. DISCUSSION: These findings suggest that plasma Aß42/Aß40 abnormalities may predate CSF Aß42/Aß40 and Aß-PET abnormalities. Higher sTREM2-related microglial activation is linked to thicker cortical thickness and higher metabolism in early amyloidosis stages but tends to mitigate Aß accumulation primarily at relatively advanced stages.