Highlights d Upon demyelination, Trem2 -/microglia fail to upregulate lipid metabolism genes d Trem2 -/microglia accumulate cholesteryl ester derived from myelin cholesterol d Accumulation is rescued by ACAT1 inhibitor and LXR agonist d Apoe -/glia defective in cholesterol transport also accumulate cholesteryl ester

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Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for the transition of homeostatic microglia to a disease‐associated microglial state. To enhance TREM2 activity, we sought to selectively increase the full‐length protein on the cell surface via reducing its proteolytic shedding by A Disintegrin And Metalloproteinase (i.e., α‐secretase) 10/17. We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for α‐secretase‐mediated shedding. Monoclonal antibody 4D9, which has a stalk region epitope close to the cleavage site, demonstrated dual mechanisms of action by stabilizing TREM2 on the cell surface and reducing its shedding, and concomitantly activating phospho‐SYK signaling. 4D9 stimulated survival of macrophages and increased microglial uptake of myelin debris and amyloid β‐peptide in vitro. In vivo target engagement was demonstrated in cerebrospinal fluid, where nearly all soluble TREM2 was 4D9‐bound. Moreover, in a mouse model for Alzheimer's disease‐related pathology, 4D9 reduced amyloidogenesis, enhanced microglial TREM2 expression, and reduced a homeostatic marker, suggesting a protective function by driving microglia toward a disease‐associated state.

Background:To verify whether the concentrations and integrity index of circulating cell-free DNA (ccf-DNA) in serum may be clinically useful for the diagnosis and progression monitoring of colorectal cancer (CRC) patients.Methods:Serum samples were collected from 104 with primary CRC, 85 with operated CRC, 16 with recurrent/metastatic CRC, 63 patients with intestinal polyps and 110 normal controls. Long (247 bp) and short (115 bp) DNA fragments in serum were detected by real-time quantitative PCR by amplifying the ALU repeats (ALU-qPCR). Serum carcinoembryonic antigen (CEA) level was detected by ARCHITECT assay.Results:The median absolute serum ALU115 and ALU247/115 in primary CRC group was significantly higher than those in intestinal polyp and normal control groups (both P<0.0001), in recurrent/metastatic CRC was significantly higher compared with primary CRC (P=0.0021, P=0.0018) or operated CRC (P<0.0001, respectively) and during follow-up, ALU115 and ALU247/115 were increased before surgery and decreased significantly after surgery.Conclusions:Combined detection of ALU115, ALU247/115 and CEA could improve the diagnostic efficiency for CRC. Serum DNA concentrations and integrity index may be valuable in early complementary diagnosis and monitoring of progression and prognosis of CRC.

Peripheral inflammation leads to immune responses in brain characterized by microglial activation, elaboration of pro-inflammatory cytokines and reactive oxygen species, and secondary neuronal injury. The inducible cyclooxygenase COX-2 mediates a significant component of this response in brain via downstream pro-inflammatory prostaglandin signaling. Here, we investigated the function of the PGE2 EP4 receptor in the central nervous system (CNS) innate immune response to the bacterial endotoxin lipopolysaccharide (LPS). We report that PGE2 EP4 signaling mediates an anti-inflammatory effect in brain by blocking LPS-induced pro-inflammatory gene expression in mice. This was associated in cultured murine microglial cells with decreased Akt and IKK phosphorylation and decreased nuclear translocation of p65 and p50 NF-kappaB subunits. In vivo, conditional deletion of EP4 in macrophages and microglia increased lipid peroxidation and pro-inflammatory gene expression in brain and in isolated adult microglia following peripheral LPS administration. Conversely, EP4 selective agonist decreased LPS-induced pro-inflammatory gene expression in hippocampus and in isolated adult microglia. In plasma, EP4 agonist significantly reduced levels of pro-inflammatory cytokines and chemokines, indicating that peripheral EP4 activation protects the brain from systemic inflammation. The innate immune response is an important component of disease progression in a number of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In addition, recent studies demonstrate adverse vascular effects with chronic administration of COX-2 inhibitors, indicating that specific prostaglandin signaling pathways may be protective in vascular function. This study supports an analogous and beneficial effect of PGE2 EP4 receptor signaling in suppressing brain inflammation.