SummaryTriggering receptor expressed on myeloid cells 2 (TREM2) is a microglia surface receptor that triggers intracellular protein tyrosine phosphorylation. Recent genome-wide association studies have shown that a rare R47H mutation of TREM2 correlates with a substantial increase in the risk of developing Alzheimer's disease (AD). To address the basis for this genetic association, we studied TREM2 deficiency in the 5XFAD mouse model of AD. We found that TREM2 deficiency and haploinsufficiency augment β-amyloid (Aβ) accumulation due to dysfunctional response of microglia, which become apoptotic and fail to cluster around Aβ plaques. We further demonstrate that TREM2 senses a broad array of anionic and zwitterionic lipids known to associate with fibrillar Aβ in lipid membranes and to be exposed on the surface of damaged neurons. Remarkably, the R47H mutation impairs TREM2 detection of lipid ligands. Thus, TREM2 detects damage-associated lipid patterns associated with neurodegeneration, sustaining microglia response to Aβ accumulation.

A myosin for RNA Pol II T ranscription gets a boost from myosin VI, according to fi ndings from Sarah Vreugde (DIBIT Scientifi c Institute, Milano, Italy) and colleagues. The motor might drag genes into transcription neighborhoods. While trying to understand the function of myosin VI, Vreugde noticed that its localization pattern looked much like that of RNA polymer-ase II. The authors then showed an association between the motor and polymerase that depends on ongoing transcription. By cross-linking myosin VI to chromatin, the group identifi ed several genes at which the motor is found. The mRNA levels of these genes decreased when myosin VI levels were reduced. Vreugde next hopes to inhibit just the nuclear pool of myosin VI and then do genome-wide analyses to identify more affected genes. Assuming its infl uence is widespread, the motor might spool the DNA past aggregates of RNA polymerases or recruit stretches of DNA to transcription factories. "DNA recruitment to transcription factories would be heavy work," says Vreugde. "But myosin is well-suited to accomplish that." Whether its unusual preference to move toward actin minus ends helps myosin VI at all is unclear, as the polarity of the nuclear actin network is not known and probably dynamic. The only other known nuclear myosin, myosin I, is plus-end directed but still enhances transcription by all the RNA polymerases.