TREM2 and Alzheimer disease: In AD cases with a TREM2 risk variant, plaques are more diffuse and nearby microglia have reduced membrane ruffling, and shorter but more numerous filopodia when stimulated with ATP or M-CSF.47 Loss of TREM2 impairs actin ring formation and podosomes in osteoclasts, essential for phagocytosis linked to bone resorption.48 PIP2 to PIP3 conversion at the cell membrane is essential for ‘sealing off’ the membrane edges during motility, endocytosis, exocytosis and phagocytosis through the cytoskeletal system.