gms | German Medical Science

Genome-wide association studies have recently identified variations in more than 20 loci that contribute to risk of sporadic Alzheimer’s disease (AD), including a novel variant in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which triples the risk of AD. TREM2 is expressed on myeloid cells including microglia in the brain. TREM2 has previously been shown to be involved in regulating microglial phagocytosis, while a recent publication identified TREM2 as key for promoting survival of activated microglia and their peripherally derived myeloid counterparts as well as engaging these cells with Aβ plaques through lipid sensing. Animal studies aimed at exploring the effects of Trem2 deficiency on AD-related neuropathology yielded inconsistent data: while TREM2‐deficiency in one Aβ-carrying mouse model was shown to ameliorate hippocampal Aβ accumulation, it resulted in an increase in yet another AD-like mouse model exhibiting cerebral amyloidosis. In order to shed more light on the pathogenetic role of TREM2 in AD, we crossed Trem2 deficient mice to APPPS1 mice modeling AD and evaluated AD-like pathology at 120 and 250 days of age. Our analyses show that Trem2 deficiency in this AD-like mouse model led to significant alterations in pathology, thus providing important insights into the impact of Trem2 on microglia function in AD and the role of microglia in AD pathogenesis in general.