Wei-Ting Chen

mice over time demonstrate that progressive amyloid-β accumulation accelerates two main activated microglia states that are also present during normal aging. Activated response microglia (ARMs) are composed of specialized subgroups overexpressing MHC type II and putative tissue repair genes (Dkk2, Gpnmb, and Spp1) and are strongly enriched with Alzheimer's disease (AD) risk genes. Microglia from female mice progress faster in this activation trajectory. Similar activated states are also found in a second AD model and in human brain. Apoe, the major genetic risk factor for AD, regulates the ARMs but not the interferon response microglia (IRMs). Thus, the ARMs response is the converging point for aging, sex, and genetic AD risk factors.

Significance In vertebrates, steroid hormones regulate developmental transition from juveniles to adults. Insect steroid hormone, 20-hydroxyecdysone (20E), coordinates with juvenile hormone (JH) to regulate metamorphosis; however, the precise cross-talk mechanism is not well understood. Here, we report that JH and 20E antagonize each other’s biosynthesis in a major endocrine organ of Drosophila larvae: JH suppresses ecdysone biosynthesis and inhibits metamorphosis, whereas 20E suppresses JH biosynthesis and promotes metamorphosis. These data answer a long-standing question on how the mutual antagonism between the two major insect hormones regulates metamorphosis and may help to understand the hormonal regulation of developmental transition in mammals.

Neuronal cell loss is a defining feature of Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. We xenografted human or mouse neurons into the brain of a mouse model of AD. Only human neurons displayed tangles, Gallyas silver staining, granulovacuolar neurodegeneration (GVD), phosphorylated tau blood biomarkers, and considerable neuronal cell loss. The long noncoding RNA MEG3 was strongly up-regulated in human neurons . This neuron-specific long noncoding RNA is also up-regulated in AD patients. MEG3 expression alone was sufficient to induce necroptosis in human neurons in vitro. Down-regulation of MEG3 and inhibition of necroptosis using pharmacological or genetic manipulation of receptor-interacting protein kinase 1 (RIPK1), RIPK3, or mixed lineage kinase domain-like protein (MLKL) rescued neuronal cell loss in xenografted human neurons. This model suggests potential therapeutic approaches for AD and reveals a human-specific vulnerability to AD.