His group was the first to identify Aβ as an endogenous ligand for TREM2, providing mechanistic insight as to how TREM2-expressing microglia are attracted to the Aβ plaque. Xu’s most recent work focused on addressing how a microglia-specific gene, TREM2, impacts AD risk. Xu’s research as an independent investigator at the Sanford-Burnham Prebys Medical Discovery Institute (2003–2020) expanded further, leading him to explore new mechanisms related to tau pathogenesis, novel molecular links between AD and Down’s syndrome (DS), and groundbreaking findings related to tauopathy, and neuroinflammation/glial biology. One milestone finding was that estrogen can reduce Aβ generation, providing a potential mechanistic link between menopause and a higher risk for developing AD.ĭr. Importantly, his postdoctoral research led to seminal findings describing the regulatory mechanisms for Aβ generation occurring via signal transduction pathways involving PKA, PKC, Abl kinase and insulin that controlled sorting of APP through intracellular compartments such as the endoplasmic reticulum, trans-Golgi network, and endosomal-lysosomal system. Together with Greengard and Gandy, Huaxi defined subcellular mechanisms underlying APP processing and consequent generation of the pathogenic amyloid-β (Aβ) peptide in AD. Xu then pursued postdoctoral training with another Nobel laureate, Paul Greengard at Rockefeller University (1994–1998), where he joined the Alzheimer’s disease (AD) program co-directed by Greengard and Sam Gandy, now a Professor at the Icahn School of Medicine at Mount Sinai. Xu’s early training during his PhD included areas of biochemistry, cell biology and neuroscience at Albert Einstein College of Medicine (1988–1993) where he was co-mentored by Dennis Shields and Nobel laureate, Gunter Blobel, investigating the mechanisms underlying proteolysis and trafficking of membrane and secretory proteins.
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