Browsing by Subject "ADAM10"

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    ADAM10 Expression and Promoter Haplotype in Alzheimer’s Disease
    (Elsevier, 2012) Bekris, L. M.; Lutz, F.; Li, G.; Galasko, D. R.; Farlow, M. R.; Quinn, J. F.; Kaye, J. A.; Leverenz, J. B.; Tsuang, D. W.; Montine, T. J.; Peskind, E. R.; Yu, C. E.; Neurology, School of Medicine
    Alzheimer's disease is confirmed at autopsy according to the accumulation of brain neuritic plaques and neurofibrillary tangles in the brain. Neuritic plaques contain amyloid-β (Aβ) and lower levels of Aβ correspond to an increase in ADAM10 α-secretase activity. ADAM10 α-secretase activity produces a soluble amyloid precursor protein (APP) alpha (sAPPα) product and negates the pathological production of Aβ. In this investigation, it was hypothesized that genetic variation with the ADAM10 promoter is associated with ADAM10 expression levels as well as cerebrospinal fluid sAPPα levels. Results from this investigation suggest that the ADAM10 rs514049-rs653765 C-A promoter haplotype is associated with: (1) higher CSF sAPPα levels in cognitively normal controls compared with Alzheimer's disease (AD) patients, (2) higher postmortem brain hippocampus, but not cerebellum, ADAM10 protein levels in subjects with low plaque scores compared with those with high plaque scores, and (3) higher promoter activity for promoter-only reporter constructs compared with promoter 3' untranslated region (3'UTR) constructs in the human neuroblastoma SHSY5Y cell line, but not in HepG2 or U118 cell lines. Taken together, these findings suggest that ADAM10 expression is modulated according to a promoter haplotype that is influenced in a brain region- and cell type-specific manner.
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    Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling
    (Nature Research, 2019-06-17) Gunner, Georgia; Cheadle, Lucas; Johnson, Kasey M.; Ayata, Pinar; Badimon, Ana; Mondo, Erica; Nagy, M. Aurel; Liu, Liwang; Bemiller, Shane M.; Kim, Ki-Wook; Lira, Sergio A.; Lamb, Bruce T.; Tapper, Andrew R.; Ransohoff, Richard M.; Greenberg, Michael E.; Schaefer, Anne; Schafer, Dorothy P.; Psychiatry, School of Medicine
    Microglia rapidly respond to changes in neural activity and inflammation to regulate synaptic connectivity. The extracellular signals, particularly neuron-derived molecules, that drive these microglial functions at synapses remain a key open question. Here we show that whisker lesioning, known to dampen cortical activity, induces microglia-mediated synapse elimination. This synapse elimination is dependent on signaling by CX3CR1, the receptor for microglial fractalkine (also known as CXCL1), but not complement receptor 3. Furthermore, mice deficient in CX3CL1 have profound defects in synapse elimination. Single-cell RNA sequencing revealed that Cx3cl1 is derived from cortical neurons, and ADAM10, a metalloprotease that cleaves CX3CL1 into a secreted form, is upregulated specifically in layer IV neurons and in microglia following whisker lesioning. Finally, inhibition of ADAM10 phenocopies Cx3cr1−/− and Cx3cl1−/− synapse elimination defects. Together, these results identify neuron-to-microglia signaling necessary for cortical synaptic remodeling and reveal that context-dependent immune mechanisms are utilized to remodel synapses in the mammalian brain.