title: Impaired TNF-alpha control of IP3R-mediated Ca2+ release in Alzheimer's disease mouse neurons.
abstract: The misguided control of inflammatory signaling has been previously implicated in the pathogenesis of several neurological disorders, including Alzheimer's disease (AD). Induction of tumor necrosis factor-alpha (TNF-alpha), a central mediator of neuroinflammation, occurs commensurate with the onset of early disease in 3xTg-AD mice, which develop both amyloid plaque and neurofibrillary tangle pathologies in an age- and region-dependent pattern. Herein, we describe regulation inherent to 3xTg-AD neurons, which results in the loss of TNF-alpha mediated enhancement of inositol 1,4,5 trisphosphate (IP3R)-mediated Ca2+ release. This modulation also leads to significant down-regulation of IP3R signaling following protracted cytokine exposure. Through the experimental isolation of each AD-related transgene, it was determined that expression of the PS1M146V transgene product is responsible for the loss of the TNF-alpha effect on IP3R-mediated Ca2+ release. Furthermore, it was determined that the suppression of TNF-alpha receptor expression occurred in the presence of the presenilin transgene. Our findings attribute this familial AD mutation to suppressing a Ca2+-regulated signal cascade potentially intended to "inform" neurons of proximal neuroinflammatory events and trigger compensatory responses for protection of neural transmission.
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Keigan M
authors.initials: KM
authors.lastname: Park
authors.forename: David I
authors.initials: DI
authors.lastname: Yule
authors.forename: William J
authors.initials: WJ
authors.lastname: Bowers
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D053763:Presenilins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D053763:Presenilins; D034741:RNA, Small Interfering; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium