Impaired TNF-alpha control of IP3R-mediated Ca2+ release in Alzheimer's disease mouse neurons.
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.
Park
Keigan M
KM
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Yule
David I
DI
Bowers
William J
WJ
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*
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