Impaired TNF-α control of IP3R-mediated Ca2+ release in Alzheimer's disease mouse neurons |
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| Authors: | Keigan M Park David I Yule William J Bowers |
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| Institution: | 1. Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA;2. Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA;3. Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA;4. Center for Neural Development and Disease, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14642, USA;1. Division of Molecular Pharmacology, Department of Pharmacology, Jichi Medical University, Tochigi 329-0498, Japan;2. Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan;1. Division of Molecular Pharmacology, Department of Pharmacology, Jichi Medical University, Tochigi 329-0498, Japan;2. Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Tochigi 329-0498, Japan;3. Department of Clinical Laboratory Medicine, Jichi Medical University, Tochigi 329-0498, Japan;1. Department of Neurosciences, University of California, San Diego, CA 92037, USA;2. Departments of Medicine and Physiology, National University of Singapore, Yong Loo Lin School of Medicine, Singapore, 117597, Singapore;3. Department of Neuroscience, University of Florida, Gainesville, FL 32611, USA;4. Department of Neurology, Soonchunhyang University Bucheon Hospital, Bucheon, 14584, Republic of Korea;5. Université de Montpellier, Montepellier, F-34095, France;6. Inserm, U 1198, Montepellier, F-34095, France;7. EPHE, Paris, F-75014, France;1. Center for Human Genetics, Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven, Leuven, Belgium;2. VIB Center for the Biology of Disease, Leuven, Belgium;3. German Center for Neurodegenerative Diseases, Munich and Technical University Munich, Munich, Germany;4. Laboratory of Biological Psychology and Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven, Belgium;5. Shire-Movetis NV, Turnhout, Belgium;1. Department of Pharmacy, Pharmaceutical Biotechnology, Center for System based Drug Research, Ludwig Maximilians University, Munich, Germany;2. Institute of Experimental Oncology and Therapy Research, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany;3. Institute of Molecular Immunology, Helmholtz Zentrum München, Munich, Germany;4. Center for NanoScience (CeNS), Ludwig Maximilians University, Munich, Germany;1. Université Lille 1, F-59650 Villeneuve d’Ascq, France;2. INSERM U908, F-59650 Villeneuve d’Ascq, France;3. CNRS UMR 8161, Institut Pasteur de Lille, F-59800 Lille, France |
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| 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-α), 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-α 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-α effect on IP3R-mediated Ca2+ release. Furthermore, it was determined that the suppression of TNF-α 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. |
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