Suppression of InsP3 receptor-mediated Ca2+ signaling alleviates mutant presenilin-linked familial Alzheimer's disease pathogenesis.
Exaggerated intracellular Ca(2+) signaling is a robust proximal phenotype observed in cells expressing familial Alzheimer's disease (FAD)-causing mutant presenilins (PSs). The mechanisms that underlie this phenotype are controversial and their in vivo relevance for AD pathogenesis is unknown. Here, we used a genetic approach to identify the mechanisms involved and to evaluate their role in the etiology of AD in two FAD mouse models. Genetic reduction of the type 1 inositol trisphosphate receptor (InsP3R1) by 50% normalized exaggerated Ca(2+) signaling observed in cortical and hippocampal neurons in both animal models. In PS1M146V knock-in mice, reduced InsP3R1 expression restored normal ryanodine receptor and cAMP response element-binding protein (CREB)-dependent gene expression and rescued aberrant hippocampal long-term potentiation (LTP). In 3xTg mice, reduced InsP3R1 expression profoundly attenuated amyloid β accumulation and tau hyperphosphorylation and rescued hippocampal LTP and memory deficits. These results indicate that exaggerated Ca(2+) signaling, which is associated with FAD PS, is mediated by InsP3R and contributes to disease pathogenesis in vivo. Targeting the InsP3 signaling pathway could be considered a potential therapeutic strategy for patients harboring mutations in PS linked to AD.
Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Dustin
D
Shilling
Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Marioly
M
Müller
Departments of Pediatrics, Neurology, and Neuroscience, Perelman School of Medicine, University of Pennsylvania and the Division of Neurology and the Pediatric Regional Epilepsy Program, the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
Hajime
H
Takano
Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Don-On Daniel
DO
Mak
Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, and.
Ted
T
Abel
Departments of Pediatrics, Neurology, and Neuroscience, Perelman School of Medicine, University of Pennsylvania and the Division of Neurology and the Pediatric Regional Epilepsy Program, the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
Douglas A
DA
Coulter
Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 foskett@mail.med.upenn.edu.
J Kevin
JK
Foskett
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D020013:Calcium Signaling / Q000235:genetics*; D002540:Cerebral Cortex / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000235:genetics; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D053496:Inositol 1,4,5-Trisphosphate Receptors; D053764:Presenilin-1; D019837:Ryanodine Receptor Calcium Release Channel
Alzheimer's disease; Mouse model; amyloid; calcium; ion channel; memory