title: Neurogranin restores amyloid β-mediated synaptic transmission and long-term potentiation deficits.
abstract: Amyloid β (Aβ) is widely considered one of the early causes of cognitive deficits observed in Alzheimer's disease. Many of the deficits caused by Aβ are attributed to its disruption of synaptic function represented by its blockade of long-term potentiation (LTP) and its induction of synaptic depression. Identifying pathways that reverse these synaptic deficits may open the door to new therapeutic targets. In this study, we explored the possibility that Neurogranin (Ng)-a postsynaptic calmodulin (CaM) targeting protein that enhances synaptic function-may rescue Aβ-mediated deficits in synaptic function. Our results show that Ng is able to reverse synaptic depression and LTP deficits induced by Aβ. Furthermore, Ng's restoration of synaptic transmission is through the insertion of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs). These restorative effects of Ng are dependent on the interaction of Ng and CaM and CaM-dependent activation of CaMKII. Overall, this study identifies a novel mechanism to rescue synaptic deficits induced by Aβ oligomers. It also suggests Ng and CaM signaling as potential therapeutic targets for Alzheimer's disease as well as important tools to further explore the pathophysiology underlying the disease.
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 West Watertown Plank Rd., Milwaukee, WI 53132, United States; Neuroscience Research Center, Medical College of Wisconsin, 8701 West Watertown Plank Rd., Milwaukee, WI 53132, United States.
authors.forename: Kanwardeep Singh
authors.initials: KS
authors.lastname: Kaleka
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 West Watertown Plank Rd., Milwaukee, WI 53132, United States; Neuroscience Research Center, Medical College of Wisconsin, 8701 West Watertown Plank Rd., Milwaukee, WI 53132, United States. Electronic address: ngerges@mcw.edu.
authors.forename: Nashaat Z
authors.initials: NZ
authors.lastname: Gerges
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000166:cytology*; D006801:Humans; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects*; D016296:Mutagenesis; D009154:Mutation / Q000235:genetics; D009415:Nerve Net / Q000187:drug effects; D051579:Neurogranin / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018691:Excitatory Amino Acid Antagonists; D026941:Sodium Channel Blockers; D051579:Neurogranin; D013779:Tetrodotoxin
keywords: CaMKII; Calmodulin; LTP; Synaptic plasticity