title: L-Stepholidine rescues memory deficit and synaptic plasticity in models of Alzheimer's disease via activating dopamine D1 receptor/PKA signaling pathway.
abstract: It is accepted that amyloid β-derived diffusible ligands (ADDLs) have a prominent role in triggering the early cognitive deficits that constitute Alzheimer's disease (AD). However, there is still no effective treatment for preventing or reversing the progression of the disease. Targeting α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor trafficking and its regulation is a new strategy for AD early treatment. Here we investigate the effect and mechanism of L-Stepholidine (L-SPD), which elicits dopamine D1-type receptor agonistic activity, while acting as D2-type receptor antagonist on cognition and synaptic plasticity in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (APP/PS1) mice, and hippocampal cultures or slices treated with ADDLs. L-SPD could improve the hippocampus-dependent memory, surface expression of glutamate receptor A (GluA1)-containing AMPA receptors and spine density in hippocampus of APP/PS1 transgenic mice. L-SPD not only rescued decreased phosphorylation and surface expression of GluA1 in hippocampal cultures but also protected the long-term potentiation in hippocampal slices induced by ADDLs. Protein kinase A (PKA) agonist Sp-cAMPS or D1-type receptor agonist SKF81297 had similar effects, whereas PKA antagonist Rp-cAMPS or D1-type receptor antagonist SCH23390 abolished the effect of L-SPD on GluA1 trafficking. This was mediated mainly by PKA, which could phosphorylate serine residue at 845 of the GluA1. L-SPD may be explored as a potential therapeutic drug for AD through a mechanism that improves AMPA receptor trafficking and synaptic plasticity via activating D1/PKA signaling pathway.
authors.affiliation: Jiangsu Key Laboratory of Anesthesiology, Xuzhou Medical College, Jiangsu 221004, China.|Jiangsu Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical College, Jiangsu 221004, China.
authors.forename: J-R
authors.initials: JR
authors.lastname: Hao
authors.affiliation: Jiangsu Key Laboratory of Anesthesiology, Xuzhou Medical College, Jiangsu 221004, China.|Jiangsu Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical College, Jiangsu 221004, China.
authors.forename: N
authors.initials: N
authors.lastname: Sun
authors.affiliation: Jiangsu Key Laboratory of Anesthesiology, Xuzhou Medical College, Jiangsu 221004, China.|Jiangsu Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical College, Jiangsu 221004, China.
authors.forename: L
authors.initials: L
authors.lastname: Lei
authors.affiliation: Jiangsu Key Laboratory of Anesthesiology, Xuzhou Medical College, Jiangsu 221004, China.|Jiangsu Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical College, Jiangsu 221004, China.
authors.forename: X-Y
authors.initials: XY
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Anesthesiology, Xuzhou Medical College, Jiangsu 221004, China.|Jiangsu Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical College, Jiangsu 221004, China.
authors.forename: B
authors.initials: B
authors.lastname: Yao
authors.affiliation: Jiangsu Key Laboratory of Anesthesiology, Xuzhou Medical College, Jiangsu 221004, China.|Jiangsu Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical College, Jiangsu 221004, China.
authors.forename: K
authors.initials: K
authors.lastname: Sun
authors.affiliation: Jiangsu Key Laboratory of Anesthesiology, Xuzhou Medical College, Jiangsu 221004, China.|Jiangsu Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical College, Jiangsu 221004, China.
authors.forename: R
authors.initials: R
authors.lastname: Hu
authors.affiliation: Jiangsu Key Laboratory of Anesthesiology, Xuzhou Medical College, Jiangsu 221004, China.|Jiangsu Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical College, Jiangsu 221004, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Anesthesiology, Xuzhou Medical College, Jiangsu 221004, China.|Jiangsu Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical College, Jiangsu 221004, China.
authors.forename: X-D
authors.initials: XD
authors.lastname: Shi
authors.affiliation: Jiangsu Key Laboratory of Anesthesiology, Xuzhou Medical College, Jiangsu 221004, China.|Jiangsu Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical College, Jiangsu 221004, China.
authors.forename: C
authors.identifier: http://orcid.org/0000-0001-5552-9639
authors.initials: C
authors.lastname: Gao
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001599:Berberine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1; D001599:Berberine; C010513:stepholidine; D017868:Cyclic AMP-Dependent Protein Kinases