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.

Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer’s disease

“…The activation of D1 receptors was followed by the increase of GluA1 expression in the PSD (Fig. 6b), in line with previous reports5556. Similar results were also obtained by L -DOPA sub-chronic treatment that led to a restoration of both D1 receptors and GluA1 expression in hippocampal PSD fractions (Fig.…”

“…In recent years accumulating evidence has demonstrated a link between AD-related memory dysfunction and deficits in DA signalling in patients and experimental models of AD (refs 49, 50, 51, 52, 56, 57, 58, 59, 60, 61). Here, in a mouse model of AD, at a stage when no Aβ-plaque deposition, hyperphosphorylated tau tangles or any sign of neuronal loss in cortical and hippocampal regions involved in memory deficits has yet occurred212324, we provide evidence that a specific apoptotic process is taking place in the VTA, causing a progressive degeneration of the DAergic neuronal population.…”

Differences in DNA Methylation Reprogramming Underlie the Sexual Dimorphism of Behavioral Disorder Caused by Prenatal Stress in Rats

“…Rats were anesthetized with isoflurane and sacrificed by decapitation. The whole brain was removed from the skull and stained using the FD Rapid Golgi stain Kit (FD NeuroTechnologies, Columbia, MD, United States; PK401) as we previously described (Hao et al, 2015). Specially, there were 5 rats per group and about six neurons from brain slices of the same coronal section in each rat were chosen.…”

Acetylation of AMPA Receptors Regulates Receptor Trafficking and Rescues Memory Deficits in Alzheimer's Disease

“…However, although compounds showed some success in animal models ( Bretin et al., 2017 ; Giralt et al., 2017 ; Lauterborn et al., 2016 ), they have had low clinical success ( Bernard et al., 2019 ; Trzepacz et al., 2013 ; Wezenberg et al., 2007 ). Owing to a lack of chemical diversity among the Ampakines, alternative strategies for AMPAR-based treatment are being considered ( Chang et al., 2012 ; Hao et al., 2015 ; Lee et al., 2016 ; Zhao et al., 2019 ). Our results provide a basis for pharmacological manipulation of AMPAR acetylation as a potential therapeutic strategy.…”