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.
Highlights
We demonstrated for the first time that L-SPD improved the impaired memory that was correlated with decreased phosphorylation and surface expression of GluA1-containing amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors, as well as spine loss in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (APP/PS1) mice
L-SPD significantly rescued the impaired context-dependent fear memory (P = 0.045, compared with vehicle group of APP/PS1 mice) and partly improved tone-dependent fear memory (P = 0.005, compared with L-SPD group of WT mice; P = 0.037, compared with vehicle group of APP/PS1 mice) in APP/ PS1 mice. These results demonstrate that L-SPD can improve hippocampus-dependent memory loss
L-SPD (3 μM) itself could display long-term potentiation (LTP) and significantly preserved field excitatory postsynaptic potential (fEPSP) when it was co-perfused with amyloid β-derived diffusible ligands (ADDLs) (P = 0.027; Figure 7a and b). These results suggest that L-SPD significantly prevent LTP impairment induced by ADDLs, which links with cell surface and synaptic expression of GluA1-containing AMPA receptors
Summary
Protein kinase A (PKA) activation strongly increases exocytosis of AMPA receptors by direct phosphorylation of AMPA receptors.[11] Dopamine receptors have been grouped into two families, D1 type and D2 type. Our previous works have demonstrated that brief activation of D1-type receptor accelerates GluA1 externalization at extrasynaptic sites through a PKA-dependent pathway in hippocampal pyramidal neurons.[12] Another study has shown that activation of D1-type dopamine receptors protects neurons from synapse dysfunction induced by amyloid-β oligomers.[13] L-Stepholidine. We demonstrated for the first time that L-SPD improved the impaired memory that was correlated with decreased phosphorylation and surface expression of GluA1-containing AMPA receptors, as well as spine loss in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (APP/PS1) mice. L-SPD prevented ADDL-induced dysfunction of AMPA receptor trafficking in cultured hippocampal neurons and the inhibition of LTP in hippocampal slices through activation of D1/PKA signaling pathway
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