L-Stepholidine rescues memory deficit and synaptic plasticity in models of Alzheimer’s disease via activating dopamine D1 receptor/PKA signaling pathway
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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.
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The increase of DA drive, evoked by dopaminergic drugs or stimulation of dopaminergic neurotransmission, improves synaptic plasticity dysfunctions, cognitive impairment and memory deficits in different experimental models of AD.
“the increase of DA drive -evoked by dopaminergic drugs or stimulation of the dopa minergic neurotransmission -improves synaptic plasticity dysfunctions, cognitive impairment and memory deficits in different experimental models of AD”
From Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s Disease (2021) · cites this paper as Hao et al., 2015
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- Authors
- Hao, J.-R., Sun, N., Lei, L., Li, X.-Y., Yao, B., Sun, K., Hu, R., Zhang, X., Shi, X.-D., & Gao, C.
- Affiliations
- Xuzhou Medical College (CN)
- Corresponding author
- Gao, C
- Venue
- Cell Death & Disease
- Published
- 2015-11-05
- Volume
- 6
- Issue
- 11
- Pages
- e1965-e1965
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC4670924
- OpenAlex
- W1931174500
- Cited by
- 53
- References
- 46
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 2 · 2023: 3 · 2022: 7 · 2021: 6 · 2020: 4 · 2019: 12 · 2018: 5 · 2017: 4 · 2016: 3
- FWCI
- 3.19
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81300930, 81471101, BK20130232, 81273489)
- Government of Jiangsu Province
- Natural Science Foundation of Jiangsu Province
- Qinglan Project of Jiangsu Province of China
- Key University Science Research Project of Jiangsu Province
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, dopamine D1 receptor, protein kinase A signaling, AMPA receptor trafficking, GluA1 phosphorylation, APP/PS1 mice, hippocampal-dependent memory, synaptic plasticity, long-term potentiation, dopamine D2 receptor antagonists, cognitive impairment
- MeSH terms
- Alzheimer Disease, Animals, Berberine, Male, Memory Disorders, Mice, Transgenic, Antipsychotic Agents, Signal Transduction, Rats, Sprague-Dawley, Receptors, Dopamine D1, Cyclic AMP-Dependent Protein Kinases, Dopamine Agonists, Mice, Rats
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