ArticlePsychopharmacology2019
Chronic low dose of AM404 ameliorates the cognitive impairment and pathological features in hyperglycemic 3xTg-AD mice.
Article in Psychopharmacology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 18 citations in OpenAlex.
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- Rose Bengal inhibits β-amyloid oligomers-induced tau hyperphosphorylation via acting on Akt and CDK5 kinases.Psychopharmacology · 2022Article
- Stem cell therapy for Alzheimer's disease: An overview of experimental models and reality.Animal models and experimental medicine · 2022Review
- Targeting the cannabinoid system to counteract the deleterious effects of stress in Alzheimer's disease.Frontiers in aging neuroscience · 2022Review
- On the Biomedical Properties of Endocannabinoid Degradation and Reuptake Inhibitors: Pre-clinical and Clinical Evidence.Neurotoxicity research · 2021Review
- When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer's and Huntington's Disease.International journal of molecular sciences · 2021Review
- Anti-Inflammatory and Anti-Oxidative Effects of AM404 in IL-1β-Stimulated SK-N-SH Neuroblastoma Cells.Frontiers in pharmacology · 2021Article
- Functional Mechanism of Bone Marrow-Derived Mesenchymal Stem Cells in the Treatment of Animal Models with Alzheimer's Disease: Inhibition of Neuroinflammation.Journal of inflammation research · 2021Review
- Article
- Targeting Inflammation, PHA-767491 Shows a Broad Spectrum in Protein Aggregation Diseases.Journal of molecular neuroscience : MN · 2020Article
- Alcohol drinking exacerbates neural and behavioral pathology in the 3xTg-AD mouse model of Alzheimer's disease.International review of neurobiology · 2019Review
- Neuroprotective Effect of AM404 Against NMDA-Induced Hippocampal Excitotoxicity.Frontiers in cellular neuroscience · 2019Article
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
rationaleHyperglycemia accelerates the progression of Alzheimer's disease (AD), and GSK3β plays a potential link between AD and hyperglycemia. Therefore, a direct or indirect GSK3β inhibition may have potential to delay the progression of AD. Our previous biochemical assay identified AM404 as a GSK3β inhibitor at high dose (IC50 = 5.353 μM); however, other study suggests that AM404 impaired synaptic plasticity of hippocampus at high dose (10 mg/kg; i.p.). Therefore, the dose and duration of treatment are crucial for the effects of AM404.
objectiveThe effects and molecular mechanisms of AM404 at low dose were evaluated from in vitro to in vivo models.
methodsAM404 (0.1-0.5 μM) was tested on tau hyperphosphorylated mouse hippocampal primary cultures treated with Wortmannin (WT) and GF109203X (GFX). Hyperglycemic triple transgenic AD (3×Tg-AD) mice at 6 months old were intraperitoneally injected with AM404 (0.25 mg/kg) for 4 weeks. The spatial learning and memory of mice were measured using the Morris water maze. Mouse brain and serum samples were collected for pathological analyses.
resultsAM404 (0.5 μM) exhibited significantly augmented neuroprotection toward tau hyperphosphorylation in primary cultures. The chronic systemic administration of AM404 (0.25 mg/kg) attenuated cognitive deficits in hyperglycemic 3×Tg-AD mice. Moreover, chronic low dose of AM404 significantly attenuated Aβ production, tau protein phosphorylation, and inflammation associated with an increase of pS473Akt and pS9-GSK3β. Therefore, AM404 at low dose, not only increased neuroprotection, but also ameliorated cognitive deficit, could be partly by regulating the Akt/GSK3β signaling, which may contribute to downregulation of Aβ, tau hyperphosphorylation, and inflammation in hyperglycemic 3×Tg-AD mice.
conclusionsThese results highlight that chronic administration of AM404 at low dose may be through the Akt/GSK3β pathway to ameliorate the impairment in hyperglycemic 3×Tg-AD mice.
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