Chronic low dose of AM404 ameliorates the cognitive impairment and pathological features in hyperglycemic 3xTg-AD mice

• Published in: Psychopharmacology Vol. 236; no. 2; pp. 763 - 773
• Main Authors: Huang, Hei-Jen, Chen, Shu-Ling, Huang, Hsin-Yu, Sun, Ying-Chieh, Lee, Guan-Chiun, Lee-Chen, Guey-Jen, Hsieh-Li, Hsiu Mei, Su, Ming-Tsan
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.02.2019; Springer; Springer Nature B.V
• Subjects: Advertising executives; AKT protein; Alzheimer Disease - drug therapy; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Animal models; Animals; Arachidonic Acids - administration & dosage; Biochemistry; Biomedical and Life Sciences; Biomedicine; Brain; Care and treatment; Cognitive ability; Cognitive disorders; Cognitive Dysfunction - drug therapy; Cognitive Dysfunction - genetics; Cognitive Dysfunction - metabolism; Culture; Development and progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Genetic engineering; Glycogen Synthase Kinase 3 beta; Health aspects; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Humans; Hyperglycemia; Hyperglycemia - drug therapy; Hyperglycemia - genetics; Hyperglycemia - metabolism; Impairment; Male; Medical schools; Metabolites; Mice; Mice, Inbred C57BL; Mice, Obese; Mice, Transgenic; Molecular modelling; Neuroprotection; Neurosciences; Original Investigation; Pharmacology/Toxicology; Phosphorylation; Pregnancy; Psychiatry; Rodents; Spatial discrimination; Spatial discrimination learning; Spatial memory; Synaptic plasticity; Tau protein; tau Proteins - genetics; tau Proteins - metabolism; Transgenic mice; Wortmannin; AM404; Hyperglycemic; Alzheimer’s disease; Therapeutics
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-018-5108-0

Rationale Hyperglycemia 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. Objective The effects and molecular mechanisms of AM404 at low dose were evaluated from in vitro to in vivo models. Methods AM404 (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 inject e d 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. Results AM404 (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. Conclusions These 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.