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

Hei Jen Huang, Shu Ling Chen, Hsin Yu Huang, Ying Chieh Sun, Guan Chiun Lee, Guey Jen Lee-Chen, Hsiu Mei Hsieh-Li, Ming Tsan Su

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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 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. 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.

Original languageEnglish
Pages (from-to)763-773
Number of pages11
JournalPsychopharmacology
Volume236
Issue number2
DOIs
Publication statusPublished - 2019 Feb 14

Fingerprint

Alzheimer Disease
Hyperglycemia
N-(4-hydroxyphenyl)arachidonylamide
Cognitive Dysfunction
Inflammation
tau Proteins
Neuronal Plasticity
Inhibitory Concentration 50
Hippocampus
Down-Regulation
Phosphorylation
Water
Brain
Serum

Keywords

  • Alzheimer’s disease
  • AM404
  • Hyperglycemic
  • Therapeutics

ASJC Scopus subject areas

  • Pharmacology

Cite this

@article{500440ed8851406cb2a37ae16ced476c,
title = "Chronic low dose of AM404 ameliorates the cognitive impairment and pathological features in hyperglycemic 3xTg-AD mice",
abstract = "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 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. 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.",
keywords = "Alzheimer’s disease, AM404, Hyperglycemic, Therapeutics",
author = "Huang, {Hei Jen} and Chen, {Shu Ling} and Huang, {Hsin Yu} and Sun, {Ying Chieh} and Lee, {Guan Chiun} and Lee-Chen, {Guey Jen} and Hsieh-Li, {Hsiu Mei} and Su, {Ming Tsan}",
year = "2019",
month = "2",
day = "14",
doi = "10.1007/s00213-018-5108-0",
language = "English",
volume = "236",
pages = "763--773",
journal = "Psychopharmacology",
issn = "0033-3158",
publisher = "Springer Verlag",
number = "2",

}

TY - JOUR

T1 - Chronic low dose of AM404 ameliorates the cognitive impairment and pathological features in hyperglycemic 3xTg-AD mice

AU - Huang, Hei Jen

AU - Chen, Shu Ling

AU - Huang, Hsin Yu

AU - Sun, Ying Chieh

AU - Lee, Guan Chiun

AU - Lee-Chen, Guey Jen

AU - Hsieh-Li, Hsiu Mei

AU - Su, Ming Tsan

PY - 2019/2/14

Y1 - 2019/2/14

N2 - 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 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. 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.

AB - 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 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. 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.

KW - Alzheimer’s disease

KW - AM404

KW - Hyperglycemic

KW - Therapeutics

UR - http://www.scopus.com/inward/record.url?scp=85056671542&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056671542&partnerID=8YFLogxK

U2 - 10.1007/s00213-018-5108-0

DO - 10.1007/s00213-018-5108-0

M3 - Article

C2 - 30426182

AN - SCOPUS:85056671542

VL - 236

SP - 763

EP - 773

JO - Psychopharmacology

JF - Psychopharmacology

SN - 0033-3158

IS - 2

ER -