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.
Highlights
Alzheimer’s disease (AD) is the most common progressive neurodegenerative disease
We suggest that chronic systemic administration of AM404 at low dose could be a potential therapeutic for AD, which might be through Akt/GSK3β pathway, not dependent by a direct GSK3β inhibitor, or receptor of CB1 and TRVP1
AM404 was further applied to hyperglycemic 3×Tg-AD mice to validate its in vivo function
Summary
Alzheimer’s disease (AD) is the most common progressive neurodegenerative disease. The annual incidence of AD is currently estimated at 4.6 million cases, and as the general population ages, the worldwide prevalence is expected to increase to more than 80 million cases by the year 2040 (Ferri et al 2005). The treatment options for AD only ameliorate the symptoms and do not inhibit the natural progression of AD. Accumulating evidence has demonstrated that GSK3β plays a role in tau hyperphosphorylation and the associated memory impairment in AD (Dolan and Johnson 2010). The oxidative stress, inflammation, and neuroinflammation associated with AD are mediated by GSK3β activation (Zhang et al 2015; D’Angelo et al 2016). Evidence shows that GSK-3β is a potential link between diabetes mellitus (DM) and AD (Zhang et al 2018), and DM might accelerate the progression of AD (Guo et al 2016). Hyperglycemia was applied to accelerate the phenotypes of 3xTg-AD mice at 6 months old in the study
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