Abstract
Nutritional factors can affect the risk of developing neurological disorders and their rate of progression. In particular, abnormalities of carbohydrate metabolism in diabetes mellitus patients lead to an increased risk of neurological disorders such as Alzheimer’s disease (AD). In this study, we investigated the relationship between nervous system disorder and the pathogenesis of AD by exposing SH-SY5Y neuroblastoma cells to glyceraldehyde (GA). We previously reported that GA-derived toxic advanced glycation end products (toxic AGEs, TAGE) induce AD-like alterations including intracellular tau phosphorylation. However, the role of TAGE and their target molecules in the pathogenesis of AD remains unclear. In this study, we investigated the target protein for TAGE by performing two-dimensional immunoblot analysis with anti-TAGE antibody and mass spectrometry and identified β-tubulin as one of the targets. GA treatment induced TAGE-β-tubulin formation and abnormal aggregation of β-tubulin, and inhibited neurite outgrowth in SH-SY5Y cells. On the other hand, glucose-derived AGEs were also involved in developing AD. However, glucose did not make abnormal aggregation of β-tubulin and did not inhibit neurite outgrowth. Understanding the underlying mechanism of TAGE-β-tubulin formation by GA and its role in neurodegeneration may aid in the development of novel therapeutics and neuroprotection strategies.
Highlights
The balanced intake of basic nutrients including carbohydrates is necessary to maintain human health
There have been many reports regarding whether type 2 diabetes mellitus (DM) is a clinical risk factor for Alzheimer’s disease (AD), given that the incidence of AD is as much as 2–5 times higher in DM patients [1]
1 mM GA increased the formation of toxic advanced glycation end products (TAGE) in SH-SY5Y cells and showed cell death within 24 h [9], but it was unclear which proteins were the targets of TAGE formation
Summary
The balanced intake of basic nutrients including carbohydrates is necessary to maintain human health. Reactive derivatives from non-enzymatic sugar–protein condensation reactions, as well as lipids and nucleic acids exposed to reducing sugars such as glucose, form a heterogeneous group of irreversible adducts called advanced glycation end products (AGEs) [2]. Glucose-derived AGE (Glu-AGE) have been mainly investigated in the AD investigation fields. Seven immunochemically distinct classes of AGEs have been detected in sera from hemodialysis patients with diabetic neuropathy (DN-HD) [7]. Using a neuronal culture system, we previously confirmed that GA-derived toxic advanced glycation end products (toxic AGEs, TAGE) are strongly neurotoxic [8]. While the anti-TAGE antibody suppressed the neurotoxicity of serum AGEs from DN-HD patients, such effects were not observed with the other antibodies, such as glucose-AGEs [8].
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