AGEs induce Alzheimer-like tau pathology and memory deficit via RAGE-mediated GSK-3 activation

Department of Pathophysiology, Key Laboratory of Neurological Diseases of Education Committee of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Neurobiology of aging (Impact Factor: 5.01). 03/2011; 33(7):1400-10. DOI: 10.1016/j.neurobiolaging.2011.02.003
Source: PubMed


Accumulation of β-amyloid and hyperphosphorylated tau with synapse damage and memory deterioration are hallmark lesions of Alzheimer disease (AD), but the upstream causative factors are elusive. The advanced glycation endproducts (AGEs) are elevated in AD brains and the AGEs can stimulate β-amyloid production. Whether and how AGEs may cause AD-like tau hyperphosphorylation and memory-related deficits is not known. Here we report that AGEs induce tau hyperphosphorylation, memory deterioration, decline of synaptic proteins, and impairment of long-term potentiation (LTP) in rats. In SK-NS-H cells, upregulation of AGEs receptor (RAGE), inhibition of Akt, and activation of glycogen synthase kinase-3 (GSK-3), Erk1/2, and p38 were observed after treatment with AGEs. In rats, blockage of RAGE attenuated the AGE-induced GSK-3 activation, tau hyperphosphorylation, and memory deficit with restoration of synaptic functions, and simultaneous inhibition of GSK-3 also antagonized the AGE-induced impairments. Our data reveal that AGEs can induce tau hyperphosphorylation and impair synapse and memory through RAGE-mediated GSK-3 activation and targeting RAGE/GSK-3 pathway can efficiently improve the AD-like histopathological changes and memory deterioration.

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    • "Here, we show that the CaMKII (but not GSK-3b) was activated in the presence of 10 mM D-ribose, indicating that CaMKII has the potential to play an important role in the phosphorylation of Tau in the presence of ribosylated AGEs. This mechanism of Tau hyperphosphorylation differs from that induced by glucosylated AGEs, where GSK-3 is activated instead (Li et al., 2012), and ribosylated and glucosylated AGEs enhance Tau phosphorylation using different kinase pathways. Note that D-glucose does not show any direct effect on Tau phosphorylation except for glucosylated AGEs. "
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    ABSTRACT: Type 2 diabetes mellitus (T2DM) is regarded as one of the serious risk factors for age-related cognitive impairment; however, a causal link between these two diseases has so far not been established. It was recently discovered that, apart from high D-glucose levels, T2DM patients also display abnormally high concentrations of uric D-ribose. Here, we show for the first time that the administration of D-ribose, the most active glycator among monosaccharides, produces high levels of advanced glycation end products (AGEs) and, importantly, triggers hyperphosphorylation of Tau in the brain of C57BL/6 mouse and neuroblastoma N2a cells. However, the administration of D-glucose showed no significant changes in Tau phosphorylation under the same experimental conditions. Crucially, suppression of AGE formation using an AGEs inhibitor (aminoguanidine) effectively prevents hyperphosphorylation of Tau protein. Further study shows AGEs resulted from ribosylation activate calcium-/calmodulin-dependent protein kinase type II (CaMKII), a key kinase responsible for Tau hyperphosphorylation. These data suggest that there is indeed a mechanistic link between ribosylation and Tau hyperphosphorylation. Targeting ribosylation by inhibiting AGE formation may be a promising therapeutic strategy to prevent Alzheimer's disease-like Tau hyperphosphorylation and diabetic encephalopathies. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
    Aging cell 06/2015; 14(5). DOI:10.1111/acel.12355 · 6.34 Impact Factor
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    • "After drug administration for 25 d, the spatial memory ability of rats was determined by the Morris water maze test [18]. "
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    ABSTRACT: Ginseng, the root of Panax ginseng (PG), is used widely as a herbal medicine to prevent and treat various diseases. Panax ginseng has pharmacological effects on neurodegenerative diseases such as Alzheimer's disease (AD). The present study evaluated the neuroprotective effects of PG and its possible neuroprotective mechanisms in advanced glycation end product (AGE)-induced AD in a rat model. Advanced glycation end products were injected bilaterally into the CA3 region of the rats' brains. The Morris water maze test and step-down type passive avoidance test were performed to evaluate their memory and cognitive abilities. The oxidation indexes in the hippocampus were detected. Immunohistochemistry was conducted to visualize the receptors for advanced glycation end products (RAGEs) and nuclear factor-kappa-light-chain-enhancer of activated B cell (NF-κB). Behavioral results showed that PG (1 g/kg, 0.5 g/kg, and 0.25 g/kg) significantly shortened the escape latency, remarkably increased the number of crossing times, significantly decreased the number of errors, and prolonged the latency in rats with AGE-induced AD. Panax ginseng also significantly reduced the malondialdehyde level, increased the glutathione content, and increased superoxide dismutase activity in the hippocampus. Panax ginseng significantly decreased the expression of RAGE and NF-κB. The blockade of anti-RAGE antibody could significantly reduce AGE-induced impairments and regulate these expressions. Our results demonstrated that PG significantly inhibits AGE-induced memory impairment and attenuates Alzheimer-like pathophysiological changes. These neuroprotective effects of PG may be associated with the RAGE/NF-κB pathway. Our results provided the experimental basis for applying PG in preventing and treating AD.
    Journal of ginseng research 11/2014; 39(2). DOI:10.1016/j.jgr.2014.09.002 · 2.82 Impact Factor
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    • "AGEs play an important role in the relationship between MMP-2 and AD. Receptor for AGEs (RAGE), a multiligand receptor in the immunoglobulin superfamily, binds a broad repertoire of ligands, including AGEs, Aβ, S100/calgranulin family of proinflammatory cytokine-like mediators, and amphoterin [9]. RAGE expression in neurons and human brain microvascular endothelial cells is increased on treatment with Aβ [10]. "
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    ABSTRACT: Alzheimer's disease (AD) is the most prevalent type of dementia. Pathological changes in the AD brain include amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs), as well as neuronal death and synaptic loss. Matrix metalloproteinases (MMPs) play an important role as inflammatory components in the pathogenesis of AD. MMP-2 might be assumed to have a protective role in AD and is the major MMP which is directly linked to Aβ in the brain. Synthesis of MMP-9 can be induced by Aβ, and the enzymes appear to exert multiple effects in AD in senile plaque homoeostasis. The proaggregatory influence on tau oligomer formation in strategic brain regions may be a potential neurotoxic side effect of MMP-9. MMP-3 levels are correlated to the duration of AD and correlate with the CSF T-tau and P-tau levels in the elderly controls. Elevated brain levels of MMP-3 might result in increased MMP-9 activity and indirectly facilitate tau aggregation. At present, the clinical utility of these proteins, particularly in plasma or serum, as potential early diagnostic biomarkers for AD remains to be established. More research is needed to understand the diverse roles of these proteases to design specific drugs and devise therapeutic strategies for AD.
    BioMed Research International 06/2014; 2014:908636. DOI:10.1155/2014/908636 · 1.58 Impact Factor
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