Article

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: 4.85). 03/2011; 33(7):1400-10. DOI: 10.1016/j.neurobiolaging.2011.02.003
Source: PubMed

ABSTRACT 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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    • "Advanced glycation end products (AGEs) can induce tau hyperphosphorylation and impair synapse and memory through the receptor for AGE (RAGE)-mediated GSK3 activation. Targeting the RAGE/GSK3 pathway can efficiently improve the AD-like histopathological changes and memory deterioration [61]. Another post-translational modification, e.g., glycosylation of tau, mainly through N-linkage, is an important factor that facilitates its hyperphosphorylation by kinases such as PKA, cdk5, and GSK3␤ [62] [63]. "
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