title: AGEs induce Alzheimer-like tau pathology and memory deficit via RAGE-mediated GSK-3 activation.
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.
authors: Department of Pathophysiology, Key Laboratory of Neurological Diseases of Education Committee of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Xiao-Hong
authors: XH
authors: Li
authors: Bing-Ling
authors: BL
authors: Lv
authors: Jia-Zhao
authors: JZ
authors: Xie
authors: Jing
authors: J
authors: Liu
authors: Xin-Wen
authors: XW
authors: Zhou
authors: Jian-Zhi
authors: JZ
authors: Wang
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D017127:Glycation End Products, Advanced / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology*; D013569:Synapses / Q000201:enzymology / Q000378:metabolism; D016875:tau Proteins / Q000096:biosynthesis* / Q000633:toxicity
chemical_list: D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D016875:tau Proteins; D038362:Glycogen Synthase Kinase 3