title: Alzheimer's phenotypes induced by overexpression of human presenilin 2 mutant proteins stimulate significant changes in key factors of glucose metabolism.
abstract: Alzheimer's disease (AD) is closely associated with significant defects in glucose metabolism. To investigate whether AD pathology induced by overexpression of human mutant presenilin 2 (PS2) protein induces changes in glucose metabolism, glucose‑related factors were analyzed in the brain of 12‑month‑old neuron‑specific enolase (NSE)/hPS2m transgenic (Tg) mice. NSE/hPS2m Tg mice used in this study showed AD‑like phenotypes such as the accumulation of Aβ‑42, the increase of γ‑secretase activity and Tau hyperphosphorylation. A significant increase of glucose levels accompanied by a decrease of insulin levels was detected in NSE/hPS2m Tg mice, while the expression levels of insulin receptors were significantly decreased in NSE/hPS2m Tg mice compared to the non‑Tg littermates without affecting the insulin‑like growth factor (IGF) receptor. Moreover, the levels of AKT phosphorylation involved in the downregulation of the insulin receptor signaling pathway were reduced in the brain of NSE/hPS2m Tg mice compared with non‑Tg littermate, although the levels of glycogen synthase kinase 3 (GSK‑3) β phosphorylation were higher in the NSE/hPS2m Tg mice compared to non-Tg littermates. Furthermore, the levels of the expression of Glut‑1 and ‑3 were significantly reduced in the NSE/hPS2m Tg mice compared to those of control mice without affecting the Glut‑4 protein expression between the two groups of mice. In particular, the levels of the Aβ‑42 peptide in the brain of insulin‑treated NSE/hPS2m Tg mice were found to be slightly lower compared with those of the Aβ‑42 peptide in the non‑treated PS2 transgenic mice. Thus, the data presented in this study provide strong evidence that key factors of glucose metabolism are closely associated with the AD pathology induced by the hPS2m protein, and that insulin can serve as a potential therapeutic for AD patients.
authors.affiliation: Department of Biomaterials Science, College of Natural Resources and Life Sciences, Pusan National University, Miryang, Gyeongsangnam‑do 627‑706, Republic of Korea.
authors.forename: Young Ju
authors.initials: YJ
authors.lastname: Lee
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: In Sik
authors.initials: IS
authors.lastname: Hwang
authors.forename: Moon Hwa
authors.initials: MH
authors.lastname: Kwak
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Lee
authors.forename: Young Jin
authors.initials: YJ
authors.lastname: Jung
authors.forename: Beum Soo
authors.initials: BS
authors.lastname: An
authors.forename: Hyeog Soong
authors.initials: HS
authors.lastname: Kwon
authors.forename: Byoung Chul
authors.initials: BC
authors.lastname: Kim
authors.forename: Seon Jong
authors.initials: SJ
authors.lastname: Kim
authors.forename: Joo Man
authors.initials: JM
authors.lastname: Kim
authors.forename: Dae Youn
authors.initials: DY
authors.lastname: Hwang
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism*; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007328:Insulin / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000378:metabolism*; D010641:Phenotype; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010766:Phosphorylation; D053766:Presenilin-2 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D051246:Glucose Transport Proteins, Facilitative; D007328:Insulin; D050505:Mutant Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D010751:Phosphopyruvate Hydratase; D005947:Glucose