Pioglitazone ameliorates Aβ42 deposition in rats with diet-induced insulin resistance associated with AKT/GSK3β activation

Yang,Sisi; Chen,Zhe; Cao,Ming; Li,Renjie; Wang,Zhigang; Zhang,Muxun

doi:10.3892/mmr.2017.6342

Pioglitazone ameliorates Aβ42 deposition in rats with diet-induced insulin resistance associated with AKT/GSK3β activation

Authors:
- Sisi Yang
- Zhe Chen
- Ming Cao
- Renjie Li
- Zhigang Wang
- Muxun Zhang
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Affiliations: Department of Geriatrics, Tongji Hospital Affiliated to The Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China, Department of Integrated Chinese Traditional and Western Medicine, Tongji Hospital Affiliated to The Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China, Department of Emergency, Tongji Hospital Affiliated to The Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China, Department of Pathogen Biology, College of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China, Department of Endocrinology, Tongji Hospital Affiliated to The Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
Published online on: March 16, 2017 https://doi.org/10.3892/mmr.2017.6342
Pages: 2588-2594
Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Pioglitazone may have potential benefits as an alternative therapeutic treatment for patients with Alzheimer's disease (AD), particularly in individuals that also have comorbid diabetes; however, the mechanisms of action remain unclear. The present study aimed to explore the effects of pioglitazone on amyloid β, isoform 42 (Aβ42) deposition in rats with diet‑induced insulin resistance (IR). Diet‑induced IR model rats were established in the presence or absence of pioglitazone. Plasma glucose and insulin levels, and cerebrospinal ﬂuid insulin levels were measured; in addition, hippocampal tissues were collected for immunohistochemical analysis of Aβ42 expression. The levels of insulin‑degrading enzyme (IDE) and peroxisome proliferator‑activated receptor γ (PPARγ) mRNA and protein expression were analyzed by reverse transcription‑quantitative polymerase chain reaction and western blotting, respectively. In addition, the activation of glycogen synthase kinase 3β (GSK3β) induced by phosphatidylinositol 3‑kinase (PI3K) /protein kinase B (AKT) signaling was detected by western blotting. Results from the present study demonstrated that pioglitazone may enhance peripheral and brain insulin sensitivity in diet‑induced IR model rats. Treatment with pioglitazone ameliorated Aβ42 deposition in the hippocampus by increasing IDE and PPARγ expression. Notably, activation of the PI3K/AKT/GSK3β pathway was also demonstrated to serve a role in pioglitazone‑induced Aβ42 degradation, which was abrogated by the PPARγ antagonist GW9662. Results from the present study indicated that pioglitazone may improve insulin sensitivity and ameliorate Aβ42 accumulation in rats with diet‑induced IR by regulating AKT/GSK3β activation, suggesting that pioglitazone may be a promising drug for AD treatment.

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1	Musiek ES and Holtzman DM: Three dimensions of the amyloid hypothesis: Time, space and ‘wingmen’. Nat Neurosci. 18:800–806. 2015. View Article : Google Scholar : PubMed/NCBI
2	Talbot K and Wang HY: The nature, significance, and glucagon-like peptide-1 analog treatment of brain insulin resistance in Alzheimer's disease. Alzheimers Dement. 10:(1 Suppl). S12–S25. 2014. View Article : Google Scholar : PubMed/NCBI
3	Tolppanen AM, Solomon A, Soininen H and Kivipelto M: Midlife vascular risk factors and Alzheimer's disease: Evidence from epidemiological studies. J Alzheimers Dis. 32:531–540. 2012.PubMed/NCBI
4	Toda N, Ayajiki K and Okamura T: Obesity-induced cerebral hypoperfusion derived from endothelial dysfunction: One of the risk factors for Alzheimer's disease. Curr Alzheimer Res. 11:733–744. 2014. View Article : Google Scholar : PubMed/NCBI
5	Craft S: Insulin resistance syndrome and Alzheimer disease: Pathophysiologic mechanisms and therapeutic implications. Alzheimer Dis Assoc Disord. 20:298–301. 2006. View Article : Google Scholar : PubMed/NCBI
6	Wang F, Song YF, Yin J, Liu ZH, Mo XD, Wang DG, Gao LP and Jing YH: Spatial memory impairment is associated with hippocampal insulin signals in ovariectomized rats. PLoS One. 9:e1044502014. View Article : Google Scholar : PubMed/NCBI
7	Tucsek Z, Toth P, Sosnowska D, Gautam T, Mitschelen M, Koller A, Szalai G, Sonntag WE, Ungvari Z and Csiszar A: Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation, and oxidative stress in the mouse hippocampus: Effects on expression of genes involved in beta-amyloid generation and Alzheimer's disease. J Gerontol A Biol Sci Med Sci. 69:1212–1226. 2014. View Article : Google Scholar : PubMed/NCBI
8	Grasso G, Mielczarek P, Niedziolka M and Silberring J: Metabolism of cryptic peptides derived from neuropeptide FF precursors: The involvement of insulin-degrading enzyme. Int J Mol Sci. 15:16787–16799. 2014. View Article : Google Scholar : PubMed/NCBI
9	Park SA: A common pathogenic mechanism linking type-2 diabetes and Alzheimer's disease: Evidence from animal models. J Clin Neurol. 7:10–18. 2011. View Article : Google Scholar : PubMed/NCBI
10	Baker LD, Cross DJ, Minoshima S, Belongia D, Watson GS and Craft S: Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch Neurol. 68:51–57. 2011. View Article : Google Scholar : PubMed/NCBI
11	Jolivalt CG, Lee CA, Beiswenger KK, Smith JL, Orlov M, Torrance MA and Masliah E: Defective insulin signaling pathway and increased glycogen synthase kinase-3 activity in the brain of diabetic mice: Parallels with Alzheimer's disease and correction by insulin. J Neurosci Res. 86:3265–3274. 2008. View Article : Google Scholar : PubMed/NCBI
12	Schubert M, Gautam D, Surjo D, Ueki K, Baudler S, Schubert D, Kondo T, Alber J, Galldiks N, Küstermann E, et al: Role for neuronal insulin resistance in neurodegenerative diseases. Proc Natl Acad Sci USA. 101:3100–3105. 2005. View Article : Google Scholar
13	Sato T, Hanyu H, Hirao K, Kanetaka H, Sakurai H and Iwamoto T: Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer disease. Neurobiol Aging. 32:1626–1633. 2011. View Article : Google Scholar : PubMed/NCBI
14	Nicolakakis N, Aboulkassim T, Ongali B, Lecrux C, Fernandes P, Rosa-Neto P, Tong XK and Hamel E: Complete rescue of cerebrovascular function in aged Alzheimer's disease transgenic mice by antioxidants and pioglitazone, a peroxisome proliferator-activated receptor γ agonist. J Neurosci. 28:9287–9996. 2008. View Article : Google Scholar : PubMed/NCBI
15	Geldmacher DS, Fritsch T, McClendon MJ and Landreth G: A randomized pilot clinical trial of the safety of pioglitazone in treatment of patients with Alzheimer's disease. Arch Neuro. 68:45–50. 2011. View Article : Google Scholar
16	Wang Z, Yan Z, Zhang B, Rao Z, Zhang Y, Liu J, Yu L, Zhao Y, Yang B, Wu T and Gao J: Identification of a 5-gene signature for clinical and prognostic prediction in gastric cancer patients upon microarray data. Med Oncol. 30:6782013. View Article : Google Scholar : PubMed/NCBI
17	Pérez MJ and Quintanilla RA: Therapeutic actions of the thiazolidinediones in Alzheimer's disease. PPAR Res. 2015:9572482015. View Article : Google Scholar : PubMed/NCBI
18	Craft S: Insulin resistance syndrome and Alzheimer's disease: Age- and obesity-related effects on memory, amyloid, and inflammation. Neurobiol Aging. 26:65–69. 2005. View Article : Google Scholar : PubMed/NCBI
19	Sato N, Takeda S, Uchio-Yamada K, Ueda H, Fujisawa T, Rakugi H and Morishita R: Role of insulin signaling in the interaction between Alzheimer disease and diabetes mellitus: A missing link to therapeutic potential. Curr Aging Sci. 4:118–127. 2011. View Article : Google Scholar : PubMed/NCBI
20	Najem D, Bamji-Mirza M, Chang N, Liu QY and Zhang W: Insulin resistance, neuroinflammation, and Alzheimer's disease. Rev Neurosci. 25:509–525. 2014. View Article : Google Scholar : PubMed/NCBI
21	Mayeux R, Honig LS, Tang MX, Manly J, Stern Y, Schupf N and Mehta PD: Plasma A[beta]40 and A[beta]42 and Alzheimer's disease: Relation to age, mortality, and risk. Neurology. 61:1185–1190. 2003. View Article : Google Scholar : PubMed/NCBI
22	Qiu WQ and Folstein MF: Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer's disease: Review and hypothesis. Neurobiol Aging. 27:190–198. 2006. View Article : Google Scholar : PubMed/NCBI
23	Neumann KF, Rojo L, Navarrete LP, Farías G, Reyes P and Maccioni RB: Insulin resistance and Alzheimer's disease: Molecular links & clinical implications. Curr Alzheimer Res. 5:438–447. 2008. View Article : Google Scholar : PubMed/NCBI
24	Zhao WQ, De Felice FG, Fernandez S, Chen H, Lambert MP, Quon MJ, Krafft GA and Klein WL: Amyloid beta oligomers induce impairment of neuronal insulin receprors. Faseb J. 22:246–260. 2008. View Article : Google Scholar : PubMed/NCBI
25	Ho L, Qin W, Pompl PN, Xiang Z, Wang J, Zhao Z, Peng Y, Cambareri G, Rocher A, Mobbs CV, et al: Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease. FASEB J. 18:902–904. 2004.PubMed/NCBI
26	Fernández-Gamba A, Leal MC, Morelli L and Castaño EM: Insulin-degrading enzyme structure-function relationship and its possible roles in health and disease. Curr Pharm Des. 15:3644–3655. 2009. View Article : Google Scholar : PubMed/NCBI
27	Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ and Guenette S: Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci USA. 100:4162–4167. 2003. View Article : Google Scholar : PubMed/NCBI
28	Bertram L, Blacker D, Mullin K, Keeney D, Jones J, Basu S, Yhu S, McInnis MG, Go RC, Vekrellis K, et al: Evidence for genetic linkage of Alzheimer's disease to chromosome 10q. Science. 290:2302–2303. 2000. View Article : Google Scholar : PubMed/NCBI
29	Zahniser NR, Goens MB, Hanaway PJ and Vinych JV: Characterization and regulation of insulin receptors in rat brain. J Neurochem. 42:1354–1362. 1984. View Article : Google Scholar : PubMed/NCBI
30	Cook DG, Leverenz JB, McMillan PJ, Kulstad JJ, Ericksen S, Roth RA, Schellenberg GD, Jin LW, Kovacina KS and Craft S: Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon 4 allele. Am J Pathol. 162:313–319. 2003. View Article : Google Scholar : PubMed/NCBI
31	Chen J, Li S, Sun W and Li J: Anti-diabetes drug pioglitazone ameliorates synaptic defects in AD transgenic mice by inhibiting cyclin-dependent kinase 5 activity. PLoS One. 10:e01238642015. View Article : Google Scholar : PubMed/NCBI
32	Yin QQ, Pei JJ, Xu S, Luo DZ, Dong SQ, Sun MH, You L, Sun ZJ and Liu XP: Pioglitazone improves cognitive function via increasing insulin sensitivity and strengthening antioxidant defense system in fructose-drinking insulin resistance rats. PLoS One. 8:e593132013. View Article : Google Scholar : PubMed/NCBI
33	Searcy JL, Phelps JT, Pancani T, Kadish I, Popovic J, Anderson KL, Beckett TL, Murphy MP, Chen KC, Blalock EM, et al: Long-term pioglitazone treatment improves learning and attenuates pathological markers in a mouse model of Alzheimer's disease. J Alzheimers Dis. 30:943–961. 2012.PubMed/NCBI
34	Lee HK, Kumar P, Fu Q, Rosen KM and Querfurth HW: The insulin/Akt signaling pathway is targeted by intracellular beta-amyloid. Mol Biol Cell. 20:1533–1544. 2009. View Article : Google Scholar : PubMed/NCBI
35	Zhu X, Wang S, Yu L, Yang H, Tan R, Yin K, Jin J, Zhao H, Guan D and Xu Y: TL-2 attenuates β-amyloid induced neuronal apoptosis through the AKT/GSK-3β/β-catenin pathway. Int J Neuropsychopharmacol. 17:1511–1519. 2014. View Article : Google Scholar : PubMed/NCBI
36	Kwon KJ, Kim HJ, Shin CY and Han SH: Melatonin potentiates the neuroprotective properties of resveratrol against beta-amyloid-induced neurodegeneration by modulating AMP-activated protein kinase pathways. J Clin Neurol. 6:127–137. 2010. View Article : Google Scholar : PubMed/NCBI