Insulin-degrading enzyme: new therapeutic target for diabetes and Alzheimer’s disease?

References

• Duckworth WC, Bennett RG, Hamel FG. Insulin degradation: progress and potential. Endocr Rev. 1998;19:608–24.
   PubMed Web of Science ®Google Scholar
• Mirsky IA, Broh-Kahn RH. The inactivation of insulin by tissue extracts; the distribution and properties of insulin inactivating extracts. Arch Biochem. 1949;20:1–9.
   PubMedGoogle Scholar
• Affholter JA, Fried VA, Roth RA. Human insulin-degrading enzyme shares structural and functional homologies with E. coli protease III. Science. 1988;242:1415–18.
   PubMed Web of Science ®Google Scholar
• Vekrellis K, Ye Z, Qiu WQ, Walsh D, Hartley D, Chesneau V, et al. Neurons regulate extracellular levels of amyloid beta-protein via proteolysis by insulin-degrading enzyme. J Neurosci. 2000;20:1657–65.
   PubMed Web of Science ®Google Scholar
• Farris W, Leissring MA, Hemming ML, Chang AY, Selkoe DJ. Alternative splicing of human insulin-degrading enzyme yields a novel isoform with a decreased ability to degrade insulin and amyloid beta-protein. Biochemistry. 2005;44:6513–25.
   PubMed Web of Science ®Google Scholar
• Leissring MA, Farris W, Wu X, Christodoulou DC, Haigis MC, Guarente L, et al. Alternative translation initiation generates a novel isoform of insulin-degrading enzyme targeted to mitochondria. Biochem J. 2004;383:439–46.
   PubMed Web of Science ®Google Scholar
• Rubenstein AH, Pottenger LA, Mako M, Getz GS, Steiner DF. The metabolism of proinsulin and insulin by the liver. J Clin Invest. 1972;51:912–21.
   PubMed Web of Science ®Google Scholar
• Kim M, Hersh LB, Leissring MA, Ingelsson M, Matsui T, Farris W, et al. Decreased catalytic activity of the insulin-degrading enzyme in chromosome 10-linked Alzheimer disease families. J Biol Chem. 2007;282:7825–32.
   PubMed Web of Science ®Google Scholar
• Pivovarova O, Gogebakan O, Pfeiffer AF, Rudovich N. Glucose inhibits the insulin-induced activation of the insulin-degrading enzyme in HepG2 cells. Diabetologia. 2009;52:1656–64.
   PubMed Web of Science ®Google Scholar
• Shen Y, Joachimiak A, Rosner MR, Tang WJ. Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism. Nature. 2006;443:870–4.
   PubMed Web of Science ®Google Scholar
• Kupfer SR, Wilson EM, French FS. Androgen and glucocorticoid receptors interact with insulin degrading enzyme. J Biol Chem. 1994;269:20622–8.
   PubMed Web of Science ®Google Scholar
• Hamel FG, Bennett RG, Upward JL, Duckworth WC. Insulin inhibits peroxisomal fatty acid oxidation in isolated rat hepatocytes. Endocrinology. 2001;142:2702–6.
   PubMed Web of Science ®Google Scholar
• Semple JW, Lang Y, Speck ER, Delovitch TL. Processing and presentation of insulin. III. Insulin degrading enzyme: a neutral metalloendoproteinase that is non-homologous to classical endoproteinases mediates the processing of insulin epitopes for helper T cells. Int Immunol. 1992;4:1161–7.
   PubMed Web of Science ®Google Scholar
• Kayalar C, Wong WT. Metalloendoprotease inhibitors which block the differentiation of L6 myoblasts inhibit insulin degradation by the endogenous insulin-degrading enzyme. J Biol Chem. 1989;264:8928–34.
   PubMed Web of Science ®Google Scholar
• Bennett RG, Fawcett J, Kruer MC, Duckworth WC, Hamel FG. Insulin inhibition of the proteasome is dependent on degradation of insulin by insulin-degrading enzyme. J Endocrinol. 2003;177:399–405.
   PubMed Web of Science ®Google Scholar
• Hamel FG, Bennett RG, Duckworth WC. Regulation of multicatalytic enzyme activity by insulin and the insulin-degrading enzyme. Endocrinology. 1998;139:4061–6.
   PubMed Web of Science ®Google Scholar
• Codogno P, Meijer AJ. Autophagy and signaling: their role in cell survival and cell death. Cell Death Differ. 2005;12:1509–18.
   PubMed Web of Science ®Google Scholar
• Jung T, Catalgol B, Grune T. The proteasomal system. Mol Aspects Med. 2009;30:191–296.
   PubMed Web of Science ®Google Scholar
• Fawcett J, Permana PA, Levy JL, Duckworth WC. Regulation of protein degradation by insulin-degrading enzyme: analysis by small interfering RNA-mediated gene silencing. Arch Biochem Biophys. 2007;468:128–33.
   PubMed Web of Science ®Google Scholar
• Bennett RG, Hamel FG, Duckworth WC. Identification and isolation of a cytosolic proteolytic complex containing insulin degrading enzyme and the multicatalytic proteinase. Biochem Biophys Res Commun. 1994;202:1047–53.
   PubMed Web of Science ®Google Scholar
• Duckworth WC, Heinemann MA, Kitabchi AE. Purification of insulin-specific protease by affinity chromatography. Proc Natl Acad Sci USA. 1972;69:3698–702.
   PubMed Web of Science ®Google Scholar
• Hong L, Huang HC, Jiang ZF. Relationship between amyloid-beta and the ubiquitin-proteasome system in Alzheimer's disease. Neurol Res. 2014;36:276–82.
   PubMed Web of Science ®Google Scholar
• Balasubramanyam M, Sampathkumar R, Mohan V. Is insulin signaling molecules misguided in diabetes for ubiquitin-proteasome mediated degradation? Mol Cell Biochem. 2005;275:117–25.
   PubMed Web of Science ®Google Scholar
• Song ES, Juliano MA, Juliano L, Hersh LB. Substrate activation of insulin-degrading enzyme (insulysin). A potential target for drug development. J Biol Chem. 2003;278:49789–94.
   PubMed Web of Science ®Google Scholar
• Hamel FG, Upward JL, Bennett RG. In vitro inhibition of insulin-degrading enzyme by long-chain fatty acids and their coenzyme A thioesters. Endocrinology. 2003;144:2404–8.
   PubMed Web of Science ®Google Scholar
• Camberos MC, Perez AA, Udrisar DP, Wanderley MI, Cresto JC. ATP inhibits insulin-degrading enzyme activity. Exp Biol Med (Maywood). 2001;226:334–41.
   PubMed Web of Science ®Google Scholar
• George S, Petit GH, Gouras GK, Brundin P, Olsson R. Nonsteroidal selective androgen receptor modulators and selective estrogen receptor beta agonists moderate cognitive deficits and amyloid-beta levels in a mouse model of Alzheimer's disease. ACS Chem Neurosci. 2013;4:1537–48.
   PubMed Web of Science ®Google Scholar
• Grasso G, Satriano C, Milardi D. A neglected modulator of insulin-degrading enzyme activity and conformation: the pH. Biophys Chem. 2015;203–204:33–40.
   PubMed Web of Science ®Google Scholar
• Ahuja N, Schwer B, Carobbio S, Waltregny D, North BJ, Castronovo V, et al. Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. J Biol Chem. 2007;282:33583–92.
   PubMed Web of Science ®Google Scholar
• Saric T, Muller D, Seitz HJ, Pavelic K. Non-covalent interaction of ubiquitin with insulin-degrading enzyme. Mol Cell Endocrinol. 2003;204:11–20.
   PubMed Web of Science ®Google Scholar
• Mirsky IA, Perisutti G. Effect of insulinase-inhibitor on hypoglycemic action of insulin. Science. 1955;122:559–60.
   PubMed Web of Science ®Google Scholar
• Leissring MA, Malito E, Hedouin S, Reinstatler L, Sahara T, Abdul-Hay SO, et al. Designed inhibitors of insulin-degrading enzyme regulate the catabolism and activity of insulin. PLoS One. 2010;5:e10504.
   PubMed Web of Science ®Google Scholar
• Du J, Zhang L, Liu S, Wang Z. Palmitic acid and docosahexaenoic acid opposingly regulate the expression of insulin-degrading enzyme in neurons. Pharmazie. 2010;65:231–2.
   PubMed Web of Science ®Google Scholar
• Dobarro M, Gerenu G, Ramirez MJ. Propranolol reduces cognitive deficits, amyloid and tau pathology in Alzheimer's transgenic mice. Int J Neuropsychopharmacol. 2013;16:2245–57.
   PubMed Web of Science ®Google Scholar
• Shin MK, Kim HG, Baek SH, Jung WR, Park DI, Park JS, et al. Neuropep-1 ameliorates learning and memory deficits in an Alzheimer's disease mouse model, increases brain-derived neurotrophic factor expression in the brain, and causes reduction of amyloid beta plaques. Neurobiol Aging. 2014;35:990–1001.
   PubMed Web of Science ®Google Scholar
• Ciaccio C, Tundo GR, Grasso G, Spoto G, Marasco D, Ruvo M, et al. Somatostatin: a novel substrate and a modulator of insulin-degrading enzyme activity. J Mol Biol. 2009;385:1556–67.
   PubMed Web of Science ®Google Scholar
• Ohyagi Y. A drug targeting intracellular amyloid-beta and oxidative stress: apomorphine. Rinsho Shinkeigaku. 2011;51:884–7.
   PubMedGoogle Scholar
• Marwarha G, Ghribi O. Leptin signaling and Alzheimer's disease. Am J Neurodegener Dis. 2012;1:245–65.
   PubMedGoogle Scholar
• Adessi C, Enderle T, Grueninger F, Roth D. AG FH-LR. Activator for insulin degrading enzyme. World Intellectual Property Organization. Patent WO2006/066847; 2006.
   Google Scholar
• Charton J, Gauriot M, Guo Q, Hennuyer N, Marechal X, Dumont J, et al. Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of insulin-degrading enzyme in amyloid-beta hydrolysis. Eur J Med Chem. 2014;79:184–93.
   PubMed Web of Science ®Google Scholar
• Kalinin S, Richardson JC, Feinstein DL. A PPARdelta agonist reduces amyloid burden and brain inflammation in a transgenic mouse model of Alzheimer's disease. Curr Alzheimer Res. 2009;6:431–7.
   PubMed Web of Science ®Google Scholar
• Wang P, Su C, Li R, Wang H, Ren Y, Sun H, et al. Mechanisms and effects of curcumin on spatial learning and memory improvement in APPswe/PS1dE9 mice. J Neurosci Res. 2014;92:218–31.
   PubMed Web of Science ®Google Scholar
• Kong Y, Ruan L, Qian L, Liu X, Le Y. Norepinephrine promotes microglia to uptake and degrade amyloid beta peptide through upregulation of mouse formyl peptide receptor 2 and induction of insulin-degrading enzyme. J Neurosci. 2010;30:11848–57.
   PubMed Web of Science ®Google Scholar
• Liu Y, Gao M, Ma L, Zhang L, Pan N. Sevoflurane alters the expression of receptors and enzymes involved in Abeta clearance in rats. Acta Anaesthesiol Scand. 2013;57:903–10.
   PubMed Web of Science ®Google Scholar
• Hamel FG, Fawcett J, Tsui BT, Bennett RG, Duckworth WC. Effect of nelfinavir on insulin metabolism, proteasome activity and protein degradation in HepG2 cells. Diabetes Obes Metab. 2006;8:661–8.
   PubMed Web of Science ®Google Scholar
• Bennett RG, Hamel FG, Duckworth WC. An insulin-degrading enzyme inhibitor decreases amylin degradation, increases amylin-induced cytotoxicity, and increases amyloid formation in insulinoma cell cultures. Diabetes. 2003;52:2315–20.
   PubMed Web of Science ®Google Scholar
• Maianti JP, McFedries A, Foda ZH, Kleiner RE, Du XQ, Leissring MA, et al. Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones. Nature. 2014;511:94–8.
   PubMed Web of Science ®Google Scholar
• Cabrol C, Huzarska MA, Dinolfo C, Rodriguez MC, Reinstatler L, Ni J, et al. Small-molecule activators of insulin-degrading enzyme discovered through high-throughput compound screening. PLoS One. 2009;4:e5274.
   PubMed Web of Science ®Google Scholar
• Cakir B, Dagliyan O, Dagyildiz E, Baris I, Kavakli IH, Kizilel S, et al. Structure based discovery of small molecules to regulate the activity of human insulin degrading enzyme. PLoS One. 2012;7:e31787.
   PubMed Web of Science ®Google Scholar
• Durham TB, Toth JL, Klimkowski VJ, Cao JX, Siesky AM, Alexander-Chacko J, et al. Dual exosite-binding inhibitors of insulin-degrading enzyme challenge its role as the primary mediator of insulin clearance in vivo. J Biol Chem. 2015;290:20044–59.
   PubMed Web of Science ®Google Scholar
• Noinaj N, Bhasin SK, Song ES, Scoggin KE, Juliano MA, Juliano L, et al. Identification of the allosteric regulatory site of insulysin. PLoS One. 2011;6:e20864.
   PubMed Web of Science ®Google Scholar
• Abdul-Hay SO, Lane AL, Caulfield TR, Claussin C, Bertrand J, Masson A, et al. Optimization of peptide hydroxamate inhibitors of insulin-degrading enzyme reveals marked substrate-selectivity. J Med Chem. 2013;56:2246–55.
   PubMed Web of Science ®Google Scholar
• Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature. 2007;445:881–5.
   PubMed Web of Science ®Google Scholar
• Gu HF, Efendic S, Nordman S, Ostenson CG, Brismar K, Brookes AJ, et al. Quantitative trait loci near the insulin-degrading enzyme (IDE) gene contribute to variation in plasma insulin levels. Diabetes. 2004;53:2137–42.
   PubMed Web of Science ®Google Scholar
• Karamohamed S, Demissie S, Volcjak J, Liu C, Heard-Costa N, Liu J, et al. Polymorphisms in the insulin-degrading enzyme gene are associated with type 2 diabetes in men from the NHLBI Framingham Heart Study. Diabetes. 2003;52:1562–7.
   PubMed Web of Science ®Google Scholar
• Rudovich N, Pivovarova O, Fisher E, Fischer-Rosinsky A, Spranger J, Mohlig M, et al. Polymorphisms within insulin-degrading enzyme (IDE) gene determine insulin metabolism and risk of type 2 diabetes. J Mol Med (Berl). 2009;87:1145–51.
   PubMed Web of Science ®Google Scholar
• Fakhrai-Rad H, Nikoshkov A, Kamel A, Fernstrom M, Zierath JR, Norgren S, et al. Insulin-degrading enzyme identified as a candidate diabetes susceptibility gene in GK rats. Hum Mol Genet. 2000;9:2149–58.
   PubMed Web of Science ®Google Scholar
• Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, et al. 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. 2003;100:4162–7.
   PubMed Web of Science ®Google Scholar
• Seta KA, Roth RA. Overexpression of insulin degrading enzyme: cellular localization and effects on insulin signaling. Biochem Biophys Res Commun. 1997;231:167–71.
   PubMed Web of Science ®Google Scholar
• Standl E, Kolb HJ. Insulin degrading enzyme activity and insulin binding of erythrocytes in normal subjects and type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1984;27:17–22.
   PubMed Web of Science ®Google Scholar
• Snehalatha C, Timothy H, Mohan V, Ramachandran A, Viswanathan M. Immunoreactive insulin and insulin degrading enzymes in erythrocytes. A preliminary report. J Assoc Phys India. 1990;38:558–61.
   PubMedGoogle Scholar
• Nikolaev SL, Strelkova MA, Komov VP. Insulin degradation in hepatocytes and erythrocytes of rats in normal condition and in experimental diabetes. Vopr Med Khim. 2001;47:329–37.
   PubMed Web of Science ®Google Scholar
• Hern EP, Shroyer LA, Varandani PT. Insulin-degrading neutral cysteine proteinase activity of adipose tissue and liver of nondiabetic, streptozotocin-diabetic, and insulin-treated diabetic rats. Arch Biochem Biophys. 1987;254:35–42.
   PubMed Web of Science ®Google Scholar
• Fawcett J, Sang H, Permana PA, Levy JL, Duckworth WC. Insulin metabolism in human adipocytes from subcutaneous and visceral depots. Biochem Biophys Res Commun. 2010;402:762–6.
   PubMed Web of Science ®Google Scholar
• Jurcovicova J, Nemeth S, Vigas M. Effect of insulin and glucose on the activity of insulin-degrading enzymes in rat liver. Endocrinol Exp. 1977;11:209–13.
   PubMedGoogle Scholar
• Li CZ, Zhang SH, Shu CD, Ren W. Relationship between insulin-degrading enzyme activity and insulin sensitivity in cell model of insulin-resistance. Di Yi Jun Yi Da Xue Xue Bao. 2002;22:151–4.
   PubMedGoogle Scholar
• Pivovarova O, von Loeffelholz C, Ilkavets I, Sticht C, Zhuk S, Murahovschi V, et al. Modulation of insulin degrading enzyme activity and liver cell proliferation. Cell Cycle. 2015;14:2293–300.
   PubMed Web of Science ®Google Scholar
• Rudovich NN, Rochlitz HJ, Pfeiffer AF. Reduced hepatic insulin extraction in response to gastric inhibitory polypeptide compensates for reduced insulin secretion in normal-weight and normal glucose tolerant first-degree relatives of type 2 diabetic patients. Diabetes. 2004;53:2359–65.
   PubMed Web of Science ®Google Scholar
• Pivovarova O, Bernigau W, Bobbert T, Isken F, Mohlig M, Spranger J, et al. Hepatic insulin clearance is closely related to metabolic syndrome components. Diabetes Care. 2013;36:3779–85.
   PubMed Web of Science ®Google Scholar
• Farris W, Mansourian S, Leissring MA, Eckman EA, Bertram L, Eckman CB, et al. Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid beta-protein. Am J Pathol. 2004;164:1425–34.
   PubMed Web of Science ®Google Scholar
• Abdul-Hay SO, Kang D, McBride M, Li L, Zhao J, Leissring MA. Deletion of insulin-degrading enzyme elicits antipodal, age-dependent effects on glucose and insulin tolerance. PLoS One. 2011;6:e20818.
   PubMed Web of Science ®Google Scholar
• Godoy-Matos AF. The role of glucagon on type 2 diabetes at a glance. Diabetol Metab Syndr. 2014;6:91.
   PubMed Web of Science ®Google Scholar
• Steneberg P, Bernardo L, Edfalk S, Lundberg L, Backlund F, Ostenson CG, et al. The type 2 diabetes-associated gene ide is required for insulin secretion and suppression of α-synuclein levels in β-cells. Diabetes. 2013;62:2004–14.
   PubMed Web of Science ®Google Scholar
• Fawcett J, Tsui BT, Duckworth WC. Nelfinavir alters both insulin and lipid metabolism in 3T3-L1 adipocytes. ADA, 63th Scientific Sessions, 2003.
   Google Scholar
• Epting CL, King FW, Pedersen A, Zaman J, Ritner C, Bernstein HS. Stem cell antigen-1 localizes to lipid microdomains and associates with insulin degrading enzyme in skeletal myoblasts. J Cell Physiol. 2008;217:250–60.
   PubMed Web of Science ®Google Scholar
• Blonski W, Kotlyar DS, Forde KA. Non-viral causes of hepatocellular carcinoma. World J Gastroenterol. 2010;16:3603–15.
   PubMed Web of Science ®Google Scholar
• Jha NK, Jha SK, Kumar D, Kejriwal N, Sharma R, Ambasta RK, et al. Impact of insulin degrading enzyme and neprilysin in Alzheimer's disease biology: characterization of putative cognates for therapeutic applications. J Alzheimers Dis. 2015;48:891–917.
   PubMed Web of Science ®Google Scholar
• de la Monte SM, Tong M. Brain metabolic dysfunction at the core of Alzheimer's disease. Biochem Pharmacol. 2014;88:548–59.
   PubMed Web of Science ®Google Scholar
• Mittal K, Katare DP. Shared links between type 2 diabetes mellitus and Alzheimer's disease: a review. Diabetes Metab Syndr. 2016. [Epub ahead of print]. doi: 10.1016/j.dsx.2016.01.021.
   PubMedGoogle Scholar
• Sims-Robinson C, Kim B, Rosko A, Feldman EL. How does diabetes accelerate Alzheimer disease pathology? Nat Rev Neurol. 2010;6:551–9.
   PubMed Web of Science ®Google Scholar
• Qiu WQ, Folstein MF. Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer's disease: review and hypothesis. Neurobiol Aging. 2006;27:190–8.
   PubMed Web of Science ®Google Scholar
• Akter K, Lanza EA, Martin SA, Myronyuk N, Rua M, Raffa RB. Diabetes mellitus and Alzheimer's disease: shared pathology and treatment? Br J Clin Pharmacol. 2011;71:365–76.
   PubMed Web of Science ®Google Scholar
• Qiu WQ, Walsh DM, Ye Z, Vekrellis K, Zhang J, Podlisny MB, et al. Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J Biol Chem. 1998;273:32730–8.
   PubMed Web of Science ®Google Scholar
• Cheng H, Wang L, Shi T, Shang Y, Jiang L. Association of insulin degrading enzyme gene polymorphisms with Alzheimer's disease: a meta-analysis. Int J Neurosci. 2015;125:328–35.
   PubMed Web of Science ®Google Scholar
• Edland SD, Wavrant-De Vriese F, Compton D, Smith GE, Ivnik R, Boeve BF, et al. Insulin degrading enzyme (IDE) genetic variants and risk of Alzheimer's disease: evidence of effect modification by apolipoprotein E (APOE). Neurosci Lett. 2003;345:21–4.
   PubMed Web of Science ®Google Scholar
• Carrasquillo MM, Belbin O, Zou F, Allen M, Ertekin-Taner N, Ansari M, et al. Concordant association of insulin degrading enzyme gene (IDE) variants with IDE mRNA, Abeta, and Alzheimer's disease. PLoS One. 2010;5:e8764.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Wang B, Wan H, Zhou Q, Li T. Meta-analysis of the insulin degrading enzyme polymorphisms and susceptibility to Alzheimer's disease. Neurosci Lett. 2013;541:132–7.
   PubMed Web of Science ®Google Scholar
• Zhao Z, Xiang Z, Haroutunian V, Buxbaum JD, Stetka B, Pasinetti GM. Insulin degrading enzyme activity selectively decreases in the hippocampal formation of cases at high risk to develop Alzheimer's disease. Neurobiol Aging. 2007;28:824–30.
   PubMed Web of Science ®Google Scholar
• Perez A, Morelli L, Cresto JC, Castano EM. Degradation of soluble amyloid beta-peptides 1-40, 1-42, and the Dutch variant 1-40Q by insulin degrading enzyme from Alzheimer disease and control brains. Neurochem Res. 2000;25:247–55.
   PubMed Web of Science ®Google Scholar
• Del Campo M, Stargardt A, Veerhuis R, Reits E, Teunissen CE. Accumulation of BRI2-BRICHOS ectodomain correlates with a decreased clearance of Aβ by insulin degrading enzyme (IDE) in Alzheimer's disease. Neurosci Lett. 2015;589:47–51.
   PubMed Web of Science ®Google Scholar
• Wang S, Wang R, Chen L, Bennett DA, Dickson DW, Wang DS. Expression and functional profiling of neprilysin, insulin-degrading enzyme, and endothelin-converting enzyme in prospectively studied elderly and Alzheimer's brain. J Neurochem. 2010;115:47–57.
   PubMed Web of Science ®Google Scholar
• Miners JS, Baig S, Tayler H, Kehoe PG, Love S. Neprilysin and insulin-degrading enzyme levels are increased in Alzheimer disease in relation to disease severity. J Neuropathol Exp Neurol. 2009;68:902–14.
   PubMed Web of Science ®Google Scholar
• Runyan K, Duckworth WC, Kitabchi AE, Huff G. The effect of age on insulin-degrading activity in rat tissue. Diabetes. 1979;28:324–5.
   PubMed Web of Science ®Google Scholar
• Caccamo A, Oddo S, Sugarman MC, Akbari Y, LaFerla FM. Age- and region-dependent alterations in Abeta-degrading enzymes: implications for Abeta-induced disorders. Neurobiol Aging. 2005;26:645–54.
   PubMed Web of Science ®Google Scholar
• Miners JS, van Helmond Z, Kehoe PG, Love S. Changes with age in the activities of beta-secretase and the Abeta-degrading enzymes neprilysin, insulin-degrading enzyme and angiotensin-converting enzyme. Brain Pathol. 2010;20:794–802.
   PubMed Web of Science ®Google Scholar
• Heni M, Kullmann S, Preissl H, Fritsche A, Haring HU. Impaired insulin action in the human brain: causes and metabolic consequences. Nat Rev Endocrinol. 2015;11:701–11.
   PubMed Web of Science ®Google Scholar
• Gasparini L, Gouras GK, Wang R, Gross RS, Beal MF, Greengard P, et al. Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci. 2001;21:2561–70.
   PubMed Web of Science ®Google Scholar
• Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease – is this type 3 diabetes? J Alzheimers Dis. 2005;7:63–80.
   PubMed Web of Science ®Google Scholar
• Bosco D, Fava A, Plastino M, Montalcini T, Pujia A. Possible implications of insulin resistance and glucose metabolism in Alzheimer's disease pathogenesis. J Cell Mol Med. 2011;15:1807–21.
   PubMed Web of Science ®Google Scholar
• Zhao L, Teter B, Morihara T, Lim GP, Ambegaokar SS, Ubeda OJ, et al. Insulin-degrading enzyme as a downstream target of insulin receptor signaling cascade: implications for Alzheimer's disease intervention. J Neurosci. 2004;24:11120–6.
   PubMed Web of Science ®Google Scholar
• Li X, Song D, Leng SX. Link between type 2 diabetes and Alzheimer's disease: from epidemiology to mechanism and treatment. Clin Interv Aging. 2015;10:549–60.
   PubMed Web of Science ®Google Scholar
• Leissring MA, Farris W, Chang AY, Walsh DM, Wu X, Sun X, et al. Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron. 2003;40:1087–93.
   PubMed Web of Science ®Google Scholar
• Kukday SS, Manandhar SP, Ludley MC, Burriss ME, Alper BJ, Schmidt WK. Cell-permeable, small-molecule activators of the insulin-degrading enzyme. J Biomol Screen. 2012;17:1348–61.
   PubMed Web of Science ®Google Scholar
• Nalivaeva NN, Fisk LR, Belyaev ND, Turner AJ. Amyloid-degrading enzymes as therapeutic targets in Alzheimer's disease. Curr Alzheimer Res. 2008;5:212–24.
   PubMed Web of Science ®Google Scholar