Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder resulting in memory and cognitive impairment. The use of somatostatin receptor subtype-4 (SSTR4) agonists have been proposed for AD treatment. This study investigated the effects of selective SSTR4 agonist NNC 26-9100 on mRNA expression of key genes associated with AD pathology (microglia mediators of Aβ phagocytosis, amyloid-beta (Aβ)-degrading enzymes, anti-oxidant enzymes and pro-inflammatory cytokines) in 3xTg-AD mice. Mice were administered NNC 26-9100 (0.2 µg, i.c.v.) or vehicle control, with cortical and subcortical brain tissue collected at 6 h and 24 h post-treatment. At 6 h, NNC 26-9100 treatment decreased cortical expression of cluster of differentiation-33 (Cd33) by 25%, while increasing cortical and subcortical macrophage scavenger receptor-1 (Msr1) by 1.8 and 2.0-fold, respectively. The Cd33 downregulation and Msr1 upregulation support a state of microglia associated Aβ phagocytosis. At 24 h, NNC 26-9100 treatment increased the cortical expression of Sstr4 (4.9-fold), Aβ-degrading enzymes neprilysin (9.3-fold) and insulin degrading enzyme (14.8-fold), and the antioxidant catalase (3.6-fold). Similar effects at 24 h were found in subcortical tissue with NNC 26-9100 treatment, but did not reach statistical significance. No changes in pro-inflammatory cytokine expression were found. These data demonstrated NNC 26-9100 facilitates transcriptional changes in brain tissue identified with Aβ phagocytosis and clearance, further supporting SSTR4 as a treatment target for AD.
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References
World Health Organisation (2019) Dementia fact sheet May 2019. https://www.who.int/news-room/fact-sheets/detail/dementia. Accessed July 9, 2019
Bradburn S, Murgatroyd C, Ray N (2019) Neuroinflammation in mild cognitive impairment and Alzheimer’s disease: a meta-analysis. Ageing ResRev 50:1–8
Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, Holtzman DM, Jagust W, Jessen F, Karlawish J, Liu E, Molinuevo JL, Montine T, Phelps C, Rankin KP, Rowe CC, Scheltens P, Siemers E, Snyder HM, Sperling R (2018) NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement 14:535–562
Wojsiat J, Zoltowska KM, Laskowska-Kaszub K, Wojda U (2018) Oxidant/antioxidant imbalance in Alzheimer’s disease: therapeutic and diagnostic prospects. Oxid Med Cell Longev 2018:6435861
Epelbaum J, Guillou JL, Gastambide F, Hoyer D, Duron E, Viollet C (2009) Somatostatin, Alzheimer’s disease and cognition: An old story coming of age? Prog Neurobiol 89:153–161
Martel G, Dutar P, Epelbaum J, Viollet C (2012) Somatostatinergic systems: an update on brain functions in normal and pathological aging. Front Endocrinol 3:154
Davies P, Katzman R, Terry RD (1980) Reduced somatostatin-like immunoreactivity in cerebral cortex from cases of Alzheimer disease and Alzheimer senile dementa. Nature 288:279–280
Ramos B, Baglietto-Vargas D, del Rio JC, Moreno-Gonzalez I, Santa-Maria C, Jimenez S, Caballero C, Lopez-Tellez JF, Khan ZU, Ruano D, Gutierrez A, Vitorica J (2006) Early neuropathology of somatostatin/NPY GABAergic cells in the hippocampus of a PS1xAPP transgenic model of Alzheimer’s disease. Neurobiol Aging 27:1658–1672
Saito T, Iwata N, Tsubuki S, Takaki Y, Takano J, Huang SM, Suemoto T, Higuchi M, Saido TC (2005) Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation. Nat Med 11:434–439
Iwata N, Tsubuki S, Takaki Y, Shirotani K, Lu B, Gerard NP, Gerard C, Hama E, Lee HJ, Saido TC (2001) Metabolic regulation of brain Abeta by neprilysin. Science 292:1550–1552
Sandoval KE, Witt KA, Crider AM, Kontoyianni M (2013) Somatostatin receptor-4 agonists as candidates for treatment of Alzheimer’s disease. In: Atta-ur-Rahman Choudhary MI (ed) Frontiers in drug design and discovery. Bentham Science, Sharjah
Viollet C, Lepousez G, Loudes C, Videau C, Simon A, Epelbaum J (2008) Somatostatinergic systems in brain: networks and functions. Mol Cell Endocrinol 286:75–87
Moller LN, Stidsen CE, Hartmann B, Holst JJ (2003) Somatostatin receptors. Biochem Biophys Acta 1616:1–84
Bruno JF, Xu Y, Song J, Berelowitz M (1993) Tissue distribution of somatostatin receptor subtype messenger ribonucleic acid in the rat. Endocrinology 133:2561–2567
Harrington KA, Schindler M, Humphrey PP, Emson PC (1995) Expression of messenger RNA for somatostatin receptor subtype 4 in adult rat brain. Neurosci Lett 188:17–20
Selmer IS, Schindler M, Humphrey PP, Emson PC (2000) Immunohistochemical localization of the somatostatin sst(4) receptor in rat brain. Neuroscience 98:523–533
Selmer IS, Schindler M, Humphrey PP, Waldvogel HJ, Faull RL, Emson PC (2000) First localisation of somatostatin sst(4) receptor protein in selected human brain areas: an immunohistochemical study. Brain Res Mol Brain Res 82:114–125
Sandoval KE, Farr SA, Banks WA, Crider AM, Morley JE, Witt KA (2012) Somatostatin receptor subtype-4 agonist NNC 26-9100 decreases extracellular and intracellular Abeta(1)(-)(4)(2) trimers. Eur J Pharmacol 683:116–124
Sandoval KE, Farr SA, Banks WA, Crider AM, Morley JE, Witt KA (2013) Somatostatin receptor subtype-4 agonist NNC 26-9100 mitigates the effect of soluble Abeta oligomers via a metalloproteinase-dependent mechanism. Brain Res 1520:145–156
Fleisher-Berkovich S, Filipovich-Rimon T, Ben-Shmuel S, Hulsmann C, Kummer MP, Heneka MT (2010) Distinct modulation of microglial amyloid beta phagocytosis and migration by neuropeptides (i). J Neuroinflamm 7:61
Tundo G, Ciaccio C, Sbardella D, Boraso M, Viviani B, Coletta M, Marini S (2012) Somatostatin modulates insulin-degrading-enzyme metabolism: implications for the regulation of microglia activity in AD. PLoS ONE 7:e34376
Ankersen M, Crider AM, Liu S, Ho B, Andersen HS, Stidsen CE (1998) Discovery of a novel non-peptide somatostatin agonist with SST4 selectivity. J Am Chem Soc 120:1368–1373
Caruso D, Barron AM, Brown MA, Abbiati F, Carrero P, Pike CJ, Garcia-Segura LM, Melcangi RC (2013) Age-related changes in neuroactive steroid levels in 3xTg-AD mice. Neurobiol Aging 34:1080–1089
Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–421
Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM (2005) Intraneuronal Abeta causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron 45:675–688
Rydbirk R, Folke J, Winge K, Aznar S, Pakkenberg B, Brudek T (2016) Assessment of brain reference genes for RT-qPCR studies in neurodegenerative diseases. Sci Rep 6:37116
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 25:402–408
Yuan JS, Reed A, Chen F, Stewart CN Jr (2006) Statistical analysis of real-time PCR data. BMC Bioinform 7:85
Hukovic N, Panetta R, Kumar U, Patel YC (1996) Agonist-dependent regulation of cloned human somatostatin receptor types 1-5 (hSSTR1-5): subtype selective internalization or upregulation. Endocrinology 137:4046–4049
Gastambide F, Lepousez G, Viollet C, Loudes C, Epelbaum J, Guillou JL (2010) Cooperation between hippocampal somatostatin receptor subtypes 4 and 2: functional relevance in interactive memory systems. Hippocampus 20:745–757
Somvanshi RK, Billova S, Kharmate G, Rajput PS, Kumar U (2009) C-tail mediated modulation of somatostatin receptor type-4 homo- and heterodimerizations and signaling. Cell Signal 21:1396–1414
Zou Y, Tan H, Zhao Y, Zhou Y, Cao L (2019) Expression and selective activation of somatostatin receptor subtypes induces cell cycle arrest in cancer cells. Oncol Lett 17:1723–1731
Nalivaeva NN, Belyaev ND, Kerridge C, Turner AJ (2014) Amyloid-clearing proteins and their epigenetic regulation as a therapeutic target in Alzheimer’s disease. Front Aging Neurosci 6:235
Saido T, Leissring MA (2012) Proteolytic degradation of amyloid beta-protein. Cold Spring Harbor Perspect Med 2:a006379
Fukami S, Watanabe K, Iwata N, Haraoka J, Lu B, Gerard NP, Gerard C, Fraser P, Westaway D, St George-Hyslop P, Saido TC (2002) Abeta-degrading endopeptidase, neprilysin, in mouse brain: synaptic and axonal localization inversely correlating with Abeta pathology. Neurosci Res 43:39–56
Kanemitsu H, Tomiyama T, Mori H (2003) Human neprilysin is capable of degrading amyloid beta peptide not only in the monomeric form but also the pathological oligomeric form. Neurosci Lett 350:113–116
Takaki Y, Iwata N, Tsubuki S, Taniguchi S, Toyoshima S, Lu B, Gerard NP, Gerard C, Lee HJ, Shirotani K, Saido TC (2000) Biochemical identification of the neutral endopeptidase family member responsible for the catabolism of amyloid beta peptide in the brain. J Biochem 128:897–902
Vekrellis K, Ye Z, Qiu WQ, Walsh D, Hartley D, Chesneau V, Rosner MR, Selkoe DJ (2000) Neurons regulate extracellular levels of amyloid beta-protein via proteolysis by insulin-degrading enzyme. J Neurosci 20:1657–1665
Qiu WQ, Walsh DM, Ye Z, Vekrellis K, Zhang J, Podlisny MB, Rosner MR, Safavi A, Hersh LB, Selkoe DJ (1998) Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J Biol Chem 273:32730–32738
Stargardt A, Gillis J, Kamphuis W, Wiemhoefer A, Kooijman L, Raspe M, Benckhuijsen W, Drijfhout JW, Hol EM, Reits E (2013) Reduced amyloid-beta degradation in early Alzheimer’s disease but not in the APPswePS1dE9 and 3xTg-AD mouse models. Aging Cell 12:499–507
Lawson LJ, Perry VH, Dri P, Gordon S (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39:151–170
Funalot B, Ouimet T, Claperon A, Fallet C, Delacourte A, Epelbaum J, Subkowski T, Leonard N, Codron V, David JP, Amouyel P, Schwartz JC, Helbecque N (2004) Endothelin-converting enzyme-1 is expressed in human cerebral cortex and protects against Alzheimer’s disease. Mol Psychiatry 9(1122–1128):1059
Arregui A, Perry EK, Rossor M, Tomlinson BE (1982) Angiotensin converting enzyme in Alzheimer’s disease increased activity in caudate nucleus and cortical areas. J Neurochem 38:1490–1492
Helyes Z, Pinter E, Nemeth J, Sandor K, Elekes K, Szabo A, Pozsgai G, Keszthelyi D, Kereskai L, Engstrom M, Wurster S, Szolcsanyi J (2006) Effects of the somatostatin receptor subtype 4 selective agonist J-2156 on sensory neuropeptide release and inflammatory reactions in rodents. Br J Pharmacol 149:405–415
Helyes Z, Pinter E, Sandor K, Elekes K, Banvolgyi A, Keszthelyi D, Szoke E, Toth DM, Sandor Z, Kereskai L, Pozsgai G, Allen JP, Emson PC, Markovics A, Szolcsanyi J (2009) Impaired defense mechanism against inflammation, hyperalgesia, and airway hyperreactivity in somatostatin 4 receptor gene-deleted mice. Proc Natl Acad Sci USA 106:13088–13093
Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A, Petzold GC, Town T, Morgan D, Shinohara ML, Perry VH, Holmes C, Bazan NG, Brooks DJ, Hunot S, Joseph B, Deigendesch N, Garaschuk O, Boddeke E, Dinarello CA, Breitner JC, Cole GM, Golenbock DT, Kummer MP (2015) Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14:388–405
Jiang T, Yu JT, Hu N, Tan MS, Zhu XC, Tan L (2014) CD33 in Alzheimer’s disease. Mol Neurobiol 49:529–535
Griciuc A, Serrano-Pozo A, Parrado AR, Lesinski AN, Asselin CN, Mullin K, Hooli B, Choi SH, Hyman BT, Tanzi RE (2013) Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78:631–643
Chung H, Brazil MI, Irizarry MC, Hyman BT, Maxfield FR (2001) Uptake of fibrillar beta-amyloid by microglia isolated from MSR-A (type I and type II) knockout mice. NeuroReport 12:1151–1154
Frenkel D, Wilkinson K, Zhao L, Hickman SE, Means TK, Puckett L, Farfara D, Kingery ND, Weiner HL, El Khoury J (2013) Scara1 deficiency impairs clearance of soluble amyloid-beta by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression. Nat Commun 4:2030
Ansari MA, Scheff SW (2010) Oxidative stress in the progression of Alzheimer disease in the frontal cortex. J Neuropathol Exp Neurol 69:155–167
Gsell W, Conrad R, Hickethier M, Sofic E, Frolich L, Wichart I, Jellinger K, Moll G, Ransmayr G, Beckmann H et al (1995) Decreased catalase activity but unchanged superoxide dismutase activity in brains of patients with dementia of Alzheimer type. J Neurochem 64:1216–1223
Karelson E, Bogdanovic N, Garlind A, Winblad B, Zilmer K, Kullisaar T, Vihalemm T, Kairane C, Zilmer M (2001) The cerebrocortical areas in normal brain aging and in Alzheimer’s disease: noticeable differences in the lipid peroxidation level and in antioxidant defense. Neurochem Res 26:353–361
Fanelli F, Sepe S, D’Amelio M, Bernardi C, Cristiano L, Cimini A, Cecconi F, Ceru MP, Moreno S (2013) Age-dependent roles of peroxisomes in the hippocampus of a transgenic mouse model of Alzheimer’s disease. Molecular neurodegeneration 8:8
Franca MB, Lima KC, Eleutherio EC (2017) Oxidative stress and amyloid toxicity: insights from yeast. J Cell Biochem 118:1442–1452
Morita M, Kurochkin IV, Motojima K, Goto S, Takano T, Okamura S, Sato R, Yokota S, Imanaka T (2000) Insulin-degrading enzyme exists inside of rat liver peroxisomes and degrades oxidized proteins. Cell Struct Funct 25:309–315
Caccamo A, Oddo S, Sugarman MC, Akbari Y, LaFerla FM (2005) Age- and region-dependent alterations in Abeta-degrading enzymes: implications for Abeta-induced disorders. Neurobiol Aging 26:645–654
Wang DS, Iwata N, Hama E, Saido TC, Dickson DW (2003) Oxidized neprilysin in aging and Alzheimer’s disease brains. Biochem Biophys Res Commun 310:236–241
Gunther T, Tulipano G, Dournaud P, Bousquet C, Csaba Z, Kreienkamp HJ, Lupp A, Korbonits M, Castano JP, Wester HJ, Culler M, Melmed S, Schulz S (2018) International union of basic and clinical pharmacology. CV. somatostatin receptors: structure, function, ligands, and new nomenclature. Pharmacol Rev 70:763–835
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This work was supported the National Institutes of Health, National Institute of Age division, grant no. R01AG047858, and Southern Illinois University Edwardsville Graduate School.
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Sandoval, K., Umbaugh, D., House, A. et al. Somatostatin Receptor Subtype-4 Regulates mRNA Expression of Amyloid-Beta Degrading Enzymes and Microglia Mediators of Phagocytosis in Brains of 3xTg-AD Mice. Neurochem Res 44, 2670–2680 (2019). https://doi.org/10.1007/s11064-019-02890-6
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DOI: https://doi.org/10.1007/s11064-019-02890-6