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当代阿耳茨海默病研究

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ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

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Research Article

棕榈酰化催乳素释放肽减少小脑 Aβ 斑块和小胶质细胞增生：APP/PS1 小鼠研究

卷 18, 期 8, 2021

发表于: 22 September, 2021

页: [607 - 622] 页: 16

弟呕挨: 10.2174/1567205018666210922110652

价格: $65

摘要

背景：催乳素释放肽 (PrRP) 是一种潜在的治疗肥胖症和相关 2 型糖尿病 (T2DM) 的药物，因为它具有很强的厌食和抗糖尿病特性。在我们最近的研究中，脂质化 PrRP 类似物 palm11-PrRP31 被证明对 APP/PS1 小鼠产生有益作用，这是一种阿尔茨海默病 (AD) 样淀粉样蛋白-β (Aβ) 病理学模型，可减少 Aβ 斑块负荷，海马和皮层的小胶质细胞增生和星形胶质细胞增生。 目的：在这项研究中，我们专注于 palm11-PrRP31 的神经保护和抗炎作用及其对 APP/PS1 小鼠小脑突触发生的可能影响，因为其他人认为小脑 Aβ 斑块会导致 AD 认知缺陷。 方法：与对照小鼠相比，APP/PS1 小鼠用 palm11-PrRP31 皮下治疗 2 个月，然后使用免疫印迹和免疫组织化学来量化与 AD 相关的病理标志物。 结果：在 8 个月大的 APP/PS1 小鼠的小脑中，我们发现广泛的 Aβ 斑块被激活的小胶质细胞包围，通过离子化的钙结合衔接分子 (Iba1) 检测到，但与星形胶质细胞标志物胶质纤维酸性蛋白 (GFAP) 相比没有增加控制。有趣的是，在 APP/PS1 和对照小鼠之间，突触前标志物 syntaxin1A 和突触后标志物 spinophilin 没有差异。 Palm11-PrRP31 治疗显着降低了小脑中的 Aβ 斑块负荷和小胶质细胞增生。此外，palm11-PrRP31 增加突触发生并减轻 APP/PS1 小鼠海马的神经炎症和细胞凋亡。 结论：这些结果表明 palm11-PrRP31 是一种有前途的治疗神经退行性疾病的药物。

关键词: APP/PS1 小鼠、阿尔茨海默病、palm11-PrRP31、海马、小脑、淀粉样蛋白-β 斑块、神经炎症、突触发生。

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[1]
Bloom GS. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 2014; 71(4): 505-8.
[http://dx.doi.org/10.1001/jamaneurol.2013.5847] [PMID: 24493463]
[2]
Rubio-Perez JM, Morillas-Ruiz JM. A review: inflammatory process in Alzheimer’s disease, role of cytokines. ScientificWorldJ 2012; 2012: 756357-7.
[http://dx.doi.org/10.1100/2012/756357] [PMID: 22566778]
[3]
Fakhoury M. Microglia and astrocytes in Alzheimer’s disease: Implications for therapy. Curr Neuropharmacol 2018; 16(5): 508-18.
[http://dx.doi.org/10.2174/1570159X15666170720095240] [PMID: 28730967]
[4]
Akiyama H, Arai T, Kondo H, Tanno E, Haga C, Ikeda K. Cell mediators of inflammation in the Alzheimer disease brain. Alzheimer Dis Assoc Disord 2000; 14(1): S47-53.
[http://dx.doi.org/10.1097/00002093-200000001-00008] [PMID: 10850730]
[5]
Heneka MT, O’Banion MK. Inflammatory processes in Alzheimer’s disease. J Neuroimmunol 2007; 184(1-2): 69-91.
[http://dx.doi.org/10.1016/j.jneuroim.2006.11.017] [PMID: 17222916]
[6]
Wyss-Coray T. Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 2006; 12(9): 1005-15.
[PMID: 16960575]
[7]
Griffin WS, Mrak RE. Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer’s disease. J Leukoc Biol 2002; 72(2): 233-8.
[PMID: 12149413]
[8]
Tuppo EE, Arias HR. The role of inflammation in Alzheimer’s disease. Int J Biochem Cell Biol 2005; 37(2): 289-305.
[http://dx.doi.org/10.1016/j.biocel.2004.07.009] [PMID: 15474976]
[9]
McGeer EMaP. Inflammatory cytokines in the CNS. CNS Drugs 1997; 7: 214-87.
[http://dx.doi.org/10.2165/00023210-199707030-00005]
[10]
Rossi F, Bianchini E. Synergistic induction of nitric oxide by beta-amyloid and cytokines in astrocytes. Biochem Biophys Res Commun 1996; 225(2): 474-8.
[http://dx.doi.org/10.1006/bbrc.1996.1197] [PMID: 8753786]
[11]
Scheff SW, Price DA, Schmitt FA, Mufson EJ. Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging 2006; 27(10): 1372-84.
[http://dx.doi.org/10.1016/j.neurobiolaging.2005.09.012] [PMID: 16289476]
[12]
Jack CR Jr, Knopman DS, Jagust WJ, et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol 2010; 9(1): 119-28.
[http://dx.doi.org/10.1016/S1474-4422(09)70299-6] [PMID: 20083042]
[13]
Walsh DM, Klyubin I, Fadeeva JV, et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002; 416(6880): 535-9.
[http://dx.doi.org/10.1038/416535a] [PMID: 11932745]
[14]
Fein JA, Sokolow S, Miller CA, et al. Co-localization of amyloid beta and tau pathology in Alzheimer’s disease synaptosomes. Am J Pathol 2008; 172(6): 1683-92.
[http://dx.doi.org/10.2353/ajpath.2008.070829] [PMID: 18467692]
[15]
Hong S, Beja-Glasser VF, Nfonoyim BM, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 2016; 352(6286): 712-6.
[http://dx.doi.org/10.1126/science.aad8373] [PMID: 27033548]
[16]
Jackson J, Jambrina E, Li J, et al. Targeting the Synapse in Alzheimer’s Disease. Front Neurosci 2019; 13: 735.
[http://dx.doi.org/10.3389/fnins.2019.00735] [PMID: 31396031]
[17]
Wang WY, Tan MS, Yu JT, Tan L. Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann Transl Med 2015; 3(10): 136.
[PMID: 26207229]
[18]
Scheff SW, Price DA, Schmitt FA, DeKosky ST, Mufson EJ. Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology 2007; 68(18): 1501-8.
[http://dx.doi.org/10.1212/01.wnl.0000260698.46517.8f] [PMID: 17470753]
[19]
Miniaci MC, De Leonibus E. Missing the egocentric spatial reference: a blank on the map. F1000 Res 2018; 7: 168.
[http://dx.doi.org/10.12688/f1000research.13675.1] [PMID: 29568496]
[20]
Hoxha E, Lippiello P, Zurlo F, et al. The emerging role of altered cerebellar synaptic processing in Alzheimer’s disease. Front Aging Neurosci 2018; 10: 396.
[http://dx.doi.org/10.3389/fnagi.2018.00396] [PMID: 30542279]
[21]
Braak H, Braak E, Bohl J, Lang W. Alzheimer’s disease: amyloid plaques in the cerebellum. J Neurol Sci 1989; 93(2-3): 277-87.
[http://dx.doi.org/10.1016/0022-510X(89)90197-4] [PMID: 2556503]
[22]
Joachim CL, Morris JH, Selkoe DJ. Diffuse senile plaques occur commonly in the cerebellum in Alzheimer’s disease. Am J Pathol 1989; 135(2): 309-19.
[PMID: 2675616]
[23]
Singh-Bains MK, Linke V, Austria MDR, et al. Altered microglia and neurovasculature in the Alzheimer’s disease cerebellum. Neurobiol Dis 2019; 132: 104589.
[http://dx.doi.org/10.1016/j.nbd.2019.104589] [PMID: 31454549]
[24]
Kozuki M, Kurata T, Miyazaki K, et al. Atorvastatin and pitavastatin protect cerebellar Purkinje cells in AD model mice and preserve the cytokines MCP-1 and TNF-α. Brain Res 2011; 1388: 32-8.
[http://dx.doi.org/10.1016/j.brainres.2011.03.024] [PMID: 21419111]
[25]
Lomoio S, López-González I, Aso E, et al. Cerebellar amyloid-β plaques: disturbed cortical circuitry in AβPP/PS1 transgenic mice as a model of familial Alzheimer’s disease. J Alzheimers Dis 2012; 31(2): 285-300.
[http://dx.doi.org/10.3233/JAD-2012-112198] [PMID: 22561329]
[26]
Bjursell M, Lennerås M, Göransson M, Elmgren A, Bohlooly-Y M. GPR10 deficiency in mice results in altered energy expenditure and obesity. Biochem Biophys Res Commun 2007; 363(3): 633-8.
[http://dx.doi.org/10.1016/j.bbrc.2007.09.016] [PMID: 17904108]
[27]
Pražienková V, Popelová A, Kuneš J, Maletínská L. Prolactin-releasing peptide: Physiological and pharmacological properties. Int J Mol Sci 2019; 20(21): 20.
[http://dx.doi.org/10.3390/ijms20215297] [PMID: 31653061]
[28]
Maletínská L, Nagelová V, Tichá A, et al. Novel lipidized analogs of prolactin-releasing peptide have prolonged half-lives and exert anti-obesity effects after peripheral administration. Int J Obes 2015; 39(6): 986-93.
[http://dx.doi.org/10.1038/ijo.2015.28] [PMID: 25771926]
[29]
Pražienková V, Holubová M, Pelantová H, et al. Impact of novel palmitoylated prolactin-releasing peptide analogs on metabolic changes in mice with diet-induced obesity. PLoS One 2017; 12(8): e0183449.
[http://dx.doi.org/10.1371/journal.pone.0183449] [PMID: 28820912]
[30]
Špolcová A, Mikulášková B, Holubová M, et al. Anorexigenic lipopeptides ameliorate central insulin signaling and attenuate tau phosphorylation in hippocampi of mice with monosodium glutamate-induced obesity. J Alzheimers Dis 2015; 45(3): 823-35.
[http://dx.doi.org/10.3233/JAD-143150] [PMID: 25624414]
[31]
Hölscher C. Novel dual GLP-1/GIP receptor agonists show neuroprotective effects in Alzheimer’s and Parkinson’s disease models. Neuropharmacology 2018; 136(Pt B): 251-9.
[http://dx.doi.org/10.1016/j.neuropharm.2018.01.040] [PMID: 29402504]
[32]
Holubová M, Hrubá L, Popelová A, et al. Liraglutide and a lipidized analog of prolactin-releasing peptide show neuroprotective effects in a mouse model of β-amyloid pathology. Neuropharmacology 2019; 144: 377-87.
[http://dx.doi.org/10.1016/j.neuropharm.2018.11.002] [PMID: 30428311]
[33]
Pražienková V, Schirmer C, Holubová M, et al. Lipidized Prolactin-Releasing Peptide Agonist Attenuates Hypothermia-Induced Tau Hyperphosphorylation in Neurons. J Alzheimers Dis 2019; 67(4): 1187-200.
[http://dx.doi.org/10.3233/JAD-180837] [PMID: 30689580]
[34]
Zmeškalová A, Popelová A, Exnerová A, Železná B, Kuneš J, Maletínská L. Cellular signaling and anti-apoptotic effects of prolactin-releasing peptide and its analog on SH-SY5Y cells. Int J Mol Sci 2020; 21(17): 21.
[http://dx.doi.org/10.3390/ijms21176343] [PMID: 32882929]
[35]
Popelová A, Pražienková V, Neprašová B, et al. Novel lipidized analog of prolactin-releasing peptide improves memory impairment and attenuates hyperphosphorylation of Tau protein in a mouse model of tauopathy. J Alzheimers Dis 2018; 62(4): 1725-36.
[http://dx.doi.org/10.3233/JAD-171041] [PMID: 29614684]
[36]
Jankowsky JL, Slunt HH, Ratovitski T, Jenkins NA, Copeland NG, Borchelt DR. Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng 2001; 17(6): 157-65.
[http://dx.doi.org/10.1016/S1389-0344(01)00067-3] [PMID: 11337275]
[37]
Maletínská L, Spolcová A, Maixnerová J, Blechová M, Zelezná B. Biological properties of prolactin-releasing peptide analogs with a modified aromatic ring of a C-terminal phenylalanine amide. Peptides 2011; 32(9): 1887-92.
[http://dx.doi.org/10.1016/j.peptides.2011.08.011] [PMID: 21872625]
[38]
Paxinos G, Franklin KBJ. The Mouse Brain In Stereotaxic Coordinates. 2003.
[39]
Mikulášková B, Holubová M, Pražienková V, et al. Lipidized prolactin-releasing peptide improved glucose tolerance in metabolic syndrome: Koletsky and spontaneously hypertensive rat study. Nutr Diabetes 2018; 8(1): 5.
[http://dx.doi.org/10.1038/s41387-017-0015-8] [PMID: 29339795]
[40]
Popelová A, Kákonová A, Hrubá L, Kuneš J, Maletínská L, Železná B. Potential neuroprotective and anti-apoptotic properties of a long-lasting stable analog of ghrelin: an in vitro study using SH-SY5Y cells. Physiol Res 2018; 67(2): 339-46.
[http://dx.doi.org/10.33549/physiolres.933761] [PMID: 29303606]
[41]
Mitew S, Kirkcaldie MT, Dickson TC, Vickers JC. Altered synapses and gliotransmission in Alzheimer’s disease and AD model mice. Neurobiol Aging 2013; 34(10): 2341-51.
[http://dx.doi.org/10.1016/j.neurobiolaging.2013.04.010] [PMID: 23643146]
[42]
Yousefi BH, von Reutern B, Scherübl D, et al. FIBT versus florbetaben and PiB: a preclinical comparison study with amyloid-PET in transgenic mice. EJNMMI Res 2015; 5: 20.
[http://dx.doi.org/10.1186/s13550-015-0090-6] [PMID: 25918674]
[43]
Caine D, Hodges JR. Heterogeneity of semantic and visuospatial deficits in early Alzheimer’s disease. Neuropsychology 2001; 15(2): 155-64.
[http://dx.doi.org/10.1037/0894-4105.15.2.155] [PMID: 11324859]
[44]
Lambon Ralph MA, Patterson K, Graham N, Dawson K, Hodges JR. Homogeneity and heterogeneity in mild cognitive impairment and Alzheimer’s disease: a cross-sectional and longitudinal study of 55 cases. Brain 2003; 126(Pt 11): 2350-62.
[http://dx.doi.org/10.1093/brain/awg236] [PMID: 12876147]
[45]
Albers MW, Gilmore GC, Kaye J, et al. At the interface of sensory and motor dysfunctions and Alzheimer’s disease. Alzheimers Dement 2015; 11(1): 70-98.
[http://dx.doi.org/10.1016/j.jalz.2014.04.514] [PMID: 25022540]
[46]
Kress BT, Iliff JJ, Xia M, et al. Impairment of paravascular clearance pathways in the aging brain. Ann Neurol 2014; 76(6): 845-61.
[http://dx.doi.org/10.1002/ana.24271] [PMID: 25204284]
[47]
Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med 2012; 4(147): 147ra111.
[http://dx.doi.org/10.1126/scitranslmed.3003748] [PMID: 22896675]
[48]
Rasmussen MK, Mestre H, Nedergaard M. The glymphatic pathway in neurological disorders. Lancet Neurol 2018; 17(11): 1016-24.
[http://dx.doi.org/10.1016/S1474-4422(18)30318-1] [PMID: 30353860]
[49]
Van Gool B, Storck SE, Reekmans SM, et al. LRP1 has a predominant role in production over clearance of Aβ in a mouse model of Alzheimer’s disease. Mol Neurobiol 2019; 56(10): 7234-45.
[http://dx.doi.org/10.1007/s12035-019-1594-2] [PMID: 31004319]
[50]
Shinohara M, Tachibana M, Kanekiyo T, Bu G. Role of LRP1 in the pathogenesis of Alzheimer’s disease: evidence from clinical and preclinical studies. J Lipid Res 2017; 58(7): 1267-81.
[http://dx.doi.org/10.1194/jlr.R075796] [PMID: 28381441]
[51]
Oddo S. The role of mTOR signaling in Alzheimer disease. Front Biosci (Schol Ed) 2012; 4: 941-52.
[http://dx.doi.org/10.2741/s310] [PMID: 22202101]
[52]
Caccamo A, Majumder S, Richardson A, Strong R, Oddo S. Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. J Biol Chem 2010; 285(17): 13107-20.
[http://dx.doi.org/10.1074/jbc.M110.100420] [PMID: 20178983]
[53]
Zhou XW, Tanila H, Pei JJ. Parallel increase in p70 kinase activation and tau phosphorylation (S262) with Abeta overproduction. FEBS Lett 2008; 582(2): 159-64.
[http://dx.doi.org/10.1016/j.febslet.2007.11.078] [PMID: 18068129]
[54]
Tramutola A, Triplett JC, Di Domenico F, et al. Alteration of mTOR signaling occurs early in the progression of Alzheimer disease (AD): analysis of brain from subjects with pre-clinical AD, amnestic mild cognitive impairment and late-stage AD. J Neurochem 2015; 133(5): 739-49.
[http://dx.doi.org/10.1111/jnc.13037] [PMID: 25645581]
[55]
Lafay-Chebassier C, Paccalin M, Page G, et al. mTOR/p70S6k signalling alteration by Abeta exposure as well as in APP-PS1 transgenic models and in patients with Alzheimer’s disease. J Neurochem 2005; 94(1): 215-25.
[http://dx.doi.org/10.1111/j.1471-4159.2005.03187.x] [PMID: 15953364]
[56]
Talboom JS, Velazquez R, Oddo S. The mammalian target of rapamycin at the crossroad between cognitive aging and Alzheimer’s disease. Npj Aging Mecha Dis 2015; 1: 15008.
[57]
Mueed Z, Tandon P, Maurya SK, Deval R, Kamal MA, Poddar NK. Tau and mTOR: The hotspots for multifarious diseases in Alzheimer’s development. Front Neurosci 2019; 12: 1017.
[http://dx.doi.org/10.3389/fnins.2018.01017] [PMID: 30686983]
[58]
Hansen DV, Hanson JE, Sheng M. Microglia in Alzheimer’s disease. J Cell Biol 2018; 217(2): 459-72.
[http://dx.doi.org/10.1083/jcb.201709069] [PMID: 29196460]
[59]
Frost GR, Li YM. The role of astrocytes in amyloid production and Alzheimer’s disease. Open Biol 2017; 7(12): 7.
[http://dx.doi.org/10.1098/rsob.170228] [PMID: 29237809]
[60]
Steele ML, Robinson SR. Reactive astrocytes give neurons less support: implications for Alzheimer’s disease. Neurobiol Aging 2012; 33(2): 423.e1-423.e13.
[http://dx.doi.org/10.1016/j.neurobiolaging.2010.09.018] [PMID: 21051108]
[61]
Serrano-Pozo A, Gómez-Isla T, Growdon JH, Frosch MP, Hyman BT. A phenotypic change but not proliferation underlies glial responses in Alzheimer disease. Am J Pathol 2013; 182(6): 2332-44.
[http://dx.doi.org/10.1016/j.ajpath.2013.02.031] [PMID: 23602650]
[62]
Belfiore R, Rodin A, Ferreira E, et al. Temporal and regional progression of Alzheimer’s disease-like pathology in 3xTg-AD mice. Aging Cell 2019; 18(1): e12873.
[http://dx.doi.org/10.1111/acel.12873] [PMID: 30488653]
[63]
Zotova E, Holmes C, Johnston D, Neal JW, Nicoll JA, Boche D. Microglial alterations in human Alzheimer’s disease following Aβ42 immunization. Neuropathol Appl Neurobiol 2011; 37(5): 513-24.
[http://dx.doi.org/10.1111/j.1365-2990.2010.01156.x] [PMID: 21166690]
[64]
Zhang L, Xie H, Cui L. Activation of astrocytes and expression of inflammatory cytokines in rats with experimental autoimmune encephalomyelitis. Exp Ther Med 2018; 16(6): 4401-6.
[http://dx.doi.org/10.3892/etm.2018.6798] [PMID: 30546391]
[65]
Su JH, Deng G, Cotman CW. Bax protein expression is increased in Alzheimer’s brain: correlations with DNA damage, Bcl-2 expression, and brain pathology. J Neuropathol Exp Neurol 1997; 56(1): 86-93.
[http://dx.doi.org/10.1097/00005072-199701000-00009] [PMID: 8990132]
[66]
Salakou S, Kardamakis D, Tsamandas AC, et al. Increased Bax/Bcl-2 ratio up-regulates caspase-3 and increases apoptosis in the thymus of patients with myasthenia gravis. In Vivo 2007; 21(1): 123-32.
[PMID: 17354625]
[67]
Tai J, Liu W, Li Y, Li L, Hölscher C. Neuroprotective effects of a triple GLP-1/GIP/glucagon receptor agonist in the APP/PS1 transgenic mouse model of Alzheimer’s disease. Brain Res 2018; 1678: 64-74.
[http://dx.doi.org/10.1016/j.brainres.2017.10.012] [PMID: 29050859]
[68]
Jordà-Siquier T, Petrel M, Kouskoff V, et al. 2020; APP accumulates around dense-core amyloid plaques with presynaptic proteins in Alzheimer’s disease brain. bioRxiv 2020.2010.2016.342196.
[69]
Yang Y, Kim J, Kim HY, et al. Amyloid-β oligomers may impair SNARE-mediated exocytosis by direct binding to syntaxin 1a. Cell Rep 2015; 12(8): 1244-51.
[http://dx.doi.org/10.1016/j.celrep.2015.07.044] [PMID: 26279571]
[70]
Hunt CA, Schenker LJ, Kennedy MB. PSD-95 is associated with the postsynaptic density and not with the presynaptic membrane at forebrain synapses. J Neurosci 1996; 16(4): 1380-8.
[http://dx.doi.org/10.1523/JNEUROSCI.16-04-01380.1996] [PMID: 8778289]
[71]
Carmody LC, Baucum AJ II, Bass MA, Colbran RJ. Selective targeting of the gamma1 isoform of protein phosphatase 1 to F-actin in intact cells requires multiple domains in spinophilin and neurabin. FASEB J 2008; 22(6): 1660-71.
[http://dx.doi.org/10.1096/fj.07-092841] [PMID: 18216290]
[72]
Allen PB, Zachariou V, Svenningsson P, et al. Distinct roles for spinophilin and neurabin in dopamine-mediated plasticity. Neuroscience 2006; 140(3): 897-911.
[http://dx.doi.org/10.1016/j.neuroscience.2006.02.067] [PMID: 16600521]

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