Skip to main content
PMC home page
Neuroscience Bulletin logoLink to Neuroscience Bulletin
. 2014 Nov 12;30(6):923–935. doi: 10.1007/s12264-014-1479-3

Humanin attenuates Alzheimer-like cognitive deficits and pathological changes induced by amyloid β-peptide in rats

Gao-Shang Chai 1,2, Dong-Xiao Duan 1,3, Rong-Hong Ma 4, Jian-Ying Shen 5, Hong-Lian Li 5, Zhi-Wei Ma 1, Yu Luo 1, Lu Wang 1, Xin-Hua Qi 6, Qun Wang 1, Jian-Zhi Wang 1, Zelan Wei 7, Darrell D Mousseau 7, Li Wang 8,✉, Gongping Liu 1,✉
PMCID: PMC5562564  PMID: 25391447

Abstract

Amyloid β-peptide (Aβ) has been implicated as a key molecule in the neurodegenerative cascades of Alzheimer’s disease (AD). Humanin (HN) is a secretory peptide that inhibits the neurotoxicity of Aβ. However, the mechanism(s) by which HN exerts its neuroprotection against Aβ-induced ADlike pathological changes and memory deficits are yet to be completely defined. In the present study, we provided evidence that treatment of rats with HN increases the number of dendritic branches and the density of dendritic spines, and upregulates pre- and post-synaptic protein levels; these effects lead to enhanced long-term potentiation and amelioration of the memory deficits induced by Aβ1–42. HN also attenuated Aβ1–42-induced tau hyperphosphorylation, apparently by inhibiting the phosphorylation of Tyr307 on the inhibitory protein phosphatase-2A (PP2A) catalytic subunit and thereby activating PP2A. HN also inhibited apoptosis and reduced the oxidative stress induced by Aβ1–42. These findings provide novel mechanisms of action for the ability of HN to protect against Aβ1–42-induced AD-like pathological changes and memory deficits.

Keywords: Humanin, amyloid-beta, Alzheimer’s disease, tau, apoptosis

Footnotes

These authors contributed equally to this work.

Contributor Information

Li Wang, Email: kyk02@126.com.

Gongping Liu, Email: liugp111@mail.hust.edu.cn.

References

  • [1].Alonso AD, Grundke-Iqbal I, Barra HS, Iqbal K. Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau. Proc Natl Acad Sci U S A. 1997;94:298–303. doi: 10.1073/pnas.94.1.298. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [2].Ramsden M, Kotilinek L, Forster C, Paulson J, McGowan E, SantaCruz K, et al. Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L) J Neurosci. 2005;25:10637–10647. doi: 10.1523/JNEUROSCI.3279-05.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [3].Terry RD. Cell death or synaptic loss in Alzheimer disease. J Neuropathol Exp Neurol. 2000;59:1118–1119. doi: 10.1093/jnen/59.12.1118. [DOI] [PubMed] [Google Scholar]
  • [4].Paulson JB, Ramsden M, Forster C, Sherman MA, McGowan E, Ashe KH. Amyloid plaque and neurofibrillary tangle pathology in a regulatable mouse model of Alzheimer’s disease. Am J Pathol. 2008;173:762–772. doi: 10.2353/ajpath.2008.080175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [5].Mount C, Downton C. Alzheimer disease: progress or profit? Nat Med. 2006;12:780–784. doi: 10.1038/nm0706-780. [DOI] [PubMed] [Google Scholar]
  • [6].Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297:353–356. doi: 10.1126/science.1072994. [DOI] [PubMed] [Google Scholar]
  • [7].Sisodia SS, St GP. gamma-Secretase, Notch, Abeta and Alzheimer’s disease: where do the presenilins fit in? Nat Rev Neurosci. 2002;3:281–290. doi: 10.1038/nrn785. [DOI] [PubMed] [Google Scholar]
  • [8].Gotz J, Chen F, van Dorpe J, Nitsch RM. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science. 2001;293:1491–1495. doi: 10.1126/science.1062097. [DOI] [PubMed] [Google Scholar]
  • [9].Lippa CF, Nee LE, Mori H, St GP. Abeta-42 deposition precedes other changes in PS-1 Alzheimer’s disease. Lancet. 1998;352:1117–1118. doi: 10.1016/S0140-6736(05)79757-9. [DOI] [PubMed] [Google Scholar]
  • [10].Roher AE, Lowenson JD, Clarke S, Woods AS, Cotter RJ, Gowing E, et al. beta-Amyloid-(1–42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease. Proc Natl Acad Sci U S A. 1993;90:10836–10840. doi: 10.1073/pnas.90.22.10836. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [11].Guo H, Albrecht S, Bourdeau M, Petzke T, Bergeron C, LeBlanc AC. Active caspase-6 and caspase-6-cleaved tau in neuropil threads, neuritic plaques, and neurofibrillary tangles of Alzheimer’s disease. Am J Pathol. 2004;165:523–531. doi: 10.1016/S0002-9440(10)63317-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [12].McPhie DL, Coopersmith R, Hines-Peralta A, Chen Y, Ivins KJ, Manly S, et al. DNA synthesis and neuronal apoptosis caused by familial Alzheimer disease mutants of the amyloid precursor protein are mediated by the p21 activated kinase PAK3. J Neurosci. 2003;23:6914–6927. doi: 10.1523/JNEUROSCI.23-17-06914.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [13].Yu W, Mechawar N, Krantic S, Quirion R. Evidence for the involvement of apoptosis-inducing factor-mediated caspase-independent neuronal death in Alzheimer disease. Am J Pathol. 2010;176:2209–2218. doi: 10.2353/ajpath.2010.090496. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [14].Kukar T, Murphy MP, Eriksen JL, Sagi SA, Weggen S, Smith TE, et al. Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Abeta42 production. Nat Med. 2005;11:545–550. doi: 10.1038/nm1235. [DOI] [PubMed] [Google Scholar]
  • [15].Moonis M, Swearer JM, Dayaw MP, St GP, Rogaeva E, Kawarai T, et al. Familial Alzheimer disease: decreases in CSF Abeta42 levels precede cognitive decline. Neurology. 2005;65:323–325. doi: 10.1212/01.wnl.0000171397.32851.bc. [DOI] [PubMed] [Google Scholar]
  • [16].Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, et al. ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science. 2012;335:1503–1506. doi: 10.1126/science.1217697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [17].Hashimoto Y, Ito Y, Niikura T, Shao Z, Hata M, Oyama F, et al. Mechanisms of neuroprotection by a novel rescue factor humanin from Swedish mutant amyloid precursor protein. Biochem Biophys Res Commun. 2001;283:460–468. doi: 10.1006/bbrc.2001.4765. [DOI] [PubMed] [Google Scholar]
  • [18].Nishimoto I, Matsuoka M, Niikura T. Unravelling the role of Humanin. Trends Mol Med. 2004;10:102–105. doi: 10.1016/j.molmed.2004.01.001. [DOI] [PubMed] [Google Scholar]
  • [19].Chiba T, Yamada M, Hashimoto Y, Sasabe J, Kita Y, Terashita K, et al. Development of a femtomolar-acting humanin derivative named colivelin by attaching activity-dependent neurotrophic factor to its N terminus: characterization of colivelin-mediated neuroprotection against Alzheimer’s disease-relevant insults in vitro and in vivo. J Neurosci. 2005;25:10252–10261. doi: 10.1523/JNEUROSCI.3348-05.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [20].Hashimoto Y, Niikura T, Tajima H, Yasukawa T, Sudo H, Ito Y, et al. A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer’s disease genes and Abeta. Proc Natl Acad Sci U S A. 2001;98:6336–6341. doi: 10.1073/pnas.101133498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [21].Hashimoto Y, Niikura T, Ito Y, Sudo H, Hata M, Arakawa E, et al. Detailed characterization of neuroprotection by a rescue factor humanin against various Alzheimer’s disease-relevant insults. J Neurosci. 2001;21:9235–9245. doi: 10.1523/JNEUROSCI.21-23-09235.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [22].Ikonen M, Liu B, Hashimoto Y, Ma L, Lee KW, Niikura T, et al. Interaction between the Alzheimer’s survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis. Proc Natl Acad Sci U S A. 2003;100:13042–13047. doi: 10.1073/pnas.2135111100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [23].Kariya S, Takahashi N, Ooba N, Kawahara M, Nakayama H, Ueno S. Humanin inhibits cell death of serum-deprived PC12h cells. Neuroreport. 2002;13:903–907. doi: 10.1097/00001756-200205070-00034. [DOI] [PubMed] [Google Scholar]
  • [24].Wang D, Li H, Yuan H, Zheng M, Bai C, Chen L, et al. Humanin delays apoptosis in K562 cells by downregulation of P38 MAP kinase. Apoptosis. 2005;10:963–971. doi: 10.1007/s10495-005-1191-x. [DOI] [PubMed] [Google Scholar]
  • [25].Pike CJ, Nguyen TV, Ramsden M, Yao M, Murphy MP, Rosario ER. Androgen cell signaling pathways involved in neuroprotective actions. Horm Behav. 2008;53:693–705. doi: 10.1016/j.yhbeh.2007.11.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [26].Frautschy SA, Baird A, Cole GM. Effects of injected Alzheimer beta-amyloid cores in rat brain. Proc Natl Acad Sci U S A. 1991;88:8362–8366. doi: 10.1073/pnas.88.19.8362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [27].Morris R. Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods. 1984;11:47–60. doi: 10.1016/0165-0270(84)90007-4. [DOI] [PubMed] [Google Scholar]
  • [28].Tu W, Xu X, Peng L, Zhong X, Zhang W, Soundarapandian MM, et al. DAPK1 interaction with NMDA receptor NR2B subunits mediates brain damage in stroke. Cell. 2010;140:222–234. doi: 10.1016/j.cell.2009.12.055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [29].Chai GS, Jiang X, Ni ZF, Ma ZW, Xie AJ, Cheng XS, et al. Betaine attenuates Alzheimer-like pathological changes and memory deficits induced by homocysteine. J Neurochem. 2013;124:388–396. doi: 10.1111/jnc.12094. [DOI] [PubMed] [Google Scholar]
  • [30].Zhu LQ, Liu D, Hu J, Cheng J, Wang SH, Wang Q, et al. GSK-3 beta inhibits presynaptic vesicle exocytosis by phosphorylating P/Q-type calcium channel and interrupting SNARE complex formation. J Neurosci. 2010;30:3624–3633. doi: 10.1523/JNEUROSCI.5223-09.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [31].Liu SJ, Zhang JY, Li HL, Fang ZY, Wang Q, Deng HM, et al. Tau becomes a more favorable substrate for GSK-3 when it is prephosphorylated by PKA in rat brain. J Biol Chem. 2004;279:50078–50088. doi: 10.1074/jbc.M406109200. [DOI] [PubMed] [Google Scholar]
  • [32].Yang Y, Shu X, Liu D, Shang Y, Wu Y, Pei L, et al. EPAC Null Mutation Impairs Learning and Social Interactions via Aberrant Regulation of miR-124 and Zif268 Translation. Neuron. 2012;73:774–788. doi: 10.1016/j.neuron.2012.02.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [33].Iqbal K, Grundke-Iqbal I, Smith AJ, George L, Tung YC, Zaidi T. Identification and localization of a tau peptide to paired helical filaments of Alzheimer disease. Proc Natl Acad Sci U S A. 1989;86:5646–5650. doi: 10.1073/pnas.86.14.5646. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [34].Liu F, Liang Z, Gong CX. Hyperphosphorylation of tau and protein phosphatases in Alzheimer disease. Panminerva Med. 2006;48:97–108. [PubMed] [Google Scholar]
  • [35].Butterfield DA, Drake J, Pocernich C, Castegna A. Evidence of oxidative damage in Alzheimer’s disease brain: central role for amyloid beta-peptide. Trends Mol Med. 2001;7:548–554. doi: 10.1016/S1471-4914(01)02173-6. [DOI] [PubMed] [Google Scholar]
  • [36].Reddy PH. Amyloid precursor protein-mediated free radicals and oxidative damage: implications for the development and progression of Alzheimer’s disease. J Neurochem. 2006;96:1–13. doi: 10.1111/j.1471-4159.2005.03530.x. [DOI] [PubMed] [Google Scholar]
  • [37].We Z, Song MS, MacTavish D, Jhamandas JH, Kar S. Role of calpain and caspase in beta-amyloid-induced cell death in rat primary septal cultured neurons. Neuropharmacology. 2008;54:721–733. doi: 10.1016/j.neuropharm.2007.12.006. [DOI] [PubMed] [Google Scholar]
  • [38].Wilkinson BL, Cramer PE, Varvel NH, Reed-Geaghan E, Jiang Q, Szabo A, et al. Ibuprofen attenuates oxidative damage through NOX2 inhibition in Alzheimer’s disease. Neurobiol Aging. 2012;33:121–197. doi: 10.1016/j.neurobiolaging.2010.06.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [39].Murray IV, Sindoni ME, Axelsen PH. Promotion of oxidative lipid membrane damage by amyloid beta proteins. Biochemistry-Us. 2005;44:12606–12613. doi: 10.1021/bi050926p. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [40].Bachar AR, Scheffer L, Schroeder AS, Nakamura HK, Cobb LJ, Oh YK, et al. Humanin is expressed in human vascular walls and has a cytoprotective effect against oxidized LDL-induced oxidative stress. Cardiovasc Res. 2010;88:360–366. doi: 10.1093/cvr/cvq191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [41].Mamiya T, Ukai M. [Gly(14)]-Humanin improved the learning and memory impairment induced by scopolamine in vivo. Br J Pharmacol. 2001;134:1597–1599. doi: 10.1038/sj.bjp.0704429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [42].Niikura T, Sidahmed E, Hirata-Fukae C, Aisen PS, Matsuoka Y. A humanin derivative reduces amyloid beta accumulation and ameliorates memory deficit in triple transgenic mice. PLoS One. 2011;6:e16259. doi: 10.1371/journal.pone.0016259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [43].Richter-Levin G, Segal M. The effects of serotonin depletion and raphe grafts on hippocampal electrophysiology and behavior. J Neurosci. 1991;11:1585–1596. doi: 10.1523/JNEUROSCI.11-06-01585.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [44].Greengard P, Valtorta F, Czernik AJ, Benfenati F. Synaptic vesicle phosphoproteins and regulation of synaptic function. Science. 1993;259:780–785. doi: 10.1126/science.8430330. [DOI] [PubMed] [Google Scholar]
  • [45].Pieribone VA, Shupliakov O, Brodin L, Hilfiker-Rothenfluh S, Czernik AJ, Greengard P. Distinct pools of synaptic vesicles in neurotransmitter release. Nature. 1995;375:493–497. doi: 10.1038/375493a0. [DOI] [PubMed] [Google Scholar]
  • [46].Slutsky I, Abumaria N, Wu LJ, Huang C, Zhang L, Li B, et al. Enhancement of learning and memory by elevating brain magnesium. Neuron. 2010;65:165–177. doi: 10.1016/j.neuron.2009.12.026. [DOI] [PubMed] [Google Scholar]
  • [47].Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A. 1986;83:4913–4917. doi: 10.1073/pnas.83.13.4913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [48].Wang JZ, Gong CX, Zaidi T, Grundke-Iqbal I, Iqbal K. Dephosphorylation of Alzheimer paired helical filaments by protein phosphatase-2A and -2B. J Biol Chem. 1995;270:4854–4860. doi: 10.1074/jbc.270.9.4854. [DOI] [PubMed] [Google Scholar]
  • [49].Tian Q, Wang J. Role of serine/threonine protein phosphatase in Alzheimer’s disease. Neurosignals. 2002;11:262–269. doi: 10.1159/000067425. [DOI] [PubMed] [Google Scholar]
  • [50].Jung SS, Van Nostrand WE. Humanin rescues human cerebrovascular smooth muscle cells from Abeta-induced toxicity. J Neurochem. 2003;84:266–272. doi: 10.1046/j.1471-4159.2003.01524.x. [DOI] [PubMed] [Google Scholar]
  • [51].Hashimoto Y, Suzuki H, Aiso S, Niikura T, Nishimoto I, Matsuoka M. Involvement of tyrosine kinases and STAT3 in Humanin-mediated neuroprotection. Life Sci. 2005;77:3092–3104. doi: 10.1016/j.lfs.2005.03.031. [DOI] [PubMed] [Google Scholar]
  • [52].Caricasole A, Bruno V, Cappuccio I, Melchiorri D, Copani A, Nicoletti F. A novel rat gene encoding a Humanin-like peptide endowed with broad neuroprotective activity. FASEB J. 2002;16:1331–1333. doi: 10.1096/fj.02-0018fje. [DOI] [PubMed] [Google Scholar]
  • [53].Guo B, Zhai D, Cabezas E, Welsh K, Nouraini S, Satterthwait AC, et al. Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature. 2003;423:456–461. doi: 10.1038/nature01627. [DOI] [PubMed] [Google Scholar]
  • [54].Butterfield DA, Bush AI. Alzheimer’s amyloid beta-peptide (1–42): involvement of methionine residue 35 in the oxidative stress and neurotoxicity properties of this peptide. Neurobiol Aging. 2004;25:563–568. doi: 10.1016/j.neurobiolaging.2003.12.027. [DOI] [PubMed] [Google Scholar]
  • [55].Mattson MP. Pathways towards and away from Alzheimer’s disease. Nature. 2004;430:631–639. doi: 10.1038/nature02621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [56].Hashimoto Y, Niilura T, Jajima H, Yasukawa T, Sudo H, Ito Y, et al. A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer’s disease genes and Abeta. Proc Natl Acad Sci U S A. 2001;98:6336–6341. doi: 10.1073/pnas.101133498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [57].Guo B, Zhai D, Cabezas E, Welsh K, Nouraini S, Satterthwait AC, et al. Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature. 2003;423:456–461. doi: 10.1038/nature01627. [DOI] [PubMed] [Google Scholar]
  • [58].Hashimoto Y, Niilura T, Chiba T, Tsukamoto E, Kadowaki H, Nishitoh H, et al. The cytoplasmic domain of Alzheimer’s amyloid-b protein precursor causes sustained ASK1/JNK mediated neurotoxic signal via dimerization. J Pharmacol Exp Ther. 2003;306:889–902. doi: 10.1124/jpet.103.051383. [DOI] [PubMed] [Google Scholar]
  • [59].Hashimoto Y, Kurita M, Aiso S, Nishimoto I, Matsuoka M. Humanin inhibits neuronal cell death by interacting with a cytokine receptor complex or complexes involving CNTF receptor alpha/WSX-1/gp130. Mol Biol Cell. 2009;20:2864–2873. doi: 10.1091/mbc.E09-02-0168. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Neuroscience Bulletin are provided here courtesy of Springer

RESOURCES