Periodic Variation of AAK1 in an Aβ1–42-Induced Mouse Model of Alzheimer’s Disease

  • Xue Fu
  • Meiling Ke
  • Weihua Yu
  • Xia Wang
  • Qian Xiao
  • Min Gu
  • Yang Lü
Article
  • 17 Downloads

Abstract

Inhibition of endocytosis in an Alzheimer’s disease (AD) model has been shown to be able to prevent amyloid β (Aβ)-induced damage and to exert a beneficial effect in treating AD. Adaptor-associated kinase 1 (AAK1), which binds to the adaptor protein complex 2 (AP-2), regulates the process of clathrin-mediated endocytosis. However, how AAK1 expression varies over the course of AD is unknown. In this study, we investigated AAK1 levels in AD model mice over time. Aβ1–42 was used to establish a mouse AD model, and the Morris water maze test was used to characterize the time course of Aβ1–42-induced cognition changes. ELISA was used to determine AAK1 levels in plasma and Aβ1–42 levels in brain tissues. Subsequently, the protein or gene levels of AAK1, AP-2, and Rab5 (an early endosome marker) were tested in each group. The cognitive function of Aβ1–42-induced mice was significantly declined compared to control group, and the deficits reached a peak on day 14, but partly recovered on day 30. Moreover, the level of Aβ1–42 detected with ELISA was highest on day 14, but reduced on day 30, paralleling the cognitive changes in the mice in our study. AAK1, AP-2, and Rab5 expression showed the same periodic variation as the changes in cognition. Thus, periodic variation in AAK1 expression is closely correlated to the decline in cognition, and AAK1 might be a suitable indicator for Alzheimer’s disease.

Keywords

1–42 AAK1 Alzheimer’s disease Cognition Endocytosis 

Abbreviations

AD

Alzheimer’s disease

AAK1

Adaptor-associated kinase 1

1–42

β-amyloid1–42

ANOVA

Analysis of variance

APP

β-amyloid precursor protein

AP-2

Adaptor protein complex 2

BACE

β-site APP cleaving enzyme

CME

Clathrin-mediated endocytosis

ELISA

Enzyme-linked immunosorbent assay

MWM

Morris water maze

NRG1

Neuregulin-1

PBS

Phosphate buffer solution

RT-PCR

Real-time polymerase chain reaction

TBST

Tris-buffered saline and Tween

WB

Western blot

Notes

Funding

This study was supported by grants from, the Key Project of Chongqing Municipal Health Bureau (2016ZDXM005), the Sub-project of National Science and Technology Supporting Program of the Ministry of Science and Technology of China (2015BAI06B04), the National Key Clinical Specialties Construction Program of China (No. [2013]544), grants from the Key Project of Social Undertakings and People’s Livelihood Security of Chongqing Science and Technology Commission (cstc2017shms-zdyfX0009), the Sub-project under the Science and Technology Benefit Plan of Chongqing Science and Technology Commission (cstc2015jcsf10001–01-01), and the Postgraduate Research Innovation Project of Chongqing (CYS16122).

Compliance with Ethical Standards

Conflicts of Interest

The authors declare that they have no conflict of interest.

References

  1. Alzheimer's Association (2014) 2014 Alzheimer’s disease facts and figures. Alzheimer’s & dementia : the journal of the Alzheimer's Association 10:e47–e92CrossRefGoogle Scholar
  2. Amin FU, Shah SA, Kim MO (2017) Vanillic acid attenuates Abeta1-42-induced oxidative stress and cognitive impairment in mice. Sci Rep 7:40753CrossRefPubMedPubMedCentralGoogle Scholar
  3. Ando K, Tomimura K, Sazdovitch V, Suain V, Yilmaz Z, Authelet M, Ndjim M, Vergara C, Belkouch M, Potier MC, Duyckaerts C, Brion JP (2016) Level of PICALM, a key component of clathrin-mediated endocytosis, is correlated with levels of phosphotau and autophagy-related proteins and is associated with tau inclusions in AD, PSP and pick disease. Neurobiol Dis 94:32–43CrossRefPubMedGoogle Scholar
  4. Ardura-Fabregat A, Boddeke E, Boza-Serrano A, Brioschi S, Castro-Gomez S, Ceyzeriat K, Dansokho C, Dierkes T, Gelders G, Heneka MT, Hoeijmakers L, Hoffmann A, Iaccarino L, Jahnert S, Kuhbandner K, Landreth G, Lonnemann N, Loschmann PA, McManus RM, Paulus A, Reemst K, Sanchez-Caro JM, Tiberi A, Van der Perren A, Vautheny A, Venegas C, Webers A, Weydt P, Wijasa TS, Xiang X, Yang Y (2017) Targeting neuroinflammation to treat Alzheimer’s disease. CNS Drugs 31:1057–1082CrossRefPubMedPubMedCentralGoogle Scholar
  5. Balducci C, Forloni G (2014) In vivo application of beta amyloid oligomers: a simple tool to evaluate mechanisms of action and new therapeutic approaches. Curr Pharm Des 20:2491–2505CrossRefPubMedGoogle Scholar
  6. Bucci C, Parton RG, Mather IH, Stunnenberg H, Simons K, Hoflack B, Zerial M (1992) The small GTPase rab5 functions as a regulatory factor in the early endocytic pathway. Cell 70:715–728CrossRefPubMedGoogle Scholar
  7. Burns A, Iliffe S (2009) Alzheimer’s disease. BMJ (Clinical research ed) 338:b158CrossRefGoogle Scholar
  8. Carare RO (2017) Editorial: clearance pathways for amyloid-beta. Significance for Alzheimer’s disease and its therapy. Front Aging Neurosci 9:339CrossRefPubMedPubMedCentralGoogle Scholar
  9. Cataldo AM, Petanceska S, Terio NB, Peterhoff CM, Durham R, Mercken M, Mehta PD, Buxbaum J, Haroutunian V, Nixon RA (2004) Abeta localization in abnormal endosomes: association with earliest Abeta elevations in AD and down syndrome. Neurobiol Aging 25:1263–1272CrossRefPubMedGoogle Scholar
  10. Chavrier P, Parton RG, Hauri HP, Simons K, Zerial M (1990) Localization of low molecular weight GTP binding proteins to exocytic and endocytic compartments. Cell 62:317–329CrossRefPubMedGoogle Scholar
  11. Conner SD, Schmid SL (2002) Identification of an adaptor-associated kinase, AAK1, as a regulator of clathrin-mediated endocytosis. J Cell Biol 156:921–929CrossRefPubMedPubMedCentralGoogle Scholar
  12. Conner SD, Schmid SL (2003) Regulated portals of entry into the cell. Nature 422:37–44CrossRefPubMedGoogle Scholar
  13. Conner SD, Schroter T, Schmid SL (2003) AAK1-mediated micro2 phosphorylation is stimulated by assembled clathrin. Traffic (Copenhagen, Denmark) 4:885–890CrossRefGoogle Scholar
  14. Doherty GJ, McMahon HT (2009) Mechanisms of endocytosis. Annu Rev Biochem 78:857–902CrossRefPubMedGoogle Scholar
  15. Fuentealba RA, Liu Q, Zhang J, Kanekiyo T, Hu X, Lee JM, LaDu MJ, Bu G (2010) Low-density lipoprotein receptor-related protein 1 (LRP1) mediates neuronal Abeta42 uptake and lysosomal trafficking. PLoS One 5:e11884CrossRefPubMedPubMedCentralGoogle Scholar
  16. Funato H, Yoshimura M, Yamazaki T, Saido TC, Ito Y, Yokofujita J, Okeda R, Ihara Y (1998) Astrocytes containing amyloid beta-protein (Abeta)-positive granules are associated with Abeta40-positive diffuse plaques in the aged human brain. Am J Pathol 152:983–992PubMedPubMedCentralGoogle Scholar
  17. Ginsberg SD, Mufson EJ, Counts SE, Wuu J, Alldred MJ, Nixon RA, Che S (2010) Regional selectivity of rab5 and rab7 protein upregulation in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis 22:631–639CrossRefPubMedPubMedCentralGoogle Scholar
  18. Hamaguchi T, Eisele YS, Varvel NH, Lamb BT, Walker LC, Jucker M (2012) The presence of Abeta seeds, and not age per se, is critical to the initiation of Abeta deposition in the brain. Acta Neuropathol 123:31–37CrossRefPubMedGoogle Scholar
  19. Hampel H, Prvulovic D, Teipel S, Jessen F, Luckhaus C, Frolich L, Riepe MW, Dodel R, Leyhe T, Bertram L, Hoffmann W, Faltraco F (2011) The future of Alzheimer’s disease: the next 10 years. Prog Neurobiol 95:718–728CrossRefPubMedGoogle Scholar
  20. de Hoop MJ, Huber LA, Stenmark H, Williamson E, Zerial M, Parton RG, Dotti CG (1994) The involvement of the small GTP-binding protein Rab5a in neuronal endocytosis. Neuron 13:11–22CrossRefPubMedGoogle Scholar
  21. Inoshita T, Arano T, Hosaka Y, Meng H, Umezaki Y, Kosugi S, Morimoto T, Koike M, Chang HY, Imai Y, Hattori N (2017) Vps35 in cooperation with LRRK2 regulates synaptic vesicle endocytosis through the endosomal pathway in drosophila. Hum Mol Genet 26:2933–2948CrossRefPubMedGoogle Scholar
  22. Kasza A, Penke B, Frank Z, Bozso Z, Szegedi V, Hunya A, Nemeth K, Kozma G, Fulop L (2017) Studies for improving a rat model of alzheimer’s disease: Icv administration of well-characterized beta-amyloid 1–42 oligomers induce dysfunction in spatial memory. Molecules (Basel, Switzerland) 22Google Scholar
  23. Kimura N, Yanagisawa K (2017) Traffic jam hypothesis: relationship between endocytic dysfunction and Alzheimer’s disease. Neurochem IntGoogle Scholar
  24. Kimura N, Okabayashi S, Ono F (2014) Dynein dysfunction disrupts beta-amyloid clearance in astrocytes through endocytic disturbances. Neuroreport 25:514–520PubMedGoogle Scholar
  25. Kinoshita A, Fukumoto H, Shah T, Whelan CM, Irizarry MC, Hyman BT (2003) Demonstration by FRET of BACE interaction with the amyloid precursor protein at the cell surface and in early endosomes. J Cell Sci 116:3339–3346CrossRefPubMedGoogle Scholar
  26. Kostich W, Hamman BD, Li YW, Naidu S, Dandapani K, Feng J, Easton A, Bourin C, Baker K, Allen J, Savelieva K, Louis JV, Dokania M, Elavazhagan S, Vattikundala P, Sharma V, Das ML, Shankar G, Kumar A, Holenarsipur VK, Gulianello M, Molski T, Brown JM, Lewis M, Huang Y, Lu Y, Pieschl R, O'Malley K, Lippy J, Nouraldeen A, Lanthorn TH, Ye G, Wilson A, Balakrishnan A, Denton R, Grace JE, Lentz KA, Santone KS, Bi Y, Main A, Swaffield J, Carson K, Mandlekar S, Vikramadithyan RK, Nara SJ, Dzierba C, Bronson J, Macor JE, Zaczek R, Westphal R, Kiss L, Bristow L, Conway CM, Zambrowicz B, Albright CF (2016) Inhibition of AAK1 kinase as a novel therapeutic approach to treat neuropathic pain. J Pharmacol Exp Ther 358:371–386CrossRefPubMedPubMedCentralGoogle Scholar
  27. Kuboyama T, Lee YA, Nishiko H, Tohda C (2015) Inhibition of clathrin-mediated endocytosis prevents amyloid beta-induced axonal damage. Neurobiol Aging 36:1808–1819CrossRefPubMedGoogle Scholar
  28. Langer F, Eisele YS, Fritschi SK, Staufenbiel M, Walker LC, Jucker M (2011) Soluble Abeta seeds are potent inducers of cerebral beta-amyloid deposition. J Neurosci Off J Soc Neurosci 31:14488–14495CrossRefGoogle Scholar
  29. Li F, Chen S, Wei C, Jia J (2017) Monetary costs of Alzheimer’s disease in China: protocol for a cluster-randomised observational study. BMC Neurol 17:15CrossRefPubMedPubMedCentralGoogle Scholar
  30. McGhee DJ, Ritchie CW, Thompson PA, Wright DE, Zajicek JP, Counsell CE (2014) A systematic review of biomarkers for disease progression in Alzheimer’s disease. PLoS One 9:e88854CrossRefPubMedPubMedCentralGoogle Scholar
  31. Motley AM, Berg N, Taylor MJ, Sahlender DA, Hirst J, Owen DJ, Robinson MS (2006) Functional analysis of AP-2 alpha and mu2 subunits. Mol Biol Cell 17:5298–5308CrossRefPubMedPubMedCentralGoogle Scholar
  32. Nixon RA (2005) Endosome function and dysfunction in Alzheimer’s disease and other neurodegenerative diseases. Neurobiol Aging 26:373–382CrossRefPubMedGoogle Scholar
  33. Olusanya O, Andrews PD, Swedlow JR, Smythe E (2001) Phosphorylation of threonine 156 of the mu2 subunit of the AP2 complex is essential for endocytosis in vitro and in vivo. Curr Biol 11:896–900CrossRefPubMedGoogle Scholar
  34. Paresce DM, Ghosh RN, Maxfield FR (1996) Microglial cells internalize aggregates of the Alzheimer’s disease amyloid beta-protein via a scavenger receptor. Neuron 17:553–565CrossRefPubMedGoogle Scholar
  35. Probst G, Xu YZ (2012) Small-molecule BACE1 inhibitors: a patent literature review (2006 - 2011). Expert opinion on therapeutic patents 22:511–540CrossRefPubMedGoogle Scholar
  36. Rajendran L, Annaert W (2012) Membrane trafficking pathways in Alzheimer’s disease. Traffic (Copenhagen, Denmark) 13:759–770CrossRefGoogle Scholar
  37. Ricotta D, Conner SD, Schmid SL, von Figura K, Honing S (2002) Phosphorylation of the AP2 mu subunit by AAK1 mediates high affinity binding to membrane protein sorting signals. J Cell Biol 156:791–795CrossRefPubMedPubMedCentralGoogle Scholar
  38. Sahoo AK, Dandapat J, Dash UC, Kanhar S (2017) Features and outcomes of drugs for combination therapy as multi-targets strategy to combat Alzheimer’s disease. J Ethnopharmacol 215:42–73CrossRefPubMedGoogle Scholar
  39. Sannerud R, Declerck I, Peric A, Raemaekers T, Menendez G, Zhou L, Veerle B, Coen K, Munck S, De Strooper B, Schiavo G, Annaert W (2011) ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1. Proc Natl Acad Sci U S A 108:E559–E568CrossRefPubMedPubMedCentralGoogle Scholar
  40. Schmid S, Jungwirth B, Gehlert V, Blobner M, Schneider G, Kratzer S, Kellermann K, Rammes G (2017) Intracerebroventricular injection of beta-amyloid in mice is associated with long-term cognitive impairment in the modified hole-board test. Behav Brain Res 324:15–20CrossRefPubMedGoogle Scholar
  41. Selkoe DJ (2008) Biochemistry and molecular biology of amyloid beta-protein and the mechanism of Alzheimer’s disease. Handb Clin Neurol 89:245–260CrossRefPubMedGoogle Scholar
  42. Semerdjieva S, Shortt B, Maxwell E, Singh S, Fonarev P, Hansen J, Schiavo G, Grant BD, Smythe E (2008) Coordinated regulation of AP2 uncoating from clathrin-coated vesicles by rab5 and hRME-6. J Cell Biol 183:499–511CrossRefPubMedPubMedCentralGoogle Scholar
  43. Smythe E, Ayscough KR (2003) The Ark1/Prk1 family of protein kinases. Regulators of endocytosis and the actin skeleton. EMBO Rep 4:246–251CrossRefPubMedPubMedCentralGoogle Scholar
  44. Sole-Domenech S, Cruz DL, Capetillo-Zarate E, Maxfield FR (2016) The endocytic pathway in microglia during health, aging and Alzheimer’s disease. Ageing Res Rev 32:89–103CrossRefPubMedPubMedCentralGoogle Scholar
  45. Srivareerat M, Tran TT, Salim S, Aleisa AM, Alkadhi KA (2011) Chronic nicotine restores normal Abeta levels and prevents short-term memory and E-LTP impairment in Abeta rat model of Alzheimer’s disease. Neurobiol Aging 32:834–844CrossRefPubMedGoogle Scholar
  46. Vogel JW, Varga Dolezalova M, La Joie R, Marks SM, Schwimmer HD, Landau SM, Jagust WJ (2017) Subjective cognitive decline and beta-amyloid burden predict cognitive change in healthy elderly. Neurology 89:2002–2009CrossRefPubMedGoogle Scholar
  47. Watanabe S, Boucrot E (2017) Fast and ultrafast endocytosis. Curr Opin Cell Biol 47:64–71CrossRefPubMedGoogle Scholar
  48. Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, Silverstein SC, Husemann J (2003) Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med 9:453–457CrossRefPubMedGoogle Scholar
  49. Xiao Q, Shi R, Yang W, Zou Y, Du Y, Zhang M, Yu W, Lu Y (2016) Time-dependent increase of chitinase1 in APP/PS1 double transgenic mice. Neurochem Res 41:1604–1611CrossRefPubMedGoogle Scholar
  50. Zhang Y, James M, Middleton FA, Davis RL (2005) Transcriptional analysis of multiple brain regions in Parkinson's disease supports the involvement of specific protein processing, energy metabolism, and signaling pathways, and suggests novel disease mechanisms. Am J Med Genet B Neuropsychiatr Genet 137b:5–16CrossRefPubMedGoogle Scholar
  51. Zhang Z, Li X, Li D, Luo M, Li Y, Song L, Jiang X (2017) Asiaticoside ameliorates beta-amyloid-induced learning and memory deficits in rats by inhibiting mitochondrial apoptosis and reducing inflammatory factors. Experimental and therapeutic medicine 13:413–420CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of GeriatricsThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
  2. 2.Institute of NeuroscienceChongqing Medical UniversityChongqingChina

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