Skip to main content

Advertisement

SpringerLink
Log in

Expression of AHI1 Rescues Amyloidogenic Pathology in Alzheimer’s Disease Model Cells

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

A hallmark of Alzheimer’s disease (AD) pathogenesis is the accumulation of extracellular plaques mainly composed of amyloid-β (Aβ) derived from amyloid precursor protein (APP) cleavage. Recent reports suggest that transport of APP in vesicles with huntingtin-associated protein-1 (HAP1) negatively regulates Aβ production. In neurons, HAP1 forms a stable complex with Abelson helper integration site-1 (AHI1), in which mutations cause neurodevelopmental and psychiatric disorders. HAP1 and AHI1 interact with tropomyosin receptor kinases (Trks), which are also associated with APP and mediate neurotrophic signaling. In this study, we hypothesize that AHI1 participates in APP trafficking and processing to rescue AD pathology. Indeed, AHI1 was significantly reduced in mouse neuroblastoma N2a cells expressing human Swedish and Indiana APP (designed as AD model cells) and in 3xTg-AD mouse brain. The AD model cells as well as Ahi1-knockdown cells expressing wild-type APP-695 exhibited a significant reduction in viability. In addition, the AD model cells were reduced in neurite outgrowth. APP C-terminal fragment-β (CTFβ) and Aβ42 were increased in the AD cell lysates and the culture media, respectively. To investigate the mechanism how AHI1 alters APP activities, we overexpressed human AHI1 in the AD model cells. The results showed that AHI1 interacted with APP physically in mouse brain and transfected N2a cells despite APP genotypes. AHI1 expression facilitated intracellular translocation of APP and inhibited APP amyloidogenic process to reduce the level of APP-CTFβ in the total lysates of AD model cells as well as Aβ in the culture media. Consequently, AHI1–APP interactions enhanced neurotrophic signaling through Erk activation and led to restored cell survival and differentiation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

Aβ:

Amyloid-β

AD:

Alzheimer’s disease

AHI1:

Abelson helper integration site-1

APP:

Amyloid precursor protein

APP-Swe/Ind:

Swedish and Indiana APP

CTF:

C-Terminal fragment

ELISA:

Enzyme-linked immunosorbent assay

Erk:

Extracellular signal-regulated protein kinase

GFP:

Green fluorescent protein

HAP1:

Huntingtin-associated protein-1

PSEN:

Presenilin

sAPPα:

Soluble APPα

Trk:

Tropomyosin receptor kinase

References

  1. Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM (2007) Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement 3(3):186–191. https://doi.org/10.1016/j.jalz.2007.04.381

    Article  PubMed  Google Scholar 

  2. Aisen P, Touchon J, Amariglio R, Andrieu S, Bateman R, Breitner J, Donohue M, Dunn B et al (2017) EU/US/CTAD task force: lessons learned from recent and current Alzheimer’s prevention trials. J Prev Alzheimers Dis 4(2):116–124. https://doi.org/10.14283/jpad.2017.13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lin CY, Sheu JJ, Tsai IS, Wang ST, Yang LY, Hsu IU, Chang HW, Lee HM et al (2018) Elevated IgM against nepsilon-(carboxyethyl)lysine-modified apolipoprotein A1 peptide 141-147 in Taiwanese with Alzheimer’s disease. Clin Biochem 56:75–82. https://doi.org/10.1016/j.clinbiochem.2018.04.009

    Article  CAS  PubMed  Google Scholar 

  4. Wolfe MS (2003) The secretases of Alzheimer’s disease. Curr Top Dev Biol 54:233–261

    Article  CAS  Google Scholar 

  5. Alonso Vilatela ME, Lopez-Lopez M, Yescas-Gomez P (2012) Genetics of Alzheimer’s disease. Arch Med Res 43(8):622–631. https://doi.org/10.1016/j.arcmed.2012.10.017

    Article  CAS  PubMed  Google Scholar 

  6. Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, Vigo-Pelfrey C, Lieberburg I et al (1992) Mutation of the beta-amyloid precursor protein in familial Alzheimer’s disease increases beta-protein production. Nature 360(6405):672–674. https://doi.org/10.1038/360672a0

    Article  CAS  PubMed  Google Scholar 

  7. Sosa LJ, Caceres A, Dupraz S, Oksdath M, Quiroga S, Lorenzo A (2017) The physiological role of the amyloid precursor protein as an adhesion molecule in the developing nervous system. J Neurochem 143(1):11–29. https://doi.org/10.1111/jnc.14122

    Article  CAS  PubMed  Google Scholar 

  8. Nalivaeva NN, Turner AJ (2013) The amyloid precursor protein: a biochemical enigma in brain development, function and disease. FEBS Lett 587(13):2046–2054. https://doi.org/10.1016/j.febslet.2013.05.010

    Article  CAS  PubMed  Google Scholar 

  9. Tcw J, Goate AM (2017) Genetics of beta-amyloid precursor protein in Alzheimer’s disease. Cold Spring Harb Perspect Med 7(6). https://doi.org/10.1101/cshperspect.a024539

    Article  Google Scholar 

  10. Zeldenrust SR, Murrell J, Farlow M, Ghetti B, Roses AD, Benson MD (1993) RFLP analysis for APP 717 mutations associated with Alzheimer’s disease. J Med Genet 30(6):476–478

    Article  CAS  Google Scholar 

  11. Sinha S, Lieberburg I (1999) Cellular mechanisms of beta-amyloid production and secretion. Proc Natl Acad Sci U S A 96(20):11049–11053

    Article  CAS  Google Scholar 

  12. Cai XD, Golde TE, Younkin SG (1993) Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science 259(5094):514–516

    Article  CAS  Google Scholar 

  13. Tsai YF, Yang DJ, Ngo TH, Shih CH, Wu YF, Lee CK, Phraekanjanavichid V, Yen SF et al (2019) Ganglioside Hp-s1 analogue inhibits amyloidogenic toxicity in Alzheimer’s disease model cells. ACS Chem Neurosci 10:528–536. https://doi.org/10.1021/acschemneuro.8b00406

    Article  CAS  PubMed  Google Scholar 

  14. Wang X, Huang T, Bu G, Xu H (2014) Dysregulation of protein trafficking in neurodegeneration. Mol Neurodegener 9:31. https://doi.org/10.1186/1750-1326-9-31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Salinas S, Bilsland LG, Schiavo G (2008) Molecular landmarks along the axonal route: axonal transport in health and disease. Curr Opin Cell Biol 20(4):445–453. https://doi.org/10.1016/j.ceb.2008.04.002

    Article  CAS  PubMed  Google Scholar 

  16. Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, Raman R, Davies P et al (2005) Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 307(5713):1282–1288. https://doi.org/10.1126/science.1105681

    Article  CAS  PubMed  Google Scholar 

  17. Lazarov O, Morfini GA, Pigino G, Gadadhar A, Chen X, Robinson J, Ho H, Brady ST et al (2007) Impairments in fast axonal transport and motor neuron deficits in transgenic mice expressing familial Alzheimer’s disease-linked mutant presenilin 1. J Neurosci 27(26):7011–7020. https://doi.org/10.1523/JNEUROSCI.4272-06.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhang YW, Chen Y, Liu Y, Zhao Y, Liao FF, Xu H (2013) APP regulates NGF receptor trafficking and NGF-mediated neuronal differentiation and survival. PLoS One 8(11):e80571. https://doi.org/10.1371/journal.pone.0080571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Galvao F Jr, Grokoski KC, da Silva BB, Lamers ML, Siqueira IR (2019) The amyloid precursor protein (APP) processing as a biological link between Alzheimer’s disease and cancer. Ageing Res Rev 49:83–91. https://doi.org/10.1016/j.arr.2018.11.007

    Article  CAS  PubMed  Google Scholar 

  20. Yang GZ, Yang M, Lim Y, Lu JJ, Wang TH, Qi JG, Zhong JH, Zhou XF (2012) Huntingtin associated protein 1 regulates trafficking of the amyloid precursor protein and modulates amyloid beta levels in neurons. J Neurochem 122(5):1010–1022. https://doi.org/10.1111/j.1471-4159.2012.07845.x

    Article  CAS  PubMed  Google Scholar 

  21. Rong J, McGuire JR, Fang ZH, Sheng G, Shin JY, Li SH, Li XJ (2006) Regulation of intracellular trafficking of huntingtin-associated protein-1 is critical for TrkA protein levels and neurite outgrowth. J Neurosci 26(22):6019–6030. https://doi.org/10.1523/JNEUROSCI.1251-06.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lim Y, Wu LL, Chen S, Sun Y, Vijayaraj SL, Yang M, Bobrovskaya L, Keating D et al (2018) HAP1 is required for endocytosis and signalling of BDNF and its receptors in neurons. Mol Neurobiol 55(3):1815–1830. https://doi.org/10.1007/s12035-016-0379-0

    Article  CAS  PubMed  Google Scholar 

  23. Li XJ, Li SH, Sharp AH, Nucifora FC Jr, Schilling G, Lanahan A, Worley P, Snyder SH et al (1995) A huntingtin-associated protein enriched in brain with implications for pathology. Nature 378(6555):398–402. https://doi.org/10.1038/378398a0

    Article  CAS  PubMed  Google Scholar 

  24. Xiang J, Yang H, Zhao T, Sun M, Xu X, Zhou XF, Li SH, Li XJ (2014) Huntingtin-associated protein 1 regulates postnatal neurogenesis and neurotrophin receptor sorting. J Clin Invest 124(1):85–98. https://doi.org/10.1172/JCI69206

    Article  CAS  PubMed  Google Scholar 

  25. Xiang J, Yan S, Li SH, Li XJ (2015) Postnatal loss of hap1 reduces hippocampal neurogenesis and causes adult depressive-like behavior in mice. PLoS Genet 11(4):e1005175. https://doi.org/10.1371/journal.pgen.1005175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li SH, Yu ZX, Li CL, Nguyen HP, Zhou YX, Deng C, Li XJ (2003) Lack of huntingtin-associated protein-1 causes neuronal death resembling hypothalamic degeneration in Huntington’s disease. J Neurosci 23(17):6956–6964

    Article  CAS  Google Scholar 

  27. Ferland RJ, Eyaid W, Collura RV, Tully LD, Hill RS, Al-Nouri D, Al-Rumayyan A, Topcu M et al (2004) Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nat Genet 36(9):1008–1013. https://doi.org/10.1038/ng1419

    Article  CAS  PubMed  Google Scholar 

  28. Lotan A, Lifschytz T, Mernick B, Lory O, Levi E, Ben-Shimol E, Goelman G, Lerer B (2017) Alterations in the expression of a neurodevelopmental gene exert long-lasting effects on cognitive-emotional phenotypes and functional brain networks: translational evidence from the stress-resilient Ahi1 knockout mouse. Mol Psychiatry 22(6):884–899. https://doi.org/10.1038/mp.2016.29

    Article  CAS  PubMed  Google Scholar 

  29. Sheng G, Xu X, Lin YF, Wang CE, Rong J, Cheng D, Peng J, Jiang X et al (2008) Huntingtin-associated protein 1 interacts with Ahi1 to regulate cerebellar and brainstem development in mice. J Clin Invest 118(8):2785–2795. https://doi.org/10.1172/JCI35339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Weng L, Lin YF, Li AL, Wang CE, Yan S, Sun M, Gaertig MA, Mitha N et al (2013) Loss of Ahi1 affects early development by impairing BM88/Cend1-mediated neuronal differentiation. J Neurosci 33(19):8172–8184. https://doi.org/10.1523/JNEUROSCI.0119-13.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Xu X, Yang H, Lin YF, Li X, Cape A, Ressler KJ, Li S, Li XJ (2010) Neuronal Abelson helper integration site-1 (Ahi1) deficiency in mice alters TrkB signaling with a depressive phenotype. Proc Natl Acad Sci U S A 107(44):19126–19131. https://doi.org/10.1073/pnas.1013032107

    Article  PubMed  PubMed Central  Google Scholar 

  32. Young-Pearse TL, Bai J, Chang R, Zheng JB, LoTurco JJ, Selkoe DJ (2007) A critical function for beta-amyloid precursor protein in neuronal migration revealed by in utero RNA interference. J Neurosci 27(52):14459–14469. https://doi.org/10.1523/JNEUROSCI.4701-07.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Canu N, Pagano I, La Rosa LR, Pellegrino M, Ciotti MT, Mercanti D, Moretti F, Sposato V et al (2017) Association of TrkA and APP is promoted by NGF and reduced by cell death-promoting agents. Front Mol Neurosci 10:15. https://doi.org/10.3389/fnmol.2017.00015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Rosenberg PB, Nowrangi MA, Lyketsos CG (2015) Neuropsychiatric symptoms in Alzheimer’s disease: what might be associated brain circuits? Mol Asp Med 43-44:25–37. https://doi.org/10.1016/j.mam.2015.05.005

    Article  Google Scholar 

  35. Amann-Zalcenstein D, Avidan N, Kanyas K, Ebstein RP, Kohn Y, Hamdan A, Ben-Asher E, Karni O et al (2006) AHI1, a pivotal neurodevelopmental gene, and C6orf217 are associated with susceptibility to schizophrenia. Eur J Hum Genet 14(10):1111–1119. https://doi.org/10.1038/sj.ejhg.5201675

    Article  CAS  PubMed  Google Scholar 

  36. Ren L, Qian X, Zhai L, Sun M, Miao Z, Li J, Xu X (2014) Loss of Ahi1 impairs neurotransmitter release and causes depressive behaviors in mice. PLoS One 9(4):e93640. https://doi.org/10.1371/journal.pone.0093640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Xu Z, Guo X, Yang Y, Tucker D, Lu Y, Xin N, Zhang G, Yang L et al (2017) Low-level laser irradiation improves depression-like behaviors in mice. Mol Neurobiol 54(6):4551–4559. https://doi.org/10.1007/s12035-016-9983-2

    Article  CAS  PubMed  Google Scholar 

  38. Wu LL, Zhou XF (2009) Huntingtin associated protein 1 and its functions. Cell Adhes Migr 3(1):71–76

    Article  Google Scholar 

  39. Huang PT, Chen CH, Hsu IU, Salim SA, Kao SH, Cheng CW, Lai CH, Lee CF et al (2015) Huntingtin-associated protein 1 interacts with breakpoint cluster region protein to regulate neuronal differentiation. PLoS One 10(2):e0116372. https://doi.org/10.1371/journal.pone.0116372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sun J, Roy S (2018) The physical approximation of APP and BACE-1: a key event in Alzheimer’s disease pathogenesis. Dev Neurobiol 78(3):340–347. https://doi.org/10.1002/dneu.22556

    Article  CAS  PubMed  Google Scholar 

  41. Woodruff G, Reyna SM, Dunlap M, Van Der Kant R, Callender JA, Young JE, Roberts EA, Goldstein LS (2016) Defective transcytosis of APP and lipoproteins in human iPSC-derived neurons with familial Alzheimer’s disease mutations. Cell Rep 17(3):759–773. https://doi.org/10.1016/j.celrep.2016.09.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Liu X, Rothe K, Yen R, Fruhstorfer C, Maetzig T, Chen M, Forrest DL, Humphries RK et al (2017) A novel AHI-1-BCR-ABL-DNM2 complex regulates leukemic properties of primitive CML cells through enhanced cellular endocytosis and ROS-mediated autophagy. Leukemia, UK 31(11):2376–2387. https://doi.org/10.1038/leu.2017.108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank Dr. Yi-Chao Lee and Mr. Jonathan Chang-Cheng Shieh in Taipei Medical University for the helps on N2a cell culture and English editing of the manuscript, respectively.

Funding

This work was supported by the Grants of Taipei Medical University Hospital (101TMU-TMUH-20 to LLT and YFL), the Ministry of Science and Technology in Taiwan (MOST105-2320-B-038-049 to YFL), and National Natural Science Foundation of China and Israel Science Foundation (NSFC-ISF) Joint Research Programme (81461148020 to XJL).

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Taipei Medical University Hospital, Taipei, 110, Taiwan

    Lai-Lei Ting

  2. School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, 110, Taiwan

    Hsien-Tsung Lu

  3. Department of Orthopedics, Taipei Medical University Hospital, Taipei, 110, Taiwan

    Hsien-Tsung Lu

  4. School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, 110, Taiwan

    Shu-Fen Yen, Thi Huong Ngo, Fang-Yu Tu, I-Shih Tsai, Yi-Hua Tsai, Fu-Yen Chang, Shu-Huei Kao & Yung-Feng Lin

  5. Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei, 110, Taiwan

    Shu-Fen Yen

  6. Department of Allergology and Clinical Immunology, Hanoi Medical University, Hanoi, Vietnam

    Thi Huong Ngo

  7. Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Xiao-Jiang Li & Shihua Li

  8. School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 110, Taiwan

    Ching-Kuo Lee

  9. Ph.D. Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, 110, Taiwan

    Shu-Huei Kao & Yung-Feng Lin

  10. Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan

    Yu-Min Kuo

Authors
  1. Lai-Lei Ting
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hsien-Tsung Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shu-Fen Yen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thi Huong Ngo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fang-Yu Tu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. I-Shih Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yi-Hua Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fu-Yen Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiao-Jiang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shihua Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ching-Kuo Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Shu-Huei Kao
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yu-Min Kuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yung-Feng Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. YFL had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design: LLT, YFL.

Providing critical materials: LLT, HTL, SL, XJL, YMK.

Acquisition of the data: SFY, THN, IST, FYT, YHT, FYC, YFL.

Analysis and interpretation of the data: HTL, SFY, IST, CKL, SHK, YFL.

Manuscript writing: LLT, HTL, SFY, YFL.

Corresponding author

Correspondence to Yung-Feng Lin.

Ethics declarations

All animal procedures were approved by the Institutional Animal Care and Use Committee in Taipei Medical University (LAC-2015-0191 and LAC-2017-0379).

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

ESM 1

(PDF 227 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ting, LL., Lu, HT., Yen, SF. et al. Expression of AHI1 Rescues Amyloidogenic Pathology in Alzheimer’s Disease Model Cells. Mol Neurobiol 56, 7572–7582 (2019). https://doi.org/10.1007/s12035-019-1587-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-019-1587-1

Keywords

Search

Navigation