Skip to main content
SpringerLink
Log in

Insoluble α-synuclein in alzheimer’s disease without lewy body formation

  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

Insoluble α-synuclein plays a central role in Lewy body diseases, with considerable controversy as to whether it plays a similar role in Alzheimer’s disease (AD). We assessed the tissue location and solubility of cortical α-synuclein in AD (without Lewy body formation) compared with controls, using sequential extraction procedures and Western immunoblotting to quantify different α-synuclein species in their different solubility states. Controls had no insoluble cortical α-synuclein and a ratio of soluble :lipid-associated α-synuclein of 1.2 ± 0.1. Total α-synuclein protein was significantly increased in AD and concentrated within the lipidassociated fraction (soluble :lipid ratio 0.9 ± 0.05, soluble:insoluble 1.5 ± 0.1, lipid:insoluble 1.7 ± 0.1) which proved difficult to localize in paraffinembedded tissue. Tissues prepared without lipid extraction revealed α-synuclein-immunoreactivity in the amorphous components of mature cored AD plaques. This lipid-association of α-synuclein in mature AD plaques links this protein with other lipid changes thought to be important in disease pathogenesis.

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

Similar content being viewed by others

References

  • Arai Y, M Yamazaki, O Mori, H Muramatsu, G Asano and Y Katayama (2001) α-Synuclein-positive structures in cases with sporadic Alzheimer’s disease: morphology and its relationship to tau aggregation.Brain Res. 888, 287–296.

    Article  PubMed  CAS  Google Scholar 

  • Arima K, T Mizutani, MA Alim, H Tonozuka-Uehara, Y Izumiyama, S Hirai and K Ueda (2000) NACP/α-synuclein and tau constitute two distinctive subsets of filaments in the same neuronal inclusions in brains from a family of parkinsonism and dementia with Lewy bodies: double-immunolabeling fluorescence and electron microscopic studies.Acta Neuropathol. 100, 115–121.

    Article  PubMed  CAS  Google Scholar 

  • Baba M, S Nakajo, PH Tu, T Tomita, K Nakaya, VMY Lee, JQ Trojanowski and T Iwatsubo (1998) Aggregation of α synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies.Am. J. Pathol. 152, 879–884.

    PubMed  CAS  Google Scholar 

  • Bajo M, BC Yoo, N Cairns, M Gratzer and G Lubec (2001) Neurofilament proteins NF-L, NF-M and NF-H in brain of patients with Down syndrome and Alzheimer’s disease.Amino Acids 21, 293–301.

    Article  PubMed  CAS  Google Scholar 

  • Bayer TA, P Jakala, T Hartmann, L Havas, C McLean, JG Culvenor, QX Li, CL Masters, P Falkai and K Beyreuther (1999) α-Synuclein accumulates in Lewy bodies in Parkinson’s disease and dementia with Lewy bodies but not in Alzheimer’s disease β-amyloid plaque cores.Neurosci. Lett. 266, 213–216.

    Article  PubMed  CAS  Google Scholar 

  • Campbell BCV, Q-X Li, JG Culvenor, P Jäkälä, R Cappai, K Beyreuther, CL Masters and CA McLean (2000) Accumulation of insoluble α-synuclein in dementia with Lewy bodies.Neurobiol. Dis. 7, 192–200.

    Article  PubMed  CAS  Google Scholar 

  • Culvenor JG, CA McLean, S Cutt, BCV Campbell, F Maher, P Jäkälä, T Hartmann, K Beyreuther, CL Masters and Q-X Li (1999) Non-Aβ component of Alzheimer’s disease amyloid (NAC) revisited. NAC and α-synuclein are not associated with Aβ amyloid.Am. J. Pathol. 155, 1173–1181.

    PubMed  CAS  Google Scholar 

  • Ditaranto K, TL Tekirian and A J Yang (2001) Lysosomal membrane damage in soluble Aβ-mediated cell death in Alzheimer’s disease.Neurobiol. Dis. 8, 19–31.

    Article  PubMed  CAS  Google Scholar 

  • El-Agnaf OMA and GB Irvine (2000) Review: formation and properties of amyloid-like fibrils derived from ?-synuclein and related proteins.J. Struct. Biol. 130, 300–309.

    Article  PubMed  CAS  Google Scholar 

  • Goedert M (2001) α-Synuclein and neurodegenerative diseases.Nat. Rev. Neurosci. 2, 492–501.

    Article  PubMed  CAS  Google Scholar 

  • Iwai A, E Masliah, MP Sundsmo, R DeTeresa, M Mallory, DP Salmon and T Saitoh (1996) The synaptic protein NACP is abnormally expressed during the progression of Alzheimer’s disease.Brain Res. 720, 230–234.

    Article  PubMed  CAS  Google Scholar 

  • Lee H-J, F Khoshaghideh, S Patel and S-J Lee (2004) Clearance of α-synuclein oligomeric intermediates via the lysosomal degradation pathway.J. Neurosci. 24, 1888–1896.

    Article  PubMed  CAS  Google Scholar 

  • Lee HJ, C Choi and SJ Lee (2002) Membrane-bound α-synuclein has a high aggregation propensity and the ability to seed the aggregation of the cytosolic form.J. Biol. Chem. 277, 671–678.

    Article  PubMed  CAS  Google Scholar 

  • Lippa CF, H Fujiwara, DMA Mann, B Gaisson, M Baba, ML Schmidt, LE Nee, B O’Connell, DA Pollen, P St George-Hyslop, B Ghetti, D Nochlin, TD Bird, NJ Cairns, VMY Lee, T Iwatsubo and JQ Trojanowski (1998) Lewy bodies contain altered α-synuclein in brains of many familial Alzheimer’s disease patients with mutations in presenilin and amyloid precursor protein genes.Am. J. Pathol. 153, 1365–1370.

    PubMed  CAS  Google Scholar 

  • Marui W, E Iseki, K Ueda and K Kosaka (2000) Occurrence of human α-synuclein immunoreactive neurons with neurofibrillary tangle formation in the limbic areas of patients with Alzheimer’s disease.J. Neurol. Sci. 174, 81–84.

    Article  PubMed  CAS  Google Scholar 

  • Masliah E, A Iwai, M Mallory, K Uéda and T Saitoh (1996) Altered presynaptic protein NACP is associated with plaque formation and neurodegeneration in Alzheimer’s disease.Am. J. Pathol. 148, 201–210.

    PubMed  CAS  Google Scholar 

  • Masliah E, E Rockenstein, I Veinbergs, Y Sagara, M Mallory, M Hashimoto and L Mucke (2001) β-Amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a transgenic model linking Alzheimer’s disease and Parkinson’s disease.Proc. Natl. Acad. Sci. USA 98, 12245–12250.

    Article  PubMed  CAS  Google Scholar 

  • Michikawa M, J-S Gong, Q-W Fan, N Sawamura and K Yanagisawa (2001) A novel action of Alzheimer’s amyloid β-protein (Aβ): oligomeric Aβ promotes lipid release.J. Neurosci. 15, 7226–7235.

    Google Scholar 

  • Mori T, D Paris, T Town, AM Rojiani, DL Sparks, A Delledonne, F Crawford, LI Abdullah, JA Humphrey, DW Dickson and MJ Mullan (2001) Cholesterol accumulates in senile plaques of Alzheimer disease patients and in transgenic APPsw mice.J. Neuropathol. Exp. Neurol. 60, 778–785.

    PubMed  CAS  Google Scholar 

  • Mukaetova-Ladinska EB, F Garcia-Siera, J Hurt, HJ Gertz, J Xuereb, R Hills, C Brayne, FA Huppert, ES Paykel, M McGee, R Jakes, WG Honer, CR Harrington and CM Wischik (2000a) Staging of cytoskeletal and β-amyloid changes in human isocortex reveals biphasic synaptic protein response during progression of Alzheimer’s disease.Am. J. Pathol. 157, 623–636.

    PubMed  CAS  Google Scholar 

  • Mukaetova-Ladinska EB, J Hurt, R Jakes, J Xuereb, WG Honer and CM Wischik (2000b) α-Synuclein inclusions in Alzheimer and Lewy body diseases.J. Neuropathol. Exp. Neurol. 59, 408–417.

    PubMed  CAS  Google Scholar 

  • Paik S, J-H Lee, D-H Kim, C-S Chang and Y-S Kim (1998) Selfoligomerization of NACP, the precursor protein of the non-amyloid β/A4 protein (Aβ) component of Alzheimer’s disease amyloid, observed in the presence of a C-terminal Aβ fragment (residues 25-35).FEBS Lett. 421, 73–76.

    Article  PubMed  CAS  Google Scholar 

  • Perrin RJ, WS Woods, DF Clayton and JM George (2001) Exposure to long chain polysaturated fatty acids trigger rapid multimerization of synucleins.J. Biol. Chem. 276, 41958–41962.

    Article  PubMed  CAS  Google Scholar 

  • Refolo LM, MA Pappolla, J LaFrancois, B Malester, SD Schmidt, T Thomas-Bryant, GS Tint, R Wang, M Mercken, SS Petanceska and KE Duff (2001) A cholesterol-lowering drug reduces β-amyloid pathology in a transgenic mouse model of Alzheimer’s disease.Neurobiol. Dis. 8, 890–899.

    Article  PubMed  CAS  Google Scholar 

  • Rekas A, CG Adda, JA Aquilina, KJ Barnham, M Sunde, D Galatis, NA Williamson, CL Masters, RF Anders, CV Robinson, R appai and JA Carver (2004) Interaction of the molecular chaperone αB-crystallin with α-synuclein: effects on amyloid fibril formation and chaperone activity.J. Mol. Biol. 340, 1167–1183.

    Article  PubMed  CAS  Google Scholar 

  • Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy.Physiol. Rev. 81, 741–766.

    PubMed  CAS  Google Scholar 

  • Sharon R, I Bar-Josef, MP Frosch, DM Walsh, JA Hamilton and DJ Selkoe (2003) The formation of highly soluble oligomers of α-synuclein is regulated by fatty acids and enhanced in Parkinson’s disease.Neuron 37, 583–595.

    Article  PubMed  CAS  Google Scholar 

  • Sharon R, MS Goldberg, I Bar-Josef, RA Betensky, J Shen and DJ Selkoe (2001) α-Synuclein occurs in lipid-rich high molecular weight complexes, binds fatty acids, and shows homology to fatty acid-binding proteins.Proc. Natl. Acad. Sci. USA 98, 9110–9115.

    Article  PubMed  CAS  Google Scholar 

  • Sparks DL (1996) Intraneuronal β-amyloid immunoreactivity in the CNS.Neurobiol. Aging 17, 291–299.

    Article  PubMed  CAS  Google Scholar 

  • Sparks DL, SW Scheff, JC Hunsaker, H Liu, T Landers and DR Gross (1994) Inducation of Alzheimer-like β-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol.Exp. Neurol. 126, 88–94.

    Article  PubMed  CAS  Google Scholar 

  • Stirling JW and PS Graff (1995) Antigen unmasking for immunoelectron microscopy: labeling is improved by treating with sodium ethoxide or sodium metaperiodate, then heating on retrieval medium.J. Histochem. Cytochem. 43, 115–123.

    PubMed  CAS  Google Scholar 

  • Takeda A, M Hashimoto, M Mallory, M Sundsumo, L Hansen and E Masliah (2000) C-terminal α-synuclein immunoreactivity in structures other than Lewy bodies in neurodegenerative disorders.Acta Neuropathol. 99, 296–304.

    Article  PubMed  CAS  Google Scholar 

  • Takeda A, M Mallory, M Sundsmo, W Honer, L Hansen and E Masliah (1998) Abnormal accumulation of NACP/α-synuclein in neurodegenerative disorders.Am. J. Pathol. 152, 367–372.

    PubMed  CAS  Google Scholar 

  • Terai K, A Iwai, S Kawabata, Y Tasaki, T Watanabe, K Miyata and T Yamaguchi (2001) β-Amyloid deposits in transgenic mice expressing human β-amyloid precursor protein have the same characteristics as those in Alzheimer’s disease.Neuroscience 104, 299–310.

    Article  PubMed  CAS  Google Scholar 

  • The National Institute on Aging and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease.Neurobiol. Aging 18 Suppl. 4, S1-S2.

    Article  Google Scholar 

  • Ueda K, H Fukushima, E Maslaih, Y Xia, A Iwai, M Yoshimoto, DAC Otero, J Kondo, Y Ihara and T Saitoh (1993) Molecular cloning of cDNA encoding an unrecognised component of amyloid in Alzheimer’s disease patients.Proc. Natl. Acad. Sci. USA 90, 11282–11286.

    Article  PubMed  CAS  Google Scholar 

  • Uversky VN, EM Cooper, KS Bower, J Li and AL Fink (2002a) Accelerated α-synuclein fibrillation in crowded milieu.FEBS Lett. 515, 99–103.

    Article  PubMed  CAS  Google Scholar 

  • Uversky VN, J Li, P Souillac, IS Millett, S Doniach, R Jakes, M Goedert and AL Fink (2002b) Biophysical properties of the synucleins and their propensities to fibrillate: inhibition of α-synuclein assembly by β- and γ-synucleins.J. Biol. Chem. 277, 11970–11978.

    Article  PubMed  CAS  Google Scholar 

  • Wirths O, S Weickert, K Majtenyi, L Havas, PJ Kahle, M Okochi, C Haass, G Multhaup, K Beyreuther and TA Bayer (2000) Lewy body variant of Alzheimer’s disease: α-synuclein in dystrophic neurites of Aβ plaques.Neuroreport 11, 3737–3741.

    Article  PubMed  CAS  Google Scholar 

  • Yang AJ, D Chandswangbhuvana, L Margol and CG Glabe (1998) Loss of endosomal/lysosomal membrane permeability is an early event in amyloid Aβ1-42 pathogenesis.J. Neurosci. Res. 52, 691–698.

    Article  PubMed  CAS  Google Scholar 

  • Yip CM, EA Elton, AA Darabie, MR Morrison and J McLaurin (2001) Cholesterol, a modulator of membrane-associated Aβ fibrillogenesis and neurotoxicity.J. Mol. Biol. 311, 723–734.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Prince of Wales Medical Research Institute, University of New South Wales, 2031, Sydney, Australia

    Melissa Broe, Claire E. Shepherd, Elizabeth A. Milward, Emma Thiel & Glenda M. Halliday

  2. Clinical Neurosciences Research Group, University of Manchester, Greater Manchester Neurosciences Centre, Hope Hospital, M6 8HD, Salford, UK

    David M. A. Mann

  3. Department of Human Physiology, Flinders University Medical School, 5042, Bedford Park, Australia

    Wei -Ping Gai

Authors
  1. Melissa Broe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Claire E. Shepherd
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David M. A. Mann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Elizabeth A. Milward
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wei -Ping Gai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Emma Thiel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Glenda M. Halliday
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Glenda M. Halliday.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Broe, M., Shepherd, C.E., Mann, D.M.A. et al. Insoluble α-synuclein in alzheimer’s disease without lewy body formation. neurotox res 7, 69–76 (2005). https://doi.org/10.1007/BF03033777

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03033777

Keywords

Search

Navigation