Alzheimer's Disease Pathology Propagation by Exosomes Containing Toxic Amyloid-beta Oligomers

Overview

Journal Acta Neuropathol

Specialty Neurology

Date 2018 Jun 24

PMID 29934873

Citations 246

Authors

Maitrayee Sardar Sinha

Anna Ansell-Schultz

Livia Civitelli

Camilla Hildesjo

Max Larsson

Lars Lannfelt

Martin Ingelsson

Martin Hallbeck

Affiliations

Soon will be listed here.

Abstract

The gradual deterioration of cognitive functions in Alzheimer's disease is paralleled by a hierarchical progression of amyloid-beta and tau brain pathology. Recent findings indicate that toxic oligomers of amyloid-beta may cause propagation of pathology in a prion-like manner, although the underlying mechanisms are incompletely understood. Here we show that small extracellular vesicles, exosomes, from Alzheimer patients' brains contain increased levels of amyloid-beta oligomers and can act as vehicles for the neuron-to-neuron transfer of such toxic species in recipient neurons in culture. Moreover, blocking the formation, secretion or uptake of exosomes was found to reduce both the spread of oligomers and the related toxicity. Taken together, our results imply that exosomes are centrally involved in Alzheimer's disease and that they could serve as targets for development of new diagnostic and therapeutic principles.

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References

Pigino G, Morfini G, Atagi Y, Deshpande A, Yu C, Jungbauer L . Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta. Proc Natl Acad Sci U S A. 2009; 106(14):5907-12. PMC: 2667037. DOI: 10.1073/pnas.0901229106. View

Fu H, Hussaini S, Wegmann S, Profaci C, Daniels J, Herman M . 3D Visualization of the Temporal and Spatial Spread of Tau Pathology Reveals Extensive Sites of Tau Accumulation Associated with Neuronal Loss and Recognition Memory Deficit in Aged Tau Transgenic Mice. PLoS One. 2016; 11(7):e0159463. PMC: 4965059. DOI: 10.1371/journal.pone.0159463. View

Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T . Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci. 2015; 18(11):1584-93. PMC: 4694577. DOI: 10.1038/nn.4132. View

Kumari S, Mg S, Mayor S . Endocytosis unplugged: multiple ways to enter the cell. Cell Res. 2010; 20(3):256-75. PMC: 7091825. DOI: 10.1038/cr.2010.19. View

McLean C, Cherny R, Fraser F, Fuller S, Smith M, Beyreuther K . Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann Neurol. 1999; 46(6):860-6. DOI: 10.1002/1531-8249(199912)46:6<860::aid-ana8>3.0.co;2-m. View

Vella L, Hill A, Cheng L . Focus on Extracellular Vesicles: Exosomes and Their Role in Protein Trafficking and Biomarker Potential in Alzheimer's and Parkinson's Disease. Int J Mol Sci. 2016; 17(2):173. PMC: 4783907. DOI: 10.3390/ijms17020173. View

Ngolab J, Trinh I, Rockenstein E, Mante M, Florio J, Trejo M . Brain-derived exosomes from dementia with Lewy bodies propagate α-synuclein pathology. Acta Neuropathol Commun. 2017; 5(1):46. PMC: 5466770. DOI: 10.1186/s40478-017-0445-5. View

Polanco J, Li C, Durisic N, Sullivan R, Gotz J . Exosomes taken up by neurons hijack the endosomal pathway to spread to interconnected neurons. Acta Neuropathol Commun. 2018; 6(1):10. PMC: 5815204. DOI: 10.1186/s40478-018-0514-4. View

Dinkins M, Dasgupta S, Wang G, Zhu G, Bieberich E . Exosome reduction in vivo is associated with lower amyloid plaque load in the 5XFAD mouse model of Alzheimer's disease. Neurobiol Aging. 2014; 35(8):1792-800. PMC: 4035236. DOI: 10.1016/j.neurobiolaging.2014.02.012. View

10.

Fitzner D, Schnaars M, van Rossum D, Krishnamoorthy G, Dibaj P, Bakhti M . Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis. J Cell Sci. 2011; 124(Pt 3):447-58. DOI: 10.1242/jcs.074088. View

11.

Logozzi M, De Milito A, Lugini L, Borghi M, Calabro L, Spada M . High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients. PLoS One. 2009; 4(4):e5219. PMC: 2667632. DOI: 10.1371/journal.pone.0005219. View

12.

Salido-Guadarrama I, Romero-Cordoba S, Peralta-Zaragoza O, Hidalgo-Miranda A, Rodriguez-Dorantes M . MicroRNAs transported by exosomes in body fluids as mediators of intercellular communication in cancer. Onco Targets Ther. 2014; 7:1327-38. PMC: 4114916. DOI: 10.2147/OTT.S61562. View

13.

Brettschneider J, Del Tredici K, Lee V, Trojanowski J . Spreading of pathology in neurodegenerative diseases: a focus on human studies. Nat Rev Neurosci. 2015; 16(2):109-20. PMC: 4312418. DOI: 10.1038/nrn3887. View

14.

Thery C, Amigorena S, Raposo G, Clayton A . Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. 2008; Chapter 3:Unit 3.22. DOI: 10.1002/0471143030.cb0322s30. View

15.

Bellingham S, Guo B, Coleman B, Hill A . Exosomes: vehicles for the transfer of toxic proteins associated with neurodegenerative diseases?. Front Physiol. 2012; 3:124. PMC: 3342525. DOI: 10.3389/fphys.2012.00124. View

16.

Gouras G, Tampellini D, Takahashi R, Capetillo-Zarate E . Intraneuronal beta-amyloid accumulation and synapse pathology in Alzheimer's disease. Acta Neuropathol. 2010; 119(5):523-41. PMC: 3183823. DOI: 10.1007/s00401-010-0679-9. View

17.

Englund H, Sehlin D, Johansson A, Nilsson L, Gellerfors P, Paulie S . Sensitive ELISA detection of amyloid-beta protofibrils in biological samples. J Neurochem. 2007; 103(1):334-45. DOI: 10.1111/j.1471-4159.2007.04759.x. View

18.

Lane R, Korbie D, Anderson W, Vaidyanathan R, Trau M . Analysis of exosome purification methods using a model liposome system and tunable-resistive pulse sensing. Sci Rep. 2015; 5:7639. PMC: 4648344. DOI: 10.1038/srep07639. View

19.

Walsh D, Selkoe D . Deciphering the molecular basis of memory failure in Alzheimer's disease. Neuron. 2004; 44(1):181-93. DOI: 10.1016/j.neuron.2004.09.010. View

20.

DeKosky S, Scheff S . Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol. 1990; 27(5):457-64. DOI: 10.1002/ana.410270502. View