CoChat
Sign Up
Cited by 129Alzheimer's disease research and treatmentsExtracellular vesicles in diseaseNeuroinflammation and Neurodegeneration Mechanisms

Extracellular vesicle-associated Aβ mediates trans-neuronal bioenergetic and Ca2+-handling deficits in Alzheimer’s disease models

Open access
Eitan, Erez, Hutchison, Emmette R, Marosi, Krisztina, Comotto, James, Mustapic, Maja, Nigam, Saket M, Suire, Caitlin, Maharana, Chinmoyee +6 more·2016·npj Aging and Mechanisms of Disease
DOI 10.1038/npjamd.2016.19PMC PMC5137253
Open this paper in CoChat — free accountOpen PDF

Abstract

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder in which aggregation-prone neurotoxic amyloid β-peptide (Aβ) accumulates in the brain. Extracellular vesicles (EVs), including exosomes, are small 50–150 nm membrane vesicles that have recently been implicated in the prion-like spread of self-aggregating proteins. Here we report that EVs isolated from AD patient cerebrospinal fluid and plasma, from the plasma of two AD mouse models, and from the medium of neural cells expressing familial AD presenilin 1 mutations, destabilize neuronal Ca 2+homeostasis, impair mitochondrial function, and sensitize neurons to excitotoxicity. EVs contain a relatively low amount of Aβ but have an increased Aβ42/ Aβ40 ratio; the majority of Aβ is located on the surface of the EVs. Impairment of lysosome function results in increased generation of EVs with elevated Aβ42 levels. EVs may mediate transcellular spread of pathogenic Aβ species that impair neuronal Ca 2+handling and mitochondrial function, and may thereby render neurons vulnerable to excitotoxicity.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/npjamd.2016.19

Cites

9 of 9 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Several studies have shown that both extracellular free Aβ and Aβ-contained EVs play a role in the progression of AD pathology.

    “Several studies have shown that both extracellular free Aβ and Aβ-contained EVs play a role in the progression of AD pathology [136–140].”

    From Extracellular vesicles as nanotheranostic platforms for targeted neurological disorder interventions (2024) · cites this paper as [138]

    The Introduction reports that injecting Aβ from biological or synthetic sources into mouse brains accelerates Aβ aggregation. The Discussion finds that Aβ-associated EVs are neurotoxic in AD models, but describes their role in propagating AD pathology as possible and says whether EV-associated Aβ has a critical role in AD pathogenesis remains to be determined. Thus the paper does not establish that both forms contribute to disease progression. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 67

  1. Mattson, M. P. Pathways towards and away from Alzheimer's disease. Nature 430, 631–639 (2004). 15295589 PMC3091392
  2. Karch, C. M., Cruchaga, C. & Goate, A. M. Alzheimer's disease genetics: from the bench to the clinic. Neuron 83, 11–26 (2014). 24991952 PMC4120741
  3. Platt, T. L., Reeves, V. L. & Murphy, M. P. Transgenic models of Alzheimer's disease: better utilization of existing models through viral transgenesis. Biochim. Biophys. Acta 1832, 1437–1448 (2013). 23619198 PMC3690778
  4. Bezprozvanny, I. & Mattson, M. P. Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease. Trends Neurosci. 31, 454–463 (2008). 18675468 PMC2566585
  5. Stutzmann, G. E. & Mattson, M. P. Endoplasmic reticulum Ca(2+) handling in excitable cells in health and disease. Pharmacol. Rev. 63, 700–727 (2011). 21737534 PMC3141879
  6. Mattson, M. P., Gleichmann, M. & Cheng, A. Mitochondria in neuroplasticity and neurological disorders. Neuron 60, 748–766 (2008). 19081372 PMC2692277
  7. Krstic, D. & Knuesel, I. Deciphering the mechanism underlying late-onset Alzheimer disease. Nat. Rev. Neurol. 9, 25–34 (2013). 23183882
  8. Aguzzi, A. & Rajendran, L. The transcellular spread of cytosolic amyloids, prions, and prionoids. Neuron 64, 783–790 (2009). 20064386
  9. Watts, J. C. et al. Serial propagation of distinct strains of Abeta prions from Alzheimer's disease patients. Proc. Natl Acad. Sci. USA 111, 10323–10328 (2014). 24982139 PMC4104857
  10. Stohr, J. et al. Purified and synthetic Alzheimer's amyloid beta (Abeta) prions. Proc. Natl Acad. Sci. USA 109, 11025–11030 (2012). 22711819 PMC3390876
  11. Colombo, E., Borgiani, B., Verderio, C. & Furlan, R. Microvesicles: novel biomarkers for neurological disorders. Front. Physiol. 3, 63 (2012). 22479250 PMC3315111
  12. Rajendran, L. et al. Emerging roles of extracellular vesicles in the nervous system. J. Neurosci. 34, 15482–15489 (2014). 25392515 PMC4228143
  13. Rajendran, L. et al. Alzheimer's disease beta-amyloid peptides are released in association with exosomes. Proc. Natl Acad. Sci. USA 103, 11172–11177 (2006). 16837572 PMC1544060
  14. Perez-Gonzalez, R., Gauthier, S. A., Kumar, A. & Levy, E. The exosome secretory pathway transports amyloid precursor protein carboxyl-terminal fragments from the cell into the brain extracellular space. J. Biol. Chem. 287, 43108–43115 (2012). 23129776 PMC3522305
  15. Grad, L. I. et al. Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms. Proc. Natl Acad. Sci. USA 111, 3620–3625 (2014). 24550511 PMC3948312
  16. Fevrier, B. et al. Cells release prions in association with exosomes. Proc. Natl Acad. Sci. USA 101, 9683–9688 (2004). 15210972 PMC470735
  17. Rajendran, L. et al. Increased Abeta production leads to intracellular accumulation of Abeta in flotillin-1-positive endosomes. Neurodegener. Dis. 4, 164–170 (2007). 17596711
  18. Colombo, M., Raposo, G. & Thery, C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu. Rev. Cell Dev. Biol. 30, 255–289 (2014). 25288114
  19. Takahashi, R. H. et al. Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am. J. Pathol. 161, 1869–1879 (2002). 12414533 PMC1850783
  20. Yuyama, K., Sun, H., Mitsutake, S. & Igarashi, Y. Sphingolipid-modulated exosome secretion promotes clearance of amyloid-beta by microglia. J. Biol. Chem. 287, 10977–10989 (2012). 22303002 PMC3322859
  21. Yuyama, K. et al. Decreased amyloid-beta pathologies by intracerebral loading of glycosphingolipid-enriched exosomes in Alzheimer model mice. J. Biol. Chem. 289, 24488–24498 (2014). 25037226 PMC4148874
  22. Yuyama, K. et al. A potential function for neuronal exosomes: sequestering intracerebral amyloid-beta peptide. FEBS Lett. 589, 84–88 (2015). 25436414
  23. An, K. et al. Exosomes neutralize synaptic-plasticity-disrupting activity of Abeta assemblies in vivo. Mol. Brain 6, 47 (2013). 24284042 PMC4222117
  24. Fiandaca, M. S. et al. Identification of preclinical Alzheimer's disease by a profile of pathogenic proteins in neurally derived blood exosomes: A case-control study. Alzheimers Dement. 11, 600–7.e1 (2014). 25130657 PMC4329112
  25. Wolfe, D. M. et al. Autophagy failure in Alzheimer's disease and the role of defective lysosomal acidification. Eur. J. Neurosci. 37, 1949–1961 (2013). 23773064 PMC3694736
  26. Witwer, K. W. et al. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J. Extracell Vesicles 2 (2013). PMC3760646 24009894
  27. Lotvall, J. et al. Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J. Extracell Vesicles 3, 26913 (2014). 25536934 PMC4275645
  28. Spies, P. E. et al. The cerebrospinal fluid amyloid beta42/40 ratio in the differentiation of Alzheimer's disease from non-Alzheimer's dementia. Curr. Alzheimer Res. 7, 470–476 (2010). 20043812
  29. Sauvee, M. et al. Additional use of Abeta(4)(2)/Abeta(4)(0) ratio with cerebrospinal fluid biomarkers P-tau and Abeta(4)(2) increases the level of evidence of Alzheimer's disease pathophysiological process in routine practice. J. Alzheimers Dis. 41, 377–386 (2014). 24614902
  30. Mahairaki, V. et al. Induced pluripotent stem cells from familial Alzheimer's disease patients differentiate into mature neurons with amyloidogenic properties. Stem Cells Dev. 23, 2996–3010 (2014). 25027006 PMC4267410
  31. Bulloj, A., Leal, M. C., Xu, H., Castano, E. M. & Morelli, L. Insulin-degrading enzyme sorting in exosomes: a secretory pathway for a key brain amyloid-beta degrading protease. J. Alzheimers Dis. 19, 79–95 (2010). 20061628 PMC4414343
  32. Ghidoni, R. et al. Cystatin C is released in association with exosomes: a new tool of neuronal communication which is unbalanced in Alzheimer's disease. Neurobiol. Aging 32, 1435–1442 (2011). 19773092 PMC2891183
  33. Yuyama, K., Yamamoto, N. & Yanagisawa, K. Accelerated release of exosome-associated GM1 ganglioside (GM1) by endocytic pathway abnormality: another putative pathway for GM1-induced amyloid fibril formation. J. Neurochem. 105, 217–224 (2008). 18021298
  34. Thinakaran, G. & Koo, E. H. Amyloid precursor protein trafficking, processing, and function. J. Biol. Chem. 283, 29615–29619 (2008). 18650430 PMC2573065
  35. Vingtdeux, V. et al. Intracellular pH regulates amyloid precursor protein intracellular domain accumulation. Neurobiol. Dis. 25, 686–696 (2007). 17207630
  36. Haass, C., Capell, A., Citron, M., Teplow, D. B. & Selkoe, D. J. The vacuolar H(+)-ATPase inhibitor bafilomycin A1 differentially affects proteolytic processing of mutant and wild-type beta-amyloid precursor protein. J. Biol. Chem. 270, 6186–6192 (1995). 7890753
  37. Mattson, M. P. et al. beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J. Neurosci. 12, 376–389 (1992). 1346802 PMC6575616
  38. Xin, H. et al. Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J. Cereb. Blood Flow Metab. 33, 1711–1715 (2013). 23963371 PMC3824189
  39. Borchelt, D. R. et al. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19, 939–945 (1997). 9354339
  40. Dumurgier, J. et al. Cerebrospinal fluid amyloid-beta 42/40 ratio in clinical setting of memory centers: a multicentric study. Alzheimers Res. Ther. 7, 30 (2015). 26034513 PMC4450486
  41. Pauwels, K. et al. Structural basis for increased toxicity of pathological abeta42:abeta40 ratios in Alzheimer disease. J. Biol Chem. 287, 5650–5660 (2012). 22157754 PMC3285338
  42. Kokubo, H. et al. Oligomeric proteins ultrastructurally localize to cell processes, especially to axon terminals with higher density, but not to lipid rafts in Tg2576 mouse brain. Brain Res. 1045, 224–228 (2005). 15910781
  43. Williamson, R., Usardi, A., Hanger, D. P. & Anderton, B. H. Membrane-bound beta-amyloid oligomers are recruited into lipid rafts by a fyn-dependent mechanism. FASEB J. 22, 1552–1559 (2008). 18096814
  44. Rushworth, J. V. & Hooper, N. M. Lipid rafts: linking Alzheimer's Amyloid-beta production, aggregation, and toxicity at neuronal membranes. Int. J. Alzheimers Dis. 2011, 603052 (2010). 21234417 PMC3014710
  45. Evangelisti, E. et al. Lipid rafts mediate amyloid-induced calcium dyshomeostasis and oxidative stress in Alzheimer's disease. Curr. Alzheimers Res. 10, 143–153 (2013). 22950913
  46. Laulagnier, K. et al. Mast cell- and dendritic cell-derived exosomes display a specific lipid composition and an unusual membrane organization. Biochem J. 380, 161–171 (2004). 14965343 PMC1224152
  47. Butterfield, D. A., Hensley, K., Harris, M., Mattson, M. & Carney, J. beta-Amyloid peptide free radical fragments initiate synaptosomal lipoperoxidation in a sequence-specific fashion: implications to Alzheimer's disease. Biochem. Biophys. Res. Commun. 200, 710–715 (1994). 8179604
  48. Bruce-Keller, A. J. et al. Bcl-2 protects isolated plasma and mitochondrial membranes against lipid peroxidation induced by hydrogen peroxide and amyloid beta-peptide. J. Neurochem. 70, 31–39 (1998). 9422344
  49. Mark, R. J., Pang, Z., Geddes, J. W., Uchida, K. & Mattson, M. P. Amyloid beta-peptide impairs glucose transport in hippocampal and cortical neurons: involvement of membrane lipid peroxidation. J. Neurosci. 17, 1046–1054 (1997). 8994059 PMC6573165
  50. Mark, R. J., Lovell, M. A., Markesbery, W. R., Uchida, K. & Mattson, M. P. A role for 4-hydroxynonenal, an aldehydic product of lipid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid beta-peptide. J. Neurochem. 68, 255–264 (1997). 8978733
  51. Tamboli, I. Y. et al. Statins promote the degradation of extracellular amyloid {beta}-peptide by microglia via stimulation of exosome-associated insulin-degrading enzyme (IDE) secretion. J. Biol. Chem. 285, 37405–37414 (2010). 20876579 PMC2988346
  52. Pasternak, S. H., Callahan, J. W. & Mahuran, D. J. The role of the endosomal/lysosomal system in amyloid-beta production and the pathophysiology of Alzheimer's disease: reexamining the spatial paradox from a lysosomal perspective. J. Alzheimers Dis. 6, 53–65 (2004). 15004328
  53. Shen, B., Wu, N., Yang, J. M. & Gould, S. J. Protein targeting to exosomes/microvesicles by plasma membrane anchors. J. Biol. Chem. 286, 14383–14395 (2011). 21300796 PMC3077638
  54. Abache, T. et al. The transferrin receptor and the tetraspanin web molecules CD9, CD81, and CD9P-1 are differentially sorted into exosomes after TPA treatment of K562 cells. J. Cell Biochem. 102, 650–664 (2007). 17407154
  55. Andreu, Z. & Yanez-Mo, M. Tetraspanins in extracellular vesicle formation and function. Front. Immunol. 5, 442 (2014). 25278937 PMC4165315
  56. Cataldo, A. M., Hamilton, D. J. & Nixon, R. A. Lysosomal abnormalities in degenerating neurons link neuronal compromise to senile plaque development in Alzheimer disease. Brain Res. 640, 68–80 (1994). 8004466
  57. Cataldo, A. M. & Nixon, R. A. Enzymatically active lysosomal proteases are associated with amyloid deposits in Alzheimer brain. Proc. Natl Acad. Sci. USA 87, 3861–3865 (1990). 1692625 PMC54003
  58. Lee, J. H. et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141, 1146–1158 (2010). 20541250 PMC3647462
  59. Nixon, R. A. et al. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J. Neuropathol. Exp. Neurol. 64, 113–122 (2005). 15751225
  60. Pickford, F. et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J. Clin. Invest. 118, 2190–2199 (2008). 18497889 PMC2391284
  61. Goetzl, E. J. et al. Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease. Neurology 85, 40–47 (2015). 26062630 PMC4501943
  62. Swerdlow, R. H. Alzheimer's disease pathologic cascades: who comes first, what drives what. Neurotox. Res. 22, 182–194 (2012). 21913048 PMC3635146
  63. Mattson, M. P., Barger, S. W., Begley, J. G. & Mark, R. J. Calcium, free radicals, and excitotoxic neuronal death in primary cell culture. Methods Cell Biol. 46, 187–216 (1995). 7541884
  64. McKhann, G. M. et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 7, 263–269 (2011). 21514250 PMC3312024
  65. Dubois, B. et al. Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurol. 13, 614–629 (2014). 24849862
  66. Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676–682 (2012). 22743772 PMC3855844
  67. Eitan, E., Zhang, S., Witwer, K. W. & Mattson, M. P. Extracellular vesicle-depleted fetal bovine and human sera have reduced capacity to support cell growth. J. Extracell Vesicles 4, 26373 (2015). 25819213 PMC4376846

Cited by

Sorted by citations

Authors
Eitan, E., Hutchison, E. R., Marosi, K., Comotto, J., Mustapic, M., Nigam, S. M., Suire, C., Maharana, C., Jicha, G. A., Liu, D., Machairaki, V., Witwer, K. W., Kapogiannis, D., & Mattson, M. P.
Affiliations
  • National Institutes of Health (US)
  • University of Kentucky (US)
  • Johns Hopkins University (US)
Corresponding author
Mattson, Mark P
ORCID
Venue
npj Aging and Mechanisms of Disease
Publisher
Springer Science and Business Media LLC
Published
2016-09-22
Volume
2
Issue
1
ISSN
2056-3973 (ISSN-L)
DOI
10.1038/npjamd.2016.19
PMC
PMC5137253
OpenAlex
W2522545878
Cited by
129
References
9
Citations by year
2026: 8 · 2025: 12 · 2024: 11 · 2023: 12 · 2022: 17 · 2021: 17 · 2020: 26 · 2019: 10 · 2018: 11 · 2017: 5
FWCI
6.98
Type
journal article
Language
en
Open access
Licence
Locations
  • npj Aging and Mechanisms of Disease (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UKnowledge (University of Kentucky) (submittedVersion, cc-by)
Funders
  • University of Kentucky
  • National Institutes of Health
  • National Institute on Aging (P30AG028383, ZIAAG000312)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, extracellular vesicles, exosomes, amyloid-beta, Aβ42/Aβ40 ratio, calcium homeostasis, mitochondrial dysfunction, excitotoxicity, lysosomal dysfunction, presenilin 1 mutations, cerebrospinal fluid, plasma vesicles, neurodegeneration

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review