Generic placeholder image

Current Alzheimer Research

Author(s): Hector Rosas-Hernandez, Elvis Cuevas, James B. Raymick, Bonnie L. Robinson, Syed F. Ali, Joseph Hanig and Sumit Sarkar*

DOI: 10.2174/1567205016666190321155422

DownloadDownload PDF Flyer Cite As
Characterization of Serum Exosomes from a Transgenic Mouse Model of Alzheimer’s Disease

Page: [388 - 395] Pages: 8

  • * (Excluding Mailing and Handling)

Abstract

Background: Alzheimer’s Disease (AD) is the most common type of dementia characterized by amyloid plaques containing Amyloid Beta (Aβ) peptides and neurofibrillary tangles containing tau protein. In addition to neuronal loss, Cerebral Amyloid Angiopathy (CAA) commonly occurs in AD. CAA is characterized by Aβ deposition in brain microvessels. Recent studies have suggested that exosomes (cell-derived vesicles containing a diverse cargo) may be involved in the pathogenesis of AD.

Objective: Isolate and characterize brain-derived exosomes from a transgenic mouse model of AD that presents CAA.

Methods: Exosomes were isolated from serum obtained from 13-month-old wild type and AD transgenic female mice using an exosome precipitation solution. Characterization of exosomal proteins was performed by western blots and dot blots.

Results: Serum exosomes were increased in transgenic mice compared to wild types as determined by increased levels of the exosome markers flotillin and alix. High levels of neuronal markers were found in exosomes, without any difference any between the 2 groups. Markers for endothelial-derived exosomes were decreased in the transgenic model, while astrocytic-derived exosomes were increased. Exosome characterization showed increased levels of oligomeric Aβ and oligomeric and monomeric forms tau on the transgenic animals. Levels of amyloid precursor protein were also increased. In addition, pathological and phosphorylated forms of tau were detected, but no difference was observed between the groups.

Conclusion: These data suggest that monomeric and oligomeric forms of Aβ and tau are secreted into serum via brain exosomes, most likely derived from astrocytes in the transgenic mouse model of AD with CAA. Studies on the implication of this event in the propagation of AD are underway.

Keywords: Alzheimer's disease, cerebral amyloid angiopathy, exosomes, amyloid beta, tau, amyloid precursor protein.

[1]
Erkkinen MG, Kim MO, Geschwind M. D. Clinical Neurology and Epidemiology of the Major Neurodegenerative Diseases. Cold Spring Harb Perspect Biol 10(4): a033118. (2018).
[2]
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, 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(3): 263-9. (2011).
[3]
Lane CA, Hardy J, Schott JM. Alzheimer’s disease. Eur J Neurol 25(1): 59-70. (2018).
[4]
Braak H, et al. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112(4): 389-404. (2006).
[5]
Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, et al. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement 8(1): 1-13. (2012).
[6]
Vingtdeux V, Sergeant N, Buee L. Potential contribution of exosomes to the prion-like propagation of lesions in Alzheimer’s disease. Front Physiol 3: 229. (2012).
[7]
Schönheit B, Zarski R, Ohm TG. Spatial and temporal relationships between plaques and tangles in Alzheimer-pathology. Neurobiol Aging 25(6): 697-711. (2004).
[8]
Lim YJ, Lee SJ. Are exosomes the vehicle for protein aggregate propagation in neurodegenerative diseases? Acta Neuropathol Commun 5(1): 64. (2017).
[9]
Medina M, Avila J. The role of extracellular Tau in the spreading of neurofibrillary pathology. Front Cell Neurosci 8: 113. (2014).
[10]
Polanco JC, Scicluna BJ, Hill AF, Götz J. Extracellular vesicles isolated from the brains of rtg4510 mice seed tau protein aggregation in a threshold-dependent manner. J Biol Chem 291(24): 12445-66. (2016).
[11]
Sardar Sinha M, Ansell-Schultz A, Civitelli L, Hildesjö C, Larsson M, Lannfelt L, et al. Alzheimer’s disease pathology propagation by exosomes containing toxic amyloid-beta oligomers. Acta Neuropathol 136(1): 41-56. (2018).
[12]
Zheng T, Pu J, Chen Y, Mao Y, Guo Z, Pan H, et al. Plasma exosomes spread and cluster around beta-amyloid plaques in an animal model of Alzheimer’s disease. Front Aging Neurosci 9: 12. (2017).
[13]
Holm MM, Kaiser J, Schwab ME. Extracellular vesicles: multimodal envoys in neural maintenance and repair. Trends Neurosci 41(6): 360-72. (2018).
[14]
Fiandaca MS, Kapogiannis D, Mapstone M, Boxer A, Eitan E, Schwartz JB, 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(6): 600-7 e1 (2015).
[15]
Goetzl EJ, Mustapic M, Kapogiannis D, Eitan E, Lobach IV, Goetzl L, et al. Cargo proteins of plasma astrocyte-derived exosomes in Alzheimer’s disease. FASEB J 30(11): 3853-9. (2016).
[16]
Saman S, Kim W, Raya M, Visnick Y, Miro S, Saman S, et al. Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem 287(6): 3842-9. (2012).
[17]
Wang Y, Balaji V, Kaniyappan S, Krüger L, Irsen S, Tepper K, et al. The release and trans-synaptic transmission of Tau via exosomes. Mol Neurodegener 12(1): 5. (2017).
[18]
Yang Y, Keene CD, Peskind ER, Galasko DR, Hu SC, Cudaback E, et al. Cerebrospinal Fluid Particles in Alzheimer Disease and Parkinson Disease. J Neuropathol Exp Neurol 74(7): 672-87. (2015).
[19]
Davis J, Xu F, Deane R, Romanov G, Previti ML, Zeigler K, et al. Early-onset and robust cerebral microvascular accumulation of amyloid beta-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid beta-protein precursor. J Biol Chem 279(19): 20296-306. (2004).
[20]
Miao J, Xu F, Davis J, Otte-Höller I, Verbeek MM, Van Nostrand WE. Cerebral microvascular amyloid β protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid β precursor protein. Am J Pathol 167(2): 505-15. (2005).
[21]
Hondius DC, Eigenhuis KN, Morrema THJ, van der Schors RC, van Nierop P, Bugiani M, et al. Proteomics analysis identifies new markers associated with capillary cerebral amyloid angiopathy in Alzheimer’s disease. Acta Neuropathol Commun 6(1): 46. (2018).
[22]
Chistiakov DA, Chistiakov AA. alpha-Synuclein-carrying extracellular vesicles in Parkinson’s disease: deadly transmitters. Acta Neurol Belg 117(1): 43-51. (2017).
[23]
Tomlinson PR, Zheng Y, Fischer R, Heidasch R, Gardiner C, Evetts S, et al. Identification of distinct circulating exosomes in Parkinson’s disease. Ann Clin Transl Neurol 2(4): 353-61. (2015).
[24]
Rajendran L, Honsho M, Zahn TR, Keller P, Geiger KD, Verkade P, et al. Alzheimer’s disease beta-amyloid peptides are released in association with exosomes. Proc Natl Acad Sci USA 103(30): 11172-7. (2006).
[25]
Polanco JC, Li C, Durisic N, Sullivan R, Götz J. Exosomes taken up by neurons hijack the endosomal pathway to spread to interconnected neurons. Acta Neuropathol Commun 6(1): 10. (2018).
[26]
Chiarini A, Armato U, Gardenal E, Gui L, Dal Prà I. Amyloid beta-exposed human astrocytes overproduce phospho-tau and overrelease it within exosomes, effects suppressed by calcilytic nps 2143-further implications for Alzheimer’s therapy. Front Neurosci 11: 217. (2017).
[27]
Laulagnier K, Javalet C, Hemming FJ, Chivet M, Lachenal G, Blot B, et al. Amyloid precursor protein products concentrate in a subset of exosomes specifically endocytosed by neurons. Cell Mol Life Sci 75(4): 757-73. (2018).
[28]
Goetzl EJ, Schwartz JB, Abner EL, Jicha GA, Kapogiannis D. High complement levels in astrocyte-derived exosomes of Alzheimer disease. Ann Neurol 83(3): 544-52. (2018).