Top

Published in:

01-07-2017 | ORIGINAL ARTICLE

Exosomes Secreted from HEK293-APP Swe/Ind Cells Impair the Hippocampal Neurogenesis

Authors: Tingting Zheng, Jiali Pu, Yanxing Chen, Zhangyu Guo, Hongyu Pan, Ling Zhang, Heng Zhang, Binggui Sun, Baorong Zhang

Published in: Neurotoxicity Research | Issue 1/2017

Abstract

This study aimed to investigate the neurotoxicity of exosomes to cultured neuroblastoma and neurons in vitro and to mature and newborn neurons in the hippocampus in vivo. Recent in vitro and in vivo studies have shown that exosomes, small membranous vesicles secreted from many cell types, contain pathogenic proteins including full-length amyloid precursor protein (flAPP) and amyloid precursor protein (APP) metabolites. However, the function of these exosomes in Alzheimer disease (AD) has not been much explored. In the present study, exosomes were harvested from the conditioned medium of HEK293-APP Swe/Ind cells and injected into the hippocampal dentate gyrus region via a stereotactic method to detect their effects on the neuronal survival in vivo. These exosomes containing pathogenic proteins showed high neurotoxicity and could impair neurogenesis in the hippocampus. The data demonstrated that exosomes secreted from sick cells might damage neurogenesis and promote disease progression in AD.

Bond AM, Ming GL, Song H (2015) Adult mammalian neural stem cells and neurogenesis. Five Decades Later Cell stem cell 17:385–395. doi:10.1016/j.stem.2015.09.003 CrossRefPubMed

Christian KM, Song H, Ming GL (2014) Functions and dysfunctions of adult hippocampal neurogenesis. Annu Rev Neurosci 37:243–262. doi:10.1146/annurev-neuro-071013-014134 CrossRefPubMed

Chuang TT (2010) Neurogenesis in mouse models of Alzheimer's disease. Biochim Biophys Acta 1802:872–880. doi:10.1016/j.bbadis.2009.12.008 CrossRefPubMed

Coleman BM, Hill AF (2015) Extracellular vesicles—their role in the packaging and spread of misfolded proteins associated with neurodegenerative diseases. Semin Cell Dev Biol 40:89–96. doi:10.1016/j.semcdb.2015.02.007 CrossRefPubMed

Deng W, Aimone JB, Gage FH (2010) New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat Rev Neurosci 11:339–350. doi:10.1038/nrn2822 CrossRefPubMedPubMedCentral

Donovan MH, Yazdani U, Norris RD, Games D, German DC, Eisch AJ (2006) Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer's disease. J Comp Neurol 495:70–83. doi:10.1002/cne.20840 CrossRefPubMed

Dreyer F, Baur A (2016) Biogenesis and functions of exosomes and extracellular vesicles. Methods Mol Biol 1448:201–216. doi:10.1007/978-1-4939-3753-0_15 CrossRefPubMed

Ge S, Yang CH, Hsu KS, Ming GL, Song H (2007) A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain. Neuron 54:559–566. doi:10.1016/j.neuron.2007.05.002 CrossRefPubMedPubMedCentral

Guo BB, Bellingham SA, Hill AF (2016) Stimulating the release of exosomes increases the intercellular transfer of prions. J Biol Chem 291:5128–5137. doi:10.1074/jbc.M115.684258 CrossRefPubMedPubMedCentral

Haughey NJ, Nath A, Chan SL, Borchard AC, Rao MS, Mattson MP (2002) Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease. J Neurochem 83:1509–1524CrossRefPubMed

Hock C et al (1998) Cerebrospinal fluid levels of amyloid precursor protein and amyloid beta-peptide in Alzheimer's disease and major depression - inverse correlation with dementia severity. Eur Neurol 39:111–118CrossRefPubMed

Joshi P et al (2014) Microglia convert aggregated amyloid-beta into neurotoxic forms through the shedding of microvesicles. Cell Death Differ 21:582–593. doi:10.1038/cdd.2013.180 CrossRefPubMed

Kokubo H, Saido TC, Iwata N, Helms JB, Shinohara R, Yamaguchi H (2005) Part of membrane-bound Abeta exists in rafts within senile plaques in Tg2576 mouse brain. Neurobiol Aging 26:409–418. doi:10.1016/j.neurobiolaging.2004.04.008 CrossRefPubMed

Lledo PM, Alonso M, Grubb MS (2006) Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci 7:179–193. doi:10.1038/nrn1867 CrossRefPubMed

Morgenstern NA, Giacomini D, Lombardi G, Castano EM, Schinder AF (2013) Delayed dendritic development in newly generated dentate granule cells by cell-autonomous expression of the amyloid precursor protein. Mol Cell Neurosci 56:298–306. doi:10.1016/j.mcn.2013.07.003 CrossRefPubMed

Pan H et al (2016) Amyloid beta is not the major factor accounting for impaired adult hippocampal neurogenesis in mice overexpressing amyloid precursor protein. Stem cell reports 7:707–718. doi:10.1016/j.stemcr.2016.08.019 CrossRefPubMedPubMedCentral

Perez-Gonzalez R, Gauthier SA, Kumar A, Levy E (2012) 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. doi:10.1074/jbc.M112.404467 CrossRefPubMedPubMedCentral

Podlisny MB, Mammen AL, Schlossmacher MG, Palmert MR, Younkin SG, Selkoe DJ (1990) Detection of soluble forms of the beta-amyloid precursor protein in human plasma. Biochem Biophys Res Commun 167:1094–1101

Rajendran L, Honsho M, Zahn TR, Keller P, Geiger KD, Verkade P, Simons K (2006) Alzheimer's disease beta-amyloid peptides are released in association with exosomes. Proc Natl Acad Sci U S A 103:11172–11177. doi:10.1073/pnas.0603838103 CrossRefPubMedPubMedCentral

Sastre M et al (2001) Presenilin-dependent gamma-secretase processing of beta-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch. EMBO Rep 2:835–841. doi:10.1093/embo-reports/kve180 CrossRefPubMedPubMedCentral

Schneider A, Simons M (2013) Exosomes: vesicular carriers for intercellular communication in neurodegenerative disorders. Cell Tissue Res 352:33–47. doi:10.1007/s00441-012-1428-2 CrossRefPubMed

Sharples RA et al (2008) Inhibition of gamma-secretase causes increased secretion of amyloid precursor protein C-terminal fragments in association with exosomes. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 22:1469–1478. doi:10.1096/fj.07-9357com CrossRef

Simpson RJ, Jensen SS, Lim JW (2008) Proteomic profiling of exosomes: current perspectives. Proteomics 8:4083–4099. doi:10.1002/pmic.200800109 CrossRefPubMed

Smalheiser NR (2007) Exosomal transfer of proteins and RNAs at synapses in the nervous system. Biol Direct 2:35. doi:10.1186/1745-6150-2-35 CrossRefPubMedPubMedCentral

Suh YH, Checler F (2002) Amyloid precursor protein, presenilins, and alpha-synuclein: molecular pathogenesis and pharmacological applications in Alzheimer's disease. Pharmacol Rev 54:469–525CrossRefPubMed

Tasaki M et al (2010) Transmission of circulating cell-free AA amyloid oligomers in exosomes vectors via a prion-like mechanism. Biochem Biophys Res Commun 400:559–562. doi:10.1016/j.bbrc.2010.08.101 CrossRefPubMed

Thery C (2011) Exosomes: secreted vesicles and intercellular communications F1000. Biology Reports 3:15. doi:10.3410/B3-15 PubMedPubMedCentral

Thery C, Amigorena S, Raposo G, Clayton A (2006) Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Current protocols in cell biology. Chapter 3: Unit 3 22 doi:10.1002/0471143030.cb0322s30

Van Nostrand WE et al (1992) Decreased levels of soluble amyloid beta-protein precursor in cerebrospinal fluid of live Alzheimer disease patients. Proc Natl Acad Sci U S A 89:2551–2555CrossRefPubMedPubMedCentral

Vella LJ, Sharples RA, Lawson VA, Masters CL, Cappai R, Hill AF (2007) Packaging of prions into exosomes is associated with a novel pathway of PrP processing. J Pathol 211:582–590. doi:10.1002/path.2145 CrossRefPubMed

Vetrivel KS, Thinakaran G (2006) Amyloidogenic processing of beta-amyloid precursor protein in intracellular compartments. Neurology 66:S69–S73. doi:10.1212/01.wnl.0000192107.17175.39 CrossRefPubMed

Vingtdeux V et al (2007) Alkalizing drugs induce accumulation of amyloid precursor protein by-products in luminal vesicles of multivesicular bodies. J Biol Chem 282:18197–18205. doi:10.1074/jbc.M609475200 CrossRefPubMed

Wang G et al (2012) Astrocytes secrete exosomes enriched with proapoptotic ceramide and prostate apoptosis response 4 (PAR-4): potential mechanism of apoptosis induction in Alzheimer disease (AD). J Biol Chem 287:21384–21395. doi:10.1074/jbc.M112.340513 CrossRefPubMedPubMedCentral

Winston CN et al. (2016) Prediction of conversion from mild cognitive impairment to dementia with neuronally derived blood exosome protein profile Alzheimer's & dementia. 3:63–72 doi:10.1016/j.dadm.2016.04.001

Yamazaki T, Koo EH, Selkoe DJ (1996) Trafficking of cell-surface amyloid beta-protein precursor. II. Endocytosis, recycling and lysosomal targeting detected by immunolocalization. J Cell Sci 109(Pt 5):999–1008PubMed

Yetman MJ, Jankowsky JL (2013) Wild-type neural progenitors divide and differentiate normally in an amyloid-rich environment. The Journal of neuroscience: the official journal of the Society for Neuroscience 33:17335–17341. doi:10.1523/JNEUROSCI.1917-13.2013 CrossRef

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. The Journal of neuroscience: the official journal of the Society for Neuroscience 27:14459–14469. doi:10.1523/JNEUROSCI.4701-07.2007 CrossRef

Zhang N et al (2017) Multiple target of hAmylin on rat primary hippocampal neurons. Neuropharmacology 113:241–251. doi:10.1016/j.neuropharm.2016.07.008 CrossRefPubMed

Title: Exosomes Secreted from HEK293-APP Swe/Ind Cells Impair the Hippocampal Neurogenesis
Authors: Tingting Zheng
Jiali Pu
Yanxing Chen
Zhangyu Guo
Hongyu Pan
Ling Zhang
Heng Zhang
Binggui Sun
Baorong Zhang
Publication date: 01-07-2017
Publisher: Springer US
Published in: Neurotoxicity Research / Issue 1/2017
Print ISSN: 1029-8428
Electronic ISSN: 1476-3524
DOI: https://doi.org/10.1007/s12640-017-9713-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Exosomes Secreted from HEK293-APP Swe/Ind Cells Impair the Hippocampal Neurogenesis

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2017

Suppression of Methamphetamine Self-Administration by Ketamine Pre-treatment Is Absent in the Methylazoxymethanol (MAM) Rat Model of Schizophrenia

Complex Changes in the Innate and Adaptive Immunity Accompany Progressive Degeneration of the Nigrostriatal Pathway Induced by Intrastriatal Injection of 6-Hydroxydopamine in the Rat

On the Role of DT-Diaphorase Inhibition in Aminochrome-Induced Neurotoxicity In Vivo

PACAP Protects Against Ethanol and Nicotine Toxicity in SH-SY5Y Cells: Implications for Drinking-Smoking Co-morbidity

Endothelin-1 Induces Degeneration of Cultured Motor Neurons Through a Mechanism Mediated by Nitric Oxide and PI3K/Akt Pathway

Late Effect of Developmental Exposure to 3,3′-Iminodipropionitrile on Neurogenesis in the Hippocampal Dentate Gyrus of Mice