Increased Exosome Secretion in Neurons Aging in Vitro by NPC1-mediated Endosomal Cholesterol Buildup

Overview

Journal Life Sci Alliance

Specialties Biochemistry
Biology
Cell Biology
Molecular Biology

Date 2021 Jun 29

PMID 34183444

Citations 10

Authors

Francesc X Guix

Ana Marrero Capitan

Alvaro Casadome-Perales

Irene Palomares-Perez

Ines Lopez Del Castillo

Veronica Miguel

Leigh Goedeke

Mauricio G Martin

Santiago Lamas

Hector Peinado

Carlos Fernandez-Hernando

Carlos G Dotti

Affiliations

Soon will be listed here.

Abstract

As neurons age, they show a decrease in their ability to degrade proteins and membranes. Because undegraded material is a source of toxic products, defects in degradation are associated with reduced cell function and survival. However, there are very few dead neurons in the aging brain, suggesting the action of compensatory mechanisms. We show in this work that ageing neurons in culture show large multivesicular bodies (MVBs) filled with intralumenal vesicles (ILVs) and secrete more small extracellular vesicles than younger neurons. We also show that the high number of ILVs is the consequence of the accumulation of cholesterol in MVBs, which in turn is due to decreased levels of the cholesterol extruding protein NPC1. NPC1 down-regulation is the consequence of a combination of upregulation of the NPC1 repressor microRNA 33, and increased degradation, due to Akt-mTOR targeting of NPC1 to the phagosome. Although releasing more exosomes can be beneficial to old neurons, other cells, neighbouring and distant, can be negatively affected by the waste material they contain.

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References

Terman A, Brunk U . Lipofuscin. Int J Biochem Cell Biol. 2004; 36(8):1400-4. DOI: 10.1016/j.biocel.2003.08.009. View

Boura E, Ivanov V, Carlson L, Mizuuchi K, Hurley J . Endosomal sorting complex required for transport (ESCRT) complexes induce phase-separated microdomains in supported lipid bilayers. J Biol Chem. 2012; 287(33):28144-51. PMC: 3431677. DOI: 10.1074/jbc.M112.378646. View

Levy E, El Banna N, Baille D, Heneman-Masurel A, Truchet S, Rezaei H . Causative Links between Protein Aggregation and Oxidative Stress: A Review. Int J Mol Sci. 2019; 20(16). PMC: 6719959. DOI: 10.3390/ijms20163896. View

Song P, Trajkovic K, Tsunemi T, Krainc D . Parkin Modulates Endosomal Organization and Function of the Endo-Lysosomal Pathway. J Neurosci. 2016; 36(8):2425-37. PMC: 6705497. DOI: 10.1523/JNEUROSCI.2569-15.2016. View

Bigagli E, Luceri C, Scartabelli T, Dolara P, Casamenti F, Pellegrini-Giampietro D . Long-term Neuroglial Cocultures as a Brain Aging Model: Hallmarks of Senescence, MicroRNA Expression Profiles, and Comparison With In Vivo Models. J Gerontol A Biol Sci Med Sci. 2015; 71(1):50-60. DOI: 10.1093/gerona/glu231. View

Imrie J, Heptinstall L, Knight S, Strong K . Observational cohort study of the natural history of Niemann-Pick disease type C in the UK: a 5-year update from the UK clinical database. BMC Neurol. 2015; 15:257. PMC: 4678528. DOI: 10.1186/s12883-015-0511-1. View

Martin M, Perga S, Trovo L, Rasola A, Holm P, Rantamaki T . Cholesterol loss enhances TrkB signaling in hippocampal neurons aging in vitro. Mol Biol Cell. 2008; 19(5):2101-12. PMC: 2366859. DOI: 10.1091/mbc.e07-09-0897. View

Martin M, Ahmed T, Korovaichuk A, Venero C, Menchon S, Salas I . Constitutive hippocampal cholesterol loss underlies poor cognition in old rodents. EMBO Mol Med. 2014; 6(7):902-17. PMC: 4119354. DOI: 10.15252/emmm.201303711. View

Trovo L, Ahmed T, Callaerts-Vegh Z, Buzzi A, Bagni C, Chuah M . Low hippocampal PI(4,5)P₂ contributes to reduced cognition in old mice as a result of loss of MARCKS. Nat Neurosci. 2013; 16(4):449-55. DOI: 10.1038/nn.3342. View

10.

Guix F, Corbett G, Cha D, Mustapic M, Liu W, Mengel D . Detection of Aggregation-Competent Tau in Neuron-Derived Extracellular Vesicles. Int J Mol Sci. 2018; 19(3). PMC: 5877524. DOI: 10.3390/ijms19030663. View

11.

Kaech S, Banker G . Culturing hippocampal neurons. Nat Protoc. 2007; 1(5):2406-15. DOI: 10.1038/nprot.2006.356. View

12.

Martin M, Trovo L, Perga S, Sadowska A, Rasola A, Chiara F . Cyp46-mediated cholesterol loss promotes survival in stressed hippocampal neurons. Neurobiol Aging. 2009; 32(5):933-43. DOI: 10.1016/j.neurobiolaging.2009.04.022. View

13.

Miranda A, Paolo G . Endolysosomal dysfunction and exosome secretion: implications for neurodegenerative disorders. Cell Stress. 2019; 2(5):115-118. PMC: 6551703. DOI: 10.15698/cst2018.05.136. View

14.

Lu F, Liang Q, Abi-Mosleh L, Das A, De Brabander J, Goldstein J . Identification of NPC1 as the target of U18666A, an inhibitor of lysosomal cholesterol export and Ebola infection. Elife. 2015; 4. PMC: 4718804. DOI: 10.7554/eLife.12177. View

15.

Papadopoulos V, Nikolopoulou G, Antoniadou I, Karachaliou A, Arianoglou G, Emmanouilidou E . Modulation of β-glucocerebrosidase increases α-synuclein secretion and exosome release in mouse models of Parkinson's disease. Hum Mol Genet. 2018; 27(10):1696-1710. DOI: 10.1093/hmg/ddy075. View

16.

Love S, Bridges L, Case C . Neurofibrillary tangles in Niemann-Pick disease type C. Brain. 1995; 118 ( Pt 1):119-29. DOI: 10.1093/brain/118.1.119. View

17.

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

18.

Ungureanu A, Benilova I, Krylychkina O, Braeken D, De Strooper B, Van Haesendonck C . Amyloid beta oligomers induce neuronal elasticity changes in age-dependent manner: a force spectroscopy study on living hippocampal neurons. Sci Rep. 2016; 6:25841. PMC: 4865860. DOI: 10.1038/srep25841. View

19.

Futerman A, van Meer G . The cell biology of lysosomal storage disorders. Nat Rev Mol Cell Biol. 2004; 5(7):554-65. DOI: 10.1038/nrm1423. View

20.

Perez M, Avila J, Hernandez F . Propagation of Tau via Extracellular Vesicles. Front Neurosci. 2019; 13:698. PMC: 6614378. DOI: 10.3389/fnins.2019.00698. View