Cystatin C is released in association with exosomes: a new tool of neuronal communication which is unbalanced in Alzheimer's disease.
It has recently become clear that proteins associated with neurodegenerative disorders can be selectively incorporated into intraluminal vesicles of multivesicular bodies and subsequently released within exosomes. Multiple lines of research support a neuroprotective role for cystatin C in Alzheimer's disease (AD). Herein we demonstrate that cystatin C, a protein targeted to the classical secretory pathway by its signal peptide sequence, is also secreted by mouse primary neurons in association with exosomes. Immunoproteomic analysis using SELDI-TOF MS revealed the presence in exosomes of at least 9 different cystatin C glycoforms. Moreover, the over-expression of familial AD-associated presenilin 2 mutations (PS2 M239I and PS2 T122R) resulted in reduced levels of all cystatin C forms (native and glycosylated) and of amyloid-β precursor protein (APP) metabolites within exosomes. A better understanding of the mechanisms involved in exosomal processing and release may have important implications for the fight against AD and other neurodegenerative diseases.
Ghidoni
Roberta
R
Proteomics Unit, IRCCS, Centro S.Giovanni di Dio-Fatebenefratelli, Brescia, Italy. rghidoni@fatebenefratelli.it
Paterlini
Anna
A
Albertini
Valentina
V
Glionna
Michela
M
Monti
Eugenio
E
Schiaffonati
Luisa
L
Benussi
Luisa
L
Levy
Efrat
E
Binetti
Giuliano
G
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D002450:Cell Communication / Q000502:physiology*; D002478:Cells, Cultured; D055316:Cystatin C / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D055354:Exosomes / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D053766:Presenilin-2 / Q000235:genetics / Q000502:physiology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods
D016564:Amyloid beta-Protein Precursor; C525031:Cst3 protein, mouse; D055316:Cystatin C; C508861:PSEN2 protein, human; D053766:Presenilin-2; D020033:Protein Isoforms