Extracellular vesicles: where the amyloid precursor protein carboxyl-terminal fragments accumulate and amyloid-beta oligomerizes
Por:
Perez-Gonzalez, R, Kim, Y, Miller, C, Pacheco-Quinto, J, Eckman, EA, Levy, E
Publicada:
1 sep 2020
Ahead of Print:
1 ago 2020
Resumen:
Pleiotropic roles are proposed for brain extracellular vesicles (EVs) in the development of Alzheimer's disease (AD). Our previous studies have suggested a beneficial role for EVs in AD, where the endosomal system in vulnerable neurons is compromised, contributing to the removal of accumulated material from neurons. However, the involvement of EVs in propagating AD amyloidosis throughout the brain has been considered because the amyloid-beta precursor protein (APP), APP metabolites, and key APP cleaving enzymes were identified in association with EVs. Here, we undertook to determine whether the secretase machinery is actively processing APP in EVs isolated from the brains of wild-type and APP overexpressing Tg2576 mice. We found that full-length APP is cleaved in EVs incubated in the absence of cells. The resulting metabolites, both alpha- and beta-APP carboxyl-terminal fragments and APP intracellular domain accumulate in EVs over time and amyloid-beta dimerizes. Thus, EVs contribute to the removal from neurons and transport of APP-derived neurotoxic peptides. While this is potentially a venue for propagation of the pathology throughout the brain, it may contribute to efficient removal of neurotoxic peptides from the brain.
Filiaciones:
Perez-Gonzalez, R:
Nathan S Kline Inst, Ctr Dementia Res, Orangeburg, NY USA
NYU, Sch Med, Dept Psychiat, New York, NY USA
Hosp Santa Creu & Sant Pau, St Pau Biomed Res Inst IIB St Pau, Ctr Networked Biomed Res Neurodegenerat Dis CIBER, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Dept Neurol, Barcelona, Spain
Kim, Y:
Nathan S Kline Inst, Ctr Dementia Res, Orangeburg, NY USA
NYU, Sch Med, Dept Psychiat, New York, NY USA
Miller, C:
Nathan S Kline Inst, Ctr Dementia Res, Orangeburg, NY USA
Pacheco-Quinto, J:
Biomed Res Inst New Jersey Cedar Knolls & Atlanti, Morristown, NJ USA
Eckman, EA:
Biomed Res Inst New Jersey Cedar Knolls & Atlanti, Morristown, NJ USA
Levy, E:
Nathan S Kline Inst, Ctr Dementia Res, Orangeburg, NY USA
NYU, Sch Med, Dept Psychiat, New York, NY USA
NYU, Sch Med, Dept Biochem & Mol Pharmacol, New York, NY USA
NYU, Sch Med, Neurosci Inst, New York, NY USA
Green Published, Hybrid Gold
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