Aberrant Co-localization of Synaptic Proteins Promoted by Alzheimer's Disease Amyloid-β Peptides: Protective Effect of Human Serum Albumin.
Amyloid-β (Aβ), Aβ40, Aβ42, and, recently, Aβ25-35 have been directly implicated in the pathogenesis of Alzheimer's disease. We have studied the effects of Aβ on neuronal death, reactive oxygen species (ROS) production, and synaptic assembling in neurons in primary culture. Aβ25-35, Aβ40, and Aβ42 significantly decreased neuronal viability, although Aβ25-35 showed a higher effect. Aβ25-35 showed a more penetrating ability to reach mitochondria while Aβ40 did not enter the neuronal cytosol and Aβ42 was scarcely internalized. We did not observe a direct correlation between ROS production and cell death because both Aβ40 and Aβ42 decreased neuronal viability but Aβ40 did not change ROS production. Rather, ROS production seems to correlate with the penetrating ability of each Aβ. No significant differences were found between Aβ40 and Aβ42 regarding the extent of the deleterious effects of both peptides on neuronal viability or synaptophysin expression. However, Aβ40 elicited a clear delocalization of PSD-95 and synaptotagmin from prospective synapsis to the neuronal soma, suggesting the occurrence of a crucial effect of Aβ40 on synaptic disassembling. The formation of Aβ40- or Aβ42-serum albumin complexes avoided the effects of these peptides on neuronal viability, synaptophysin expression, and PSD-95/synaptotagmin disarrangement suggesting that sequestration of Aβ by albumin prevents deleterious effects of these peptides. We can conclude that Aβ borne by albumin can be safely transported through body fluids, a fact that may be compulsory for Aβ disposal by peripheral tissues.
Marta
M
Domínguez-Prieto
Ana
A
Velasco
Lourdes
L
Vega
Arantxa
A
Tabernero
José M
JM
Medina
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016923:Cell Death / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism / Q000473:pathology; D000076122:Disks Large Homolog 4 Protein / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism*; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D000075462:Serum Albumin, Human / Q000378:metabolism*; D016708:Synaptophysin / Q000378:metabolism; D050857:Synaptotagmins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D016708:Synaptophysin; C569016:Syp protein, rat; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); D050857:Synaptotagmins; D000075462:Serum Albumin, Human
Alzheimer’s disease; Aβ disposal; PSD-95; amyloid-beta; serum albumin; synaptophysin; synaptotagmin
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