Aberrant Co-localization of Synaptic Proteins Promoted by Alzheimer’s Disease Amyloid-β Peptides: Protective Effect of Human Serum Albumin

Amyloid-β (Aβ), Aβ(40), Aβ(42), and, recently, Aβ(25-35) 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. Aβ(25-35), Aβ(40), and Aβ(42) significantly decreased neuronal viability, although Aβ(25-35) showed a higher effect. Aβ(25-35) showed a more penetrating ability to reach mitochondria while Aβ(40) did not enter the neuronal cytosol and Aβ(42) was scarcely internalized. We did not observe a direct correlation between ROS production and cell death because both Aβ(40) and Aβ(42) decreased neuronal viability but Aβ(40) did not change ROS production. Rather, ROS production seems to correlate with the penetrating ability of each Aβ. No significant differences were found between Aβ(40) and Aβ(42) regarding the extent of the deleterious effects of both peptides on neuronal viability or synaptophysin expression. However, Aβ(40) elicited a clear delocalization of PSD-95 and synaptotagmin from prospective synapsis to the neuronal soma, suggesting the occurrence of a crucial effect of Aβ(40) on synaptic disassembling. The formation of Aβ(40)- or Aβ(42)-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.