TY - JOUR
T1 - The molecular assembly of amyloid Aβ controls its neurotoxicity and binding to cellular proteins
AU - Manzoni, Claudia
AU - Colombo, Laura
AU - Bigini, Paolo
AU - Diana, Valentina
AU - Cagnotto, Alfredo
AU - Messa, Massimo
AU - Lupi, Monica
AU - Bonetto, Valentina
AU - Pignataro, Mauro
AU - Airoldi, Cristina
AU - Sironi, Erika
AU - Williams, Alun
AU - Salmona, Mario
PY - 2011/9/23
Y1 - 2011/9/23
N2 - Accumulation of β-sheet-rich peptide (Aβ) is strongly associated with Alzheimer's disease, characterized by reduction in synapse density, structural alterations of dendritic spines, modification of synaptic protein expression, loss of long-term potentiation and neuronal cell death. Aβ species are potent neurotoxins, however the molecular mechanism responsible for Aβ toxicity is still unknown. Numerous mechanisms of toxicity were proposed, although there is no agreement about their relative importance in disease pathogenesis. Here, the toxicity of Aβ 1-40 and Aβ 1-42 monomers, oligomers or fibrils, was evaluated using the N2a cell line. A structure-function relationship between peptide aggregation state and toxic properties was established. Moreover, we demonstrated that Aβ toxic species cross the plasma membrane, accumulate in cells and bind to a variety of internal proteins, especially on the cytoskeleton and in the endoplasmatic reticulum (ER). Based on these data we suggest that numerous proteins act as Aβ receptors in N2a cells, triggering a multi factorial toxicity.
AB - Accumulation of β-sheet-rich peptide (Aβ) is strongly associated with Alzheimer's disease, characterized by reduction in synapse density, structural alterations of dendritic spines, modification of synaptic protein expression, loss of long-term potentiation and neuronal cell death. Aβ species are potent neurotoxins, however the molecular mechanism responsible for Aβ toxicity is still unknown. Numerous mechanisms of toxicity were proposed, although there is no agreement about their relative importance in disease pathogenesis. Here, the toxicity of Aβ 1-40 and Aβ 1-42 monomers, oligomers or fibrils, was evaluated using the N2a cell line. A structure-function relationship between peptide aggregation state and toxic properties was established. Moreover, we demonstrated that Aβ toxic species cross the plasma membrane, accumulate in cells and bind to a variety of internal proteins, especially on the cytoskeleton and in the endoplasmatic reticulum (ER). Based on these data we suggest that numerous proteins act as Aβ receptors in N2a cells, triggering a multi factorial toxicity.
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U2 - 10.1371/journal.pone.0024909
DO - 10.1371/journal.pone.0024909
M3 - Article
C2 - 21966382
AN - SCOPUS:80053129900
VL - 6
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 9
M1 - e24909
ER -