Lipid raft disruption protects mature neurons against amyloid oligomer toxicity.
A specific neuronal vulnerability to amyloid protein toxicity may account for brain susceptibility to protein misfolding diseases. To investigate this issue, we compared the effects induced by oligomers from salmon calcitonin (sCTOs), a neurotoxic amyloid protein, on cells of different histogenesis: mature and immature primary hippocampal neurons, primary astrocytes, MG63 osteoblasts and NIH-3T3 fibroblasts. In mature neurons, sCTOs increased apoptosis and induced neuritic and synaptic damages similar to those caused by amyloid beta oligomers. Immature neurons and the other cell types showed no cytotoxicity. sCTOs caused cytosolic Ca(2+) rise in mature, but not in immature neurons and the other cell types. Comparison of plasma membrane lipid composition showed that mature neurons had the highest content in lipid rafts, suggesting a key role for them in neuronal vulnerability to sCTOs. Consistently, depletion in gangliosides protected against sCTO toxicity. We hypothesize that the high content in lipid rafts makes mature neurons especially vulnerable to amyloid proteins, as compared to other cell types; this may help explain why the brain is a target organ for amyloid-related diseases.
Malchiodi-Albedi
Fiorella
F
Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, 00161 Rome, Italy. fiorella.malchiodi@iss.it
Contrusciere
Valentina
V
Raggi
Carla
C
Fecchi
Katia
K
Rainaldi
Gabriella
G
Paradisi
Silvia
S
Matteucci
Andrea
A
Santini
Maria Teresa
MT
Sargiacomo
Massimo
M
Frank
Claudio
C
Gaudiano
Maria Cristina
MC
Diociaiuti
Marco
M
D000682:Amyloid / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D021962:Membrane Microdomains / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D041681:NIH 3T3 Cells; D016501:Neurites / Q000378:metabolism* / Q000473:pathology; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D051381:Rats
D000682:Amyloid