Amyloid beta peptide (AP) is a natural peptide, normally released into the cerebrospinal fluid (CSF), that plays a key role in Alzheimer’s disease. The conversion of the peptide from a native soluble form to a non-native and often insoluble form, such as small and large aggregates, protofibrils and fibrils of AP appears to be implicated in the pathogenesis of AD. Although the molecular mechanisms of AP neurotoxicity are not fully understood, a large body of data suggests that the primary target of amyloid peptides is the cell membrane of neurons, that may modulate the structural and functional conversion of AP into assemblies involved in pathological processes. In our study, we provide a systematic investigation of AP1-42’s ability to incorporate and form channel-like events in membranes of different lipid composition and focus on cholesterol and its oxidation products. We propose that cholesterol and its oxidation products can be considered neuroprotective factors because a) by favouring AP1-42 insertion into membranes, the fibrillation/clearance balance shifts toward clearance; b) by shifting channel selectivity toward anions, the membrane potential is moved far from the threshold of membrane excitability, thus decreasing the influx of calcium into the cell.
AβP1-42 incorporation and channel formation in planar lipid membranes: the role of cholesterol and its oxidation products
MELELEO, DANIELA ADDOLORATA;
2013-01-01
Abstract
Amyloid beta peptide (AP) is a natural peptide, normally released into the cerebrospinal fluid (CSF), that plays a key role in Alzheimer’s disease. The conversion of the peptide from a native soluble form to a non-native and often insoluble form, such as small and large aggregates, protofibrils and fibrils of AP appears to be implicated in the pathogenesis of AD. Although the molecular mechanisms of AP neurotoxicity are not fully understood, a large body of data suggests that the primary target of amyloid peptides is the cell membrane of neurons, that may modulate the structural and functional conversion of AP into assemblies involved in pathological processes. In our study, we provide a systematic investigation of AP1-42’s ability to incorporate and form channel-like events in membranes of different lipid composition and focus on cholesterol and its oxidation products. We propose that cholesterol and its oxidation products can be considered neuroprotective factors because a) by favouring AP1-42 insertion into membranes, the fibrillation/clearance balance shifts toward clearance; b) by shifting channel selectivity toward anions, the membrane potential is moved far from the threshold of membrane excitability, thus decreasing the influx of calcium into the cell.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
