Dataset Information

Lipid composition influences the release of Alzheimer's amyloid ?-peptide from membranes.

ABSTRACT: The behavior of the amyloid ?-peptide (A?) within a membrane environment is integral to its toxicity and the progression of Alzheimer's disease. Ganglioside GM1 has been shown to enhance the aggregation of A?, but the underlying mechanism is unknown. Using atomistic molecular dynamics simulations, we explored the interactions between the 40-residue alloform of A? (A?(40) ) and several model membranes, including pure palmitoyloleoylphosphatidylcholine (POPC) and palmitoyloleoylphosphatidylserine (POPS), an equimolar mixture of POPC and palmitoyloleoylphosphatidylethanolamine (POPE), and lipid rafts, both with and without GM1, to understand the behavior of A?(40) in various membrane microenvironments. A?(40) remained inserted in POPC, POPS, POPC/POPE, and raft membranes, but in several instances exited the raft containing GM1. A?(40) interacted with GM1 largely through hydrogen bonding, producing configurations containing ?-strands with C-termini that, in some cases, exited the membrane and became exposed to solvent. These observations provide insight into the release of A? from the membrane, a previously uncharacterized process of the A? aggregation pathway.

SUBMITTER: Lemkul JA

PROVIDER: S-EPMC3190148 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Lipid composition influences the release of Alzheimer's amyloid β-peptide from membranes.

Lemkul Justin A JA Bevan David R DR

Protein science : a publication of the Protein Society 20110713 9

The behavior of the amyloid β-peptide (Aβ) within a membrane environment is integral to its toxicity and the progression of Alzheimer's disease. Ganglioside GM1 has been shown to enhance the aggregation of Aβ, but the underlying mechanism is unknown. Using atomistic molecular dynamics simulations, we explored the interactions between the 40-residue alloform of Aβ (Aβ(40) ) and several model membranes, including pure palmitoyloleoylphosphatidylcholine (POPC) and palmitoyloleoylphosphatidylserine ...[more]

PMID: 21692120

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Project description:The cause of Alzheimer's disease (AD) is poorly understood. In 1991, the amyloid hypothesis postulated that ?-amyloid (A?) accumulation is a key element. It follows that clearing the brain of A? would be beneficial, which has not been the case. Therefore, A? is likely a result, not a cause, of AD and may be protective rather than harmful. The apolipoprotein E4 (apoE4) allele is the strongest genetic risk factor for AD. Klotho (KL), encoded by the KL gene, may be another AD-related protein. FGF21 is a circulating endocrine hormone, mainly secreted by the liver, mostly during fasting. FGF21 acts by binding to its receptor FGFR1 and co-receptor ?-klotho. FGF21 is neuroprotective and could delay onset of AD. In the present study, the KL protein structure was examined to determine whether it may interact with A?. Protein data bank (pdb) entries for klotho and A? were searched on the RCSB Protein Data Bank for ?-KL and AD amyloid ?-peptide. The protein structures were superimposed and aligned on PYMOL v2.3.4 with the super command, which super aligns two protein selections. To evaluate the conservation and alignment of the A? and KL genomes across species, BLAT, the Blast-Like Alignment Tool of the UCSC Genome Browser, was used. The amino acid residues phe76-val96 of KL aligned closely with residues asp7-asn27 of A?. Cross-species comparison of KL revealed a high degree of alignment and conservation in the chimp and 27 other primates; however, less alignment and conservation were observed in the mouse, dog and elephant, even less in the chicken, western clawed frog (Xenopus tropicalis), zebrafish and lamprey. The current finding of amino acid residues phe76-val96 of klotho aligning closely with residues asp7-asn27 of A? suggests that A? can enhance the ability of klotho to draw FGF21 to regions of incipient neurodegeneration in AD. The problem arises with age. Older individuals do not heal or repair tissue damage as well as younger individuals. As neurodegeneration advances in an older individual, perhaps caused by neuroinflammation related to herpes simplex virus type 1, increasing amounts of amyloid are produced, forming an adhesive web, as the brain tries to hold the pathologic process in check. Meanwhile, the damage increases and spreads. Progressive neurodegeneration and cognitive decline are the outcome.

Dataset Information

Lipid composition influences the release of Alzheimer's amyloid ?-peptide from membranes.

Publications

Lipid composition influences the release of Alzheimer's amyloid β-peptide from membranes.

Similar Datasets

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