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Role of water in mediating the assembly of Alzheimer amyloid-beta Abeta16-22 protofilaments.

ABSTRACT: The role of water in promoting the formation of protofilaments (the basic building blocks of amyloid fibrils) is investigated using fully atomic molecular dynamics simulations. Our model protofilament consists of two parallel beta-sheets of Alzheimer Amyloid-beta 16-22 peptides (Ac-K(16)-L(17)-V(18)-F(19)-F(20)-A(21)-E(22)-NH2). Each sheet presents a distinct hydrophobic and hydrophilic face and together self-assemble to a stable protofilament with a core consisting of purely hydrophobic residues (L(17), F(19), A(21)), with the two charged residues (K(16), E(22)) pointing to the solvent. Our simulations reveal a subtle interplay between a water mediated assembly and one driven by favorable energetic interactions between specific residues forming the interior of the protofilament. A dewetting transition, in which water expulsion precedes hydrophobic collapse, is observed for some, but not all molecular dynamics trajectories. In the trajectories in which no dewetting is observed, water expulsion and hydrophobic collapse occur simultaneously, with protofilament assembly driven by direct interactions between the hydrophobic side chains of the peptides (particularly between F-F residues). For those same trajectories, a small increase in the temperature of the simulation (on the order of 20 K) or a modest reduction in the peptide-water van der Waals attraction (on the order of 10%) is sufficient to induce a dewetting transition, suggesting that the existence of a dewetting transition in simulation might be sensitive to the details of the force field parametrization.

SUBMITTER: Krone MG

PROVIDER: S-EPMC3066469 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Role of water in mediating the assembly of Alzheimer amyloid-beta Abeta16-22 protofilaments.

Krone Mary Griffin MG Hua Lan L Soto Patricia P Zhou Ruhong R Berne B J BJ Shea Joan-Emma JE

Journal of the American Chemical Society 20080729 33

The role of water in promoting the formation of protofilaments (the basic building blocks of amyloid fibrils) is investigated using fully atomic molecular dynamics simulations. Our model protofilament consists of two parallel beta-sheets of Alzheimer Amyloid-beta 16-22 peptides (Ac-K(16)-L(17)-V(18)-F(19)-F(20)-A(21)-E(22)-NH2). Each sheet presents a distinct hydrophobic and hydrophilic face and together self-assemble to a stable protofilament with a core consisting of purely hydrophobic residue ...[more]

PMID: 18661994

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Project description:BackgroundNeuroinflammation in the brain consequent to activation of microglia is viewed as an important component of Alzheimer's disease (AD) pathology. Amyloid beta (A?) protein is known to activate microglia and unleash an inflammatory cascade that eventually results in neuronal dysfunction and death. In this study, we sought to identify the presence of amylin receptors on human fetal and murine microglia and determine whether A? activation of the inflammasome complex and subsequent release of cytokines is mediated through these receptors.MethodsThe presence of dimeric components of the amylin receptor (calcitonin receptor and receptor activity modifying protein 3) were first immunohistochemically identified on microglia. Purified human fetal microglial (HFM) cultures were incubated with an in vivo microglial marker, DyLight 594-conjugated tomato lectin, and loaded with the membrane-permeant green fluorescent dye, Fluo-8L-AM for measurements of intracellular calcium [Ca2+]i. HFM and BV-2 cells were primed with lipopolysaccharide and then exposed to either human amylin or soluble oligomeric A?1-42 prior to treatment with and without the amylin receptor antagonist, AC253. Changes in the inflammasome complex, NLRP3 and caspase-1, were examined in treated cell cultures with Western blot and fluorometric assays. RT-PCR measurements were performed to assess cytokine release. Finally, in vivo studies were performed in transgenic mouse model of AD (5xFAD) to examine the effects of systemic administration of AC253 on markers of neuroinflammation in the brain.ResultsAcute applications of human amylin or A?1-42 resulted in an increase in [Ca2+]i that could be blocked by the amylin receptor antagonist, AC253. Activation of the NLRP3 and caspase-1 and subsequent release of cytokines, TNF? and IL-1?, was diminished by AC253 pretreatment of HFMs and BV2 cells. In vivo, intraperitoneal administration of AC253 resulted in a reduction in microglial markers (Iba-1 and CD68), caspase-1, TNF?, and IL-1?. These reductions in inflammatory markers were accompanied by reduction in amyloid plaque and size in the brains of 5xFAD mice compared to controls.ConclusionMicroglial amylin receptors mediate A?-evoked inflammation, and amylin receptor antagonists therefore offer an attractive therapeutic target for intervention in AD.

Dataset Information

Role of water in mediating the assembly of Alzheimer amyloid-beta Abeta16-22 protofilaments.

Publications

Role of water in mediating the assembly of Alzheimer amyloid-beta Abeta16-22 protofilaments.

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