C-terminal peptides coassemble into A 42 oligomers and protect neurons against A 42-induced neurotoxicity

Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 10/2008; 105(37):14175-80. DOI: 10.1073/pnas.0807163105
Source: PubMed

ABSTRACT Alzheimer's disease (AD) is an age-related disorder that threatens to become an epidemic as the world population ages. Neurotoxic oligomers of Abeta42 are believed to be the main cause of AD; therefore, disruption of Abeta oligomerization is a promising approach for developing therapeutics for AD. Formation of Abeta42 oligomers is mediated by intermolecular interactions in which the C terminus plays a central role. We hypothesized that peptides derived from the C terminus of Abeta42 may get incorporated into oligomers of Abeta42, disrupt their structure, and thereby inhibit their toxicity. We tested this hypothesis using Abeta fragments with the general formula Abeta(x-42) (x = 28-39). A cell viability screen identified Abeta(31-42) as the most potent inhibitor. In addition, the shortest peptide, Abeta(39-42), also had high activity. Both Abeta(31-42) and Abeta(39-42) inhibited Abeta-induced cell death and rescued disruption of synaptic activity by Abeta42 oligomers at micromolar concentrations. Biophysical characterization indicated that the action of these peptides likely involved stabilization of Abeta42 in nontoxic oligomers. Computer simulations suggested a mechanism by which the fragments coassembled with Abeta42 to form heterooligomers. Thus, Abeta(31-42) and Abeta(39-42) are leads for obtaining mechanism-based drugs for treatment of AD using a systematic structure-activity approach.

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Available from: Brigita Urbanc, Aug 18, 2015
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    • "Another cell viability screen [21] identified Ab 31–42 and Ab 39–42 as the most potent inhibitors. Biophysical characterisation [21] indicated that the action of these peptides likely involved stabilisation of Ab 42 into nontoxic oligomers. Therefore, in this study we focused on the region 32–42 to design mutations in Ab 42 peptide that would inhibit aggregation of the monomeric form and/or stabilise the tetramer in nontoxic form. "
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    Biochemical and Biophysical Research Communications 10/2014; DOI:10.1016/j.bbrc.2014.09.102 · 2.28 Impact Factor
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    • "Importantly, these forms should be soluble and amenable to degradation by the natural clearance mechanisms; otherwise, even if they are benign, they may accumulate and disrupt cellular function by sheer mass action. Examples of such inhibitors include predominantly two types of compounds – peptides derived from the amyloid proteins themselves [12] [13], or found through screening in vitro or in silico [14] [15] [16], and small molecules found empirically [17] [18]. Though small-molecule drug candidates typically possess superior pharmacological characteristics relative to peptides, for example higher biological stability and bioavailability, a rational basis for prediction of small-molecule efficacy is difficult to define and studies often are based on screening of large libraries or empirical findings. "
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    ABSTRACT: Most proteins need to adopt a three-dimensional structure in order to function properly. Misfolding, or inability of proteins to fold, is associated with a number of diseases. In a subset of these disorders, the misfolded protein or peptide selfassembles into stable, β-sheet rich structures known as amyloid fibrils. Alzheimer's disease is associated with the aggregation of the amyloid β-peptide (Aβ) into oligomers and amyloid fibrils. Aβ has a discordant, i.e β-sheet preferring, helix prone to misfold and it has been proposed that stabilization of this helix could prevent aggregation. We have designed small molecules that bind to this region and stabilize Aβ in a helical conformation. This interaction reduced fibril formation and cell toxicity of the peptide and also restored a memory-linked electrophysiological function in mouse hippocampal slices treated with Aβ. Moreover, when administered orally, these compounds had a rescuing effect in a Drosophila melanogaster model of Aβ aggregation. Another protein capable of forming amyloid-like fibrils in association with disease, is the human lung surfactant protein C, SP-C, which has a discordant transmembrane helix. SP-C is expressed as a pro-protein with a C-terminal, CTC, which has a Brichos domain with unknown function. Here, we show that CTC is important for the stability and folding of the pro-protein in the endoplasmic reticulum (ER). It is able to prevent the mature SP-C from aggregating in vitro, and is shown to bind specifically to non-helical segments and to amino acids that have been reported to promote membrane insertion in the ER. Together these data suggest a chaperone function for CTC, targeting transmembrane regions that have not attained an α-helical conformation. CTC interacts with and reduces amyloidlike fibril formation of Aβ as well as an additional amyloidogenic peptide – medin. In conclusion this thesis explores two new strategies for preventing protein misfolding and amyloid fibril formation. The first approach utilizes designed ligands to trap the Alzheimer's disease associated Aβ in its native helical structure. The second employs a novel, natural chaperone that bridges folding of transmembrane regions and anti-amyloid properties.
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