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: 9.67). 10/2008; 105(37):14175-80. DOI: 10.1073/pnas.0807163105
Source: PubMed


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, Sep 30, 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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    ABSTRACT: Self association of the amyloid-β (Aβ42) peptide into oligomers, high molecular weight forms, fibrils and ultimately neuritic plaques, has been correlated with progressive cognitive decline in Alzheimer's disease. Thus, insights into the drivers of the aggregation pathway have the capacity to significantly contribute to our understanding of disease mechanism. Functional assays and a three-dimensional crystal structure of the P3 amyloidogenic region 18-41 of Aβ were used to identify residues important in self-association and to design novel non-aggregating variants of the peptide. Biophysical studies (gel filtration, SDS-PAGE, dynamic light scattering, thioflavin T assay, and electron microscopy) demonstrate that in contrast to wild type Aβ these targeted mutations lose the ability to self-associate. Loss of aggregation also correlates with reduced neuronal toxicity. Our results highlight residues and regions of the Aβ peptide important for future targeting agents aimed at the amelioration of Alzheimer's disease.
    Biochemical and Biophysical Research Communications 10/2014; 453(3). DOI:10.1016/j.bbrc.2014.09.102 · 2.30 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: Abnormal protein folding and self-assembly causes over 30 cureless human diseases for which no disease-modifying therapies are available. The common side to all these diseases is formation of aberrant toxic protein oligomers and amyloid fibrils. Both types of assemblies are drug targets, yet each presents major challenges to drug design, discovery, and development. In this review, we focus on two small molecules that inhibit formation of toxic amyloid protein assemblies - the green-tea derivative (-)-epigallocatechin-3-gallate (EGCG), which was identified through a combination of epidemiologic data and a compound library screen, and the molecular tweezer CLR01, whose inhibitory activity was discovered in our group based on rational reasoning, and subsequently confirmed experimentally. Both compounds act in a manner that is not specific to one particular protein and thus are useful against a multitude of amyloidogenic proteins, yet they act via distinct putative mechanisms. CLR01 disrupts protein aggregation through specific binding to lysine residues, whereas the mechanisms underlying the activity of EGCG are only recently beginning to unveil. We discuss current in vitro and, where available, in vivo literature related to EGCG and CLR01's effects on amyloid beta-protein, alpha-synuclein, transthyretin, islet amyloid polypeptide, and calcitonin. We also describe the toxicity, pharmacokinetics, and mechanism of action of each compound.
    12/2013; 4(4-4):385-409. DOI:10.2478/s13380-013-0137-y
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    • "The peptides additionally prevented the disturbance of synaptic activity by Aβ oligomers. To investigate the in vitro mechanism of action, dynamic light scattering, photo-induced cross-linking and discrete molecular dynamics were applied and gave clear hints that the peptides inhibit Aβ induced toxicity by stabilizing Aβ in non-toxic oligomers [62]. "
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    ABSTRACT: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with devastating effects. The greatest risk factor to develop AD is age. Today, only symptomatic therapies are available. Additionally, AD can be diagnosed with certainty only post mortem, whereas the diagnosis "probable AD" can be established earliest when severe clinical symptoms appear. Specific neuropathological changes like neurofibrillary tangles and amyloid plaques define AD. Amyloid plaques are mainly composed of the amyloid-βpeptide (Aβ). Several lines of evidence suggest that the progressive concentration and subsequent aggregation and accumulation of Aβ play a fundamental role in the disease progress. Therefore, substances which bind to Aβ and influence aggregation thereof are of great interest. An enormous number of organic substances for therapeutic purposes are described. This review focuses on peptides developed for diagnosis and therapy of AD and discusses the pre- and disadvantages of peptide drugs.
    Current pharmaceutical design 02/2012; 18(6):755-67. DOI:10.2174/138161212799277752 · 3.45 Impact Factor
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