Controlling Amyloid β-Peptide Fibril Formation with Protease-stable Ligands

Tjernberg, Lars O.; Lilliehöök, Christina; Callaway, David J.E.; Näslund, Jan; Hahne, Solveig; Thyberg, Johan; Terenius, Lars; Nordstedt, Christer

doi:10.1074/jbc.272.19.12601

Cited by 229 publications

(228 citation statements)

References 32 publications

Supporting

Mentioning

219

Contrasting

Unclassified

Order By: Relevance

“…It is tempting to speculate that RO-47-1816/001, after it has bound to the amyloid fibril, binds to the soluble peptide and brings it into close proximity to the fibril (Fig. 8), thereby facilitating docking of the peptides via their specific binding sequences (20,21,36). Whether cross-linking is mediated directly by RO-47-1816/001 or by a composite surface of RO-47-1816/001 and the A␤ polymer is not clear.…”

Section: A␤ Ligands Structurally Related To Ro-47-1816/001mentioning

confidence: 99%

Controlling Polymerization of β-Amyloid and Prion-derived Peptides with Synthetic Small Molecule Ligands

Kuner¹,

Bohrmann²,

Tjernberg³

et al. 2000

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The Alzheimer ␤-amyloid peptide (A␤) and a fragment of the prion protein have the capacity of forming amyloid-like fibrils when incubated under physiological conditions in vitro. Here we show that a small amyloid ligand, RO-47-1816/001, enhances this process severalfold by binding to amyloid molecules and apparently promote formation of the peptide-to-peptide bonds that join the monomers of the amyloid fibrils. This effect could be antagonized by other ligands, including analogues of RO-47-1816/001, as well as the structurally unrelated ligand Congo red. Analogues of RO-47-1816/001 with low affinity for amyloid did not display any antagonistic effect. In conclusion, these data suggest that synthetic molecules, and possibly also small natural substances present in the brain, may act in a chaperone-like fashion, promoting A␤ polymerization and growth of amyloid fibrils in vitro and possibly also in vivo. Furthermore, we demonstrate that small organic molecules can be used to inhibit the action of amyloid-enhancing compounds.The amyloid deposits in brain vasculature and parenchyma that are the main histopathological hallmarks of Alzheimer's disease (1) are composed of large polymers of Alzheimer ␤-amyloid peptide (A␤). 1 This peptide is present in two major forms, one being 40 amino acids long, and the other, more aggregable form being 42 amino acids long (2-4). The A␤ peptide is secreted by numerous cell types in the body but the amyloid deposits are only present in the central nervous system.The amyloid deposits are formed by the aggregation of individual monomers of A␤ peptide into very large polymers which have a fibril-like appearance when observed in an electron microscope (5). These polymers can also be observed by light microscopy following staining with certain histological dyes such as Congo red and thioflavine T (6).Soluble A␤ peptide can be detected in blood and cerebrospinal fluid. The levels are, however, very low, usually in the low nano-to picomolar range and at these concentrations the peptide polymerizes at a very slow rate (7). A number of recent studies on the mechanisms of amyloid formation have conclusively shown that the presence of preformed oligo-or polymers of the amyloid peptide in the reaction mixture increases the polymerization rate dramatically (7). These multimers serve as templates for the reaction and, as a result, the initial, slow phase of primary nucleation is eliminated.It has also been proposed that charged molecules, such as gangliosides (8) and metal ions, including Zn 2ϩ and Cu 2ϩ (9), may enhance formation of amyloid in vitro and in vivo. Apolipoprotein E4, a well established risk factor for Alzheimer's disease (10) has also been suggested to enhance amyloid formation by serving as a "pathological chaperone" (11-13). In the case of apolipoprotein E, there are conflicting data suggesting that the protein can enhance as well as inhibit amyloidogenesis (14, 15).The existence of putative co-factors capable of enhancing amyloid formation potentially offers new targets for pharm...

show abstract

Section: A␤ Ligands Structurally Related To Ro-47-1816/001mentioning

confidence: 99%

Controlling Polymerization of β-Amyloid and Prion-derived Peptides with Synthetic Small Molecule Ligands

Kuner¹,

Bohrmann²,

Tjernberg³

et al. 2000

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Tjernberg and coworkers demonstrated a specific interaction of an immobilized peptide with full-length A (30). Other studies have focused on observing the growth of immobilized amyloid fibrils (31).…”

mentioning

confidence: 99%

Affinity-Based Inhibition of β-Amyloid Toxicity

et al. 2002

View full text Add to dashboard Cite

Strategies for interfering with protein aggregation are important for elucidating and controlling the pathologies of amyloid diseases. We have previously identified compounds that block the cellular toxicity of the -amyloid peptide, but the relationship between their ability to inhibit toxicity and their affinity for A is unknown. To elucidate this relationship, we have developed an assay capable of measuring the affinities of small molecules for -amyloid peptide. Our approach employs immobilized -amyloid peptide at low density to minimize the problems that arise from variability in the -amyloid aggregation state. We found that low-molecular weight (MW of 700-1700) ligands for -amyloid can be identified readily by using surface plasmon resonance. The best of these bound effectively (K d ∼ 40 µM) to -amyloid. The affinities measured for peptides in the SPR assay correspond to results from A cell toxicity assays. The most potent ligands for immobilized -amyloid are the most potent inhibitors of the neuronal cell toxicity of -amyloid. Compounds with dissocation constants above ∼100 µΜ did not show significant activity in the cell toxicity assays. Our data support the hypothesis that ligands exhibiting greater affinity for the -amyloid peptide are effective at altering its aggregation and inhibiting cell toxicity.

show abstract

“…These amyloidogenic sequences (for example, NAC region in a-syn, SNNFGAILSS in IAPP, FNNGNCFIL in gelsolin, [27] the AGAAAAGA repeat in the prion protein (PrP) [28] ) which have been shown to be crucial in initiating and/or driving the fibrillization of these proteins. Although several studies have reported small peptide-based inhibitors that are designed to target these regions within full-length Ab, [29,30,31] IAPP [32,33] and a-syn, [34] the hydrophobicity and reduced solubility of these sequences have precluded efforts to use them in high-throughput screening aggregation assays.…”

Section: Discussionmentioning

confidence: 99%

Switch‐Peptides: Design and Characterization of Controllable Super‐Amyloid‐Forming Host–Guest Peptides as Tools for Identifying Anti‐Amyloid Agents

et al. 2008

View full text Add to dashboard Cite

Several amyloid‐forming proteins are characterized by the presence of hydrophobic and highly amyloidogenic core sequences that play critical roles in the initiation and progression of amyloid fibril formation. Therefore targeting these sequences represents a viable strategy for identifying candidate molecules that could interfere with amyloid formation and toxicity of the parent proteins. However, the highly amyloidogenic and insoluble nature of these sequences has hampered efforts to develop high‐throughput fibrillization assays. Here we describe the design and characterization of host–guest switch peptides that can be used for in vitro mechanistic and screening studies that are aimed at discovering aggregation inhibitors that target highly amyloidogenic sequences. These model systems are based on a host–guest system where the amyloidogenic sequence (guest peptide) is flanked by two β‐sheet‐promoting (Leu‐Ser)n oligomers as host sequences. Two host–guest peptides were prepared by using the hydrophobic core of Aβ comprising residues 14–24 (HQKLVFFAEDV) as the guest peptide with switch elements inserted within (peptide 1) or at the N and C termini of the guest peptide (peptide 2). Both model peptides can be triggered to undergo rapid self‐assembly and amyloid formation in a highly controllable manner and their fibrillization kinetics is tuneable by manipulating solution conditions (for example, peptide concentration and pH). The fibrillization of both peptides reproduces many features of the full‐length Aβ peptides and can be inhibited by known inhibitors of Aβ fibril formation. Our results suggest that this approach can be extended to other amyloid proteins and should facilitate the discovery of small‐molecule aggregation inhibitors and the development of more efficacious anti‐amyloid agents to treat and/or reverse the pathogenesis of neurodegenerative and systemic amyloid diseases.

show abstract

Controlling Amyloid β-Peptide Fibril Formation with Protease-stable Ligands

Abstract: We have previously shown that short peptides incorporating the sequence KLVFF can bind to the ϳ40-amino acid residue Alzheimer amyloid ␤-peptide (

Cited by 229 publications

References 32 publications

Controlling Polymerization of β-Amyloid and Prion-derived Peptides with Synthetic Small Molecule Ligands

Controlling Polymerization of β-Amyloid and Prion-derived Peptides with Synthetic Small Molecule Ligands

Affinity-Based Inhibition of β-Amyloid Toxicity

Switch‐Peptides: Design and Characterization of Controllable Super‐Amyloid‐Forming Host–Guest Peptides as Tools for Identifying Anti‐Amyloid Agents

Contact Info

Product

Resources

About