Truncated Amyloid-β(11-40/42) from Alzheimer Disease Binds Cu2+ with a Femtomolar Affinity and Influences Fiber Assembly.
27791 - 27802
MetadataShow full item record
Alzheimer disease coincides with the formation of extracellular amyloid plaques composed of the amyloid-β (Aβ) peptide. Aβ is typically 40 residues long (Aβ(1-40)) but can have variable C and N termini. Naturally occurring N-terminally truncated Aβ(11-40/42) is found in the cerebrospinal fluid and has a similar abundance to Aβ(1-42), constituting one-fifth of the plaque load. Based on its specific N-terminal sequence we hypothesized that truncated Aβ(11-40/42) would have an elevated affinity for Cu(2+). Various spectroscopic techniques, complemented with transmission electron microscopy, were used to determine the properties of the Cu(2+)-Aβ(11-40/42) interaction and how Cu(2+) influences amyloid fiber formation. We show that Cu(2+)-Aβ(11-40) forms a tetragonal complex with a 34 ± 5 fm dissociation constant at pH 7.4. This affinity is 3 orders of magnitude tighter than Cu(2+) binding to Aβ(1-40/42) and more than an order of magnitude tighter than that of serum albumin, the extracellular Cu(2+) transport protein. Furthermore, Aβ(11-40/42) forms fibers twice as fast as Aβ(1-40) with a very different morphology, forming bundles of very short amyloid rods. Substoichiometric Cu(2+) drastically perturbs Aβ(11-40/42) assembly, stabilizing much longer fibers. The very tight fm affinity of Cu(2+) for Aβ(11-40/42) explains the high levels of Cu(2+) observed in Alzheimer disease plaques.
AuthorsBarritt, JD; Viles, JH
- College Publications 
Showing items related by title, author, creator and subject.
A Comparison of Three Fluorophores for the Detection of Amyloid Fibers and Prefibrillar Oligomeric Assemblies. ThT (Thioflavin T); ANS (1-Anilinonaphthalene-8-sulfonic Acid); and bisANS (4,4'-Dianilino-1,1'-binaphthyl-5,5'-disulfonic Acid). Younan, ND; Viles, JH (2015-06-18)Amyloid fiber formation is a key event in many misfolding disorders. The ability to monitor the kinetics of fiber formation and other prefibrillar assemblies is therefore crucial for understanding these diseases. Here we ...
Cu²⁺ accentuates distinct misfolding of Aβ₁₋₄₀ and Aβ₁₋₄₂ peptides, and potentiates membrane disruption. Matheou, CJ; Younan, ND; Viles, JH (2015-03-01)Central to Alzheimer's disease is the misfolding of amyloid-beta (Aβ) peptide, which generates an assorted population of amorphous aggregates, oligomers and fibres. Metal ion homoeostasis is disrupted in the brains of ...
The cellular prion protein traps Alzheimer's Aβ in an oligomeric form and disassembles amyloid fibers. Younan, ND; Sarell, CJ; Davies, P; Brown, DR; Viles, JH (FASEB, 2013-01)There is now strong evidence to show that the presence of the cellular prion protein (PrP(C)) mediates amyloid-β (Aβ) neurotoxicity in Alzheimer's disease (AD). Here, we probe the molecular details of the interaction between ...