TY - JOUR
T1 - The cellular prion protein traps Alzheimer's Aβ in an oligomeric form and disassembles amyloid fibers
AU - Younan, N.D.
AU - Sarell, C.J.
AU - Davies, P.
AU - Brown, D.R.
AU - Viles, J.H.
PY - 2013/5
Y1 - 2013/5
N2 - There is now strong evidence to show that the presence of the cellular prion protein (PrPc) mediates amyloid-β (Aβ) neurotoxicity in Alzheimer's disease (AD). Here, we probe the molecular details of the interaction between PrP and Aβ and discover that substoichiometric amounts of PrPc, as little as 1/20, relative to Aβ will strongly inhibit amyloid fibril formation. This effect is specific to the unstructured N-terminal domain of PrPc. Electron microscopy indicates PrPc is able to trap Aβ in an oligomeric form. Unlike fibers, this oligomeric Aβ contains antiparallel β sheet and binds to a oligomer specific conformational antibody. Our NMR studies show that a specific region of PrPc, notably residues 95-113, binds to Aβ oligomers, but only once Aβ misfolds. The ability of PrPc to trap and concentrate Aβ in an oligomeric form and disassemble mature fibers suggests a mechanism by which PrPc might confer Aβ toxicity in AD, as oligomers are thought to be the toxic form of Aβ. Identification of a specific recognition site on PrPc that traps Aβ in an oligomeric form is potentially a therapeutic target for the treatment of Alzheimer's disease.
AB - There is now strong evidence to show that the presence of the cellular prion protein (PrPc) mediates amyloid-β (Aβ) neurotoxicity in Alzheimer's disease (AD). Here, we probe the molecular details of the interaction between PrP and Aβ and discover that substoichiometric amounts of PrPc, as little as 1/20, relative to Aβ will strongly inhibit amyloid fibril formation. This effect is specific to the unstructured N-terminal domain of PrPc. Electron microscopy indicates PrPc is able to trap Aβ in an oligomeric form. Unlike fibers, this oligomeric Aβ contains antiparallel β sheet and binds to a oligomer specific conformational antibody. Our NMR studies show that a specific region of PrPc, notably residues 95-113, binds to Aβ oligomers, but only once Aβ misfolds. The ability of PrPc to trap and concentrate Aβ in an oligomeric form and disassemble mature fibers suggests a mechanism by which PrPc might confer Aβ toxicity in AD, as oligomers are thought to be the toxic form of Aβ. Identification of a specific recognition site on PrPc that traps Aβ in an oligomeric form is potentially a therapeutic target for the treatment of Alzheimer's disease.
UR - http://www.scopus.com/inward/record.url?scp=84877144645&partnerID=8YFLogxK
UR - http://dx.doi.org/10.1096/fj.12-222588
U2 - 10.1096/fj.12-222588
DO - 10.1096/fj.12-222588
M3 - Article
AN - SCOPUS:84877144645
VL - 27
SP - 1847
EP - 1858
JO - FASEB Journal
JF - FASEB Journal
IS - 5
ER -