Imaging distinct conformational states of amyloid-beta fibrils in Alzheimer's disease using novel luminescent probes.
Using luminescent conjugated polyelectrolyte probes (LCPs), we demonstrate the possibility to distinguish amyloid-beta 1-42 peptide (Abeta1-42) fibril conformations, by analyzing in vitro generated amyloid fibrils of Abeta1-42 formed under quiescent and agitated conditions. LCPs were then shown to resolve such conformational heterogeneity of amyloid deposits in vivo. A diversity of amyloid deposits depending upon morphology and anatomic location was illustrated with LCPs in frozen ex vivo brain sections from a transgenic mouse model (tg-APP swe) of Alzheimer's disease. Comparative LCP fluorescence showed that compact-core plaques of amyloid beta precursor protein transgenic mice were composed of rigid dense amyloid. A more abundant form of amyloid plaque displayed morphology of a compact center with a protruding diffuse exterior. Surprisingly, the compact center of these plaques showed disordered conformations of the fibrils, and the exterior was composed of rigid amyloid protruding from the disordered center. This type of plaque appears to grow from more loosely assembled regions toward solidified amyloid tentacles. This work demonstrates how application of LCPs can prove helpful to monitor aggregate structure of in vivo formed amyloid deposits such as architecture, maturity, and origin.
Nilsson
K Peter R
KP
IFM-Department of Chemistry, Linköping University, Linköping, Sweden.
Aslund
Andreas
A
Berg
Ina
I
Nyström
Sofie
S
Konradsson
Peter
P
Herland
Anna
A
Inganäs
Olle
O
Stabo-Eeg
Frantz
F
Lindgren
Mikael
M
Westermark
Gunilla T
GT
Lannfelt
Lars
L
Nilsson
Lars N G
LN
Hammarström
Per
P
D000544:Alzheimer Disease / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D000682:Amyloid / Q000032:analysis* / Q000737:chemistry* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000032:analysis* / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D006801:Humans; D008163:Luminescent Measurements / Q000379:methods; D008164:Luminescent Proteins / Q000032:analysis*; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence / Q000379:methods; D058225:Plaque, Amyloid / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation
D000682:Amyloid; D016229:Amyloid beta-Peptides; D008164:Luminescent Proteins