PMID- 10583407
OWN - NLM
STAT- MEDLINE
DCOM- 20000131
LR  - 20190620
IS  - 0014-2956 (Print)
IS  - 0014-2956 (Linking)
VI  - 266
IP  - 3
DP  - 1999 Dec
TI  - Interactions of Alzheimer amyloid-beta peptides with glycosaminoglycans effects
      on fibril nucleation and growth.
PG  - 1101-10
AB  - Proteoglycans and their constituent glycosaminoglycans are associated with all
      amyloid deposits and may be involved in the amyloidogenic pathway. In Alzheimer's
      disease, plaques are composed of the amyloid-beta peptide and are associated with
      at least four different proteoglycans. Using CD spectroscopy, fluorescence
      spectroscopy and electron microscopy, we examined glycosaminoglycan interaction
      with the amyloid-beta peptides 1-40 (Abeta40) and 1-42 (Abeta42) to determine the
      effects on peptide conformation and fibril formation. Monomeric amyloid-beta
      peptides in trifluoroethanol, when diluted in aqueous buffer, undergo a slow
      random to amyloidogenic beta sheet transition. In the presence of heparin,
      heparan sulfate, keratan sulfate or chondroitin sulfates, this transition was
      accelerated with Abeta42 rapidly adopting a beta-sheet conformation. This was
      accompanied by the appearance of well-defined amyloid fibrils indicating an
      enhanced nucleation of Abeta42. Incubation of preformed Abeta42 fibrils with
      glycosaminoglycans resulted in extensive lateral aggregation and precipitation of
      the fibrils. The glycosaminoglycans differed in their relative activities with
      the chondroitin sulfates producing the most pronounced effects. The less
      amyloidogenic Abeta40 isoform did not show an immediate structural transition
      that was dependent upon the shielding effect by the phosphate counter ion.
      Removal or substitution of phosphate resulted in similar
      glycosaminoglycan-induced conformational and aggregation changes. These findings 
      clearly demonstrate that glycosaminoglycans act at the earliest stage of fibril
      formation, namely amyloid-beta nucleation, and are not simply involved in the
      lateral aggregation of preformed fibrils or nonspecific adhesion to plaques. The 
      identification of a structure-activity relationship between amyloid-beta and the 
      different glycosaminoglycans, as well as the condition dependence for
      glycosaminoglycan binding, are important for the successful development and
      evaluation of glycosaminoglycan-specific therapeutic interventions.
FAU - McLaurin, J
AU  - McLaurin J
AD  - Centre for Research in Neurodegenerative Diseases, University of Toronto,
      Ontario, Canada. j.mclaurin@utoronto.ca
FAU - Franklin, T
AU  - Franklin T
FAU - Zhang, X
AU  - Zhang X
FAU - Deng, J
AU  - Deng J
FAU - Fraser, P E
AU  - Fraser PE
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Eur J Biochem
JT  - European journal of biochemistry
JID - 0107600
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Glycosaminoglycans)
RN  - 0 (Peptide Fragments)
RN  - 0 (amyloid beta-protein (1-40))
RN  - 0 (amyloid beta-protein (1-42))
SB  - IM
MH  - Alzheimer Disease/*metabolism
MH  - Amino Acid Sequence
MH  - Amyloid beta-Peptides/*chemistry/*metabolism/ultrastructure
MH  - Circular Dichroism
MH  - Glycosaminoglycans/*chemistry/*metabolism
MH  - Humans
MH  - Hydrogen-Ion Concentration
MH  - In Vitro Techniques
MH  - Microscopy, Electron
MH  - Molecular Sequence Data
MH  - Peptide Fragments/*chemistry/*metabolism/ultrastructure
MH  - Protein Conformation
EDAT- 1999/12/03 00:00
MHDA- 1999/12/03 00:01
CRDT- 1999/12/03 00:00
PHST- 1999/12/03 00:00 [pubmed]
PHST- 1999/12/03 00:01 [medline]
PHST- 1999/12/03 00:00 [entrez]
AID - ejb957 [pii]
AID - 10.1046/j.1432-1327.1999.00957.x [doi]
PST - ppublish
SO  - Eur J Biochem. 1999 Dec;266(3):1101-10. doi: 10.1046/j.1432-1327.1999.00957.x.