Assembly of Alzheimer's amyloid-beta fibrils and approaches for therapeutic intervention.
Amyloid plaques are the principal features of Alzheimers disease (AD) pathology and are considered to be a major factor in the disease process. These fibrillar deposits are composed primarily of the 40-42 residue amyloid-beta (Abeta) peptide which is a proteolytic product of a larger membrane precursor protein. Electron microscopy and X-ray diffraction have revealed that the mature amyloid fibrils are assembled as a highly beta-sheet polymer that has a well-defined protofilament quaternary structure. This organization is observed for amyloid fibrils from a wide variety of disorders and appears to represent a structural superfamily. Amyloid plaques also contain a number of other components such as proteoglycans that contain highly sulfated glycosaminoglycan (GAG) chains. These amyloid-associated elements may contribute to the aggregation and/or stabilization of Abeta as insoluble fibrils. We have recently developed an aggressive model for Abeta plaque formation in transgenic mice that exhibits an "early-onset" phenotype. Immunocytochemistry has demonstrated that even with this rapid progression, Abeta deposits within the neuropil and cerebrovascular system all co-localize with heparan sulfate proteoglycans (HSPG). These findings indicate a number of structural features that can be targeted as potential sites for the development of amyloid inhibitors. In addition, the use of small compounds that interfere with the proteoglycan-amyloid pathway may be effective therapeutic agents that can be assessed through the use of these transgenic models.
Yang
D S
DS
Centre for Research in Neurodegenerative Diseases, University of Toronto, Ontario, Canada.
Serpell
L C
LC
Yip
C M
CM
McLaurin
J
J
Chrishti
M A
MA
Horne
P
P
Boudreau
L
L
Kisilevsky
R
R
Westaway
D
D
Fraser
P E
PE
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018625:Microscopy, Atomic Force; D015394:Molecular Structure; D011509:Proteoglycans / Q000378:metabolism; D014961:X-Ray Diffraction
D016229:Amyloid beta-Peptides; D046911:Macromolecular Substances; D011509:Proteoglycans