title: The nanometer-scale structure of amyloid-beta visualized by atomic force microscopy.
abstract: Amyloid-beta (A beta) is the major protein component of neuritic plaques found in Alzheimer's disease. Evidence suggests that the physical aggregation state of A beta directly influences neurotoxicity and specific cellular biochemical events. Atomic force microscopy (AFM) is used to investigate the three-dimensional structure of aggregated A beta and characterize aggregate/fibril size, structure, and distribution. Aggregates are characterized by fibril length and packing densities. The packing densities correspond to the differential thickness of fiber aggregates along a zeta axis (fiber height above the x-y imaging surface). Densely packed aggregates ( > or = 100 nm thick) were observed. At the edges of these densely packed regions and in dispersed regions, three types of A beta fibrils were observed. These were classified by fibril thickness into three size ranges: 2-3 nm thick, 4-6 nm thick, and 8-12 nm thick. Some of the two thicker classes of fibrils exhibited pronounced axial periodicity. Substructural features observed included fibril branching or annealing and a height periodicity which varied with fibril thickness. When identical samples were visualized with AFM and electron microscopy (EM) the thicker fibrils (4-6 nm and 8-12 nm thick) had similar morphology. In comparison, the densely packed regions of approximately > or = 100 nm thickness observed by AFM were difficult to resolve by EM. The small, 2- to 3-nm-thick, fibrils were not observed by EM even though they were routinely imaged by AFM. These studies demonstrate that AFM imaging of A beta fibrils can, for the first time, resolve nanometer-scale, zeta-axis, surface-height (thickness) fibril features. Concurrent x-y surface scans of fibrils reveal the surface submicrometer structure and organization of aggregated A beta. Thus, when AFM imaging of A beta is combined with, and correlated to, careful studies of cellular A beta toxicity it may be possible to relate certain A beta structural features to cellular neurotoxicity.
authors.affiliation: Cellular and Microscopic Research, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
authors.forename: W B
authors.initials: WB
authors.lastname: Stine
authors.forename: S W
authors.initials: SW
authors.lastname: Snyder
authors.forename: U S
authors.initials: US
authors.lastname: Ladror
authors.forename: W S
authors.initials: WS
authors.lastname: Wade
authors.forename: M F
authors.initials: MF
authors.lastname: Miller
authors.forename: T J
authors.initials: TJ
authors.lastname: Perun
authors.forename: T F
authors.initials: TF
authors.lastname: Holzman
authors.forename: G A
authors.initials: GA
authors.lastname: Krafft
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000648:ultrastructure; D018625:Microscopy, Atomic Force; D011487:Protein Conformation
chemical_list: D016229:Amyloid beta-Peptides