Amyloid plaques | EPFL Graph Search

Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of microglia and astrocytes can be associated with amyloid plaques. Some plaques occur in the brain as a result of aging, but large numbers of plaques and neurofibrillary tangles are characteristic features of Alzheimer's disease. Abnormal neurites in amyloid plaques are tortuous, often swollen axons and dendrites. The neurites contain a variety of organelles and cellular debris, and many of them include characteristic paired helical filaments, the ultrastructural component of neurofibrillary tangles. The plaques are highly variable in shape and size; in tissue sections immunostained for Aβ, they comprise a log-normal size distribution curve with an average plaque area of 400-450 square micrometers (μm2). The smallest plaques (less than 200 μm2), which often consist of diffuse deposits of Aβ, are particularly numerous. The apparent size of plaques is influenced by the type of stain used to detect them, and by the plane through which they are sectioned for analysis under the microscope. Plaques form when Aβ misfolds and aggregates into oligomers and longer polymers, the latter of which are characteristic of amyloid. Misfolded and aggregated Aβ is thought to be neurotoxic, especially in its oligomeric state. In 1892, Paul Blocq and Gheorghe Marinescu first described the presence of plaques in grey matter. They referred to the plaques as 'nodules of neuroglial sclerosis'. In 1898, Emil Redlich reported plaques in three patients, two of whom had clinically verified dementia. Redlich used the term 'miliary sclerosis' to describe plaques because he thought they resembled millet seeds, and he was the first to refer to the lesions as 'plaques'. In the early 20th century, Oskar Fischer noted their similarity to actinomyces 'Drusen' (geode-like lesions), leading him to call the degenerative process 'drusige Nekrose'.

Structural differences of amyloid-beta fibrils revealed by antibodies from phage display

Hilal Lashuel, Patrick Droste

Background: Beside neurofibrillary tangles, amyloid plaques are the major histological hallmarks of Alzheimer's disease (AD) being composed of aggregated fibrils of beta-amyloid (A beta). During the underlying fibrillogenic pathway, starting from a surplus of soluble A beta and leading to mature fibrils, multiple conformations of this peptide appear, including oligomers of various shapes and sizes. To further investigate the fibrillization of beta-amyloid and to have tools at hand to monitor the distribution of aggregates in the brain or even act as disease modulators, it is essential to develop highly sensitive antibodies that can discriminate between diverse aggregates of A beta. Results: Here we report the generation and characterization of a variety of amyloid-beta specific human and human-like antibodies. Distinct fractions of monomers and oligomers of various sizes were separated by size exclusion chromatography (SEC) from A beta 42 peptides. These antigens were used for the generation of two A beta 42 specific immune scFv phage display libraries from macaque (Macaca fascicularis). Screening of these libraries as well as two naive human phage display libraries resulted in multiple unique binders specific for amyloid-beta. Three of the obtained antibodies target the N-terminal part of A beta 42 although with varying epitopes, while another scFv binds to the a-helical central region of the peptide. The affinities of the antibodies to various A beta 42 aggregates as well as their ability to interfere with fibril formation and disaggregation of preformed fibrils were determined. Most significantly, one of the scFv is fibril-specific and can discriminate between two different fibril forms resulting from variations in the acidity of the milieu during fibrillogenesis. Conclusion: We demonstrated that the approach of animal immunization and subsequent phage display based antibody selection is applicable to generate highly specific anti beta-amyloid scFvs that are capable of accurately discriminating between minute conformational differences.

Biomed Central Ltd2015

Structural differences of amyloid-beta fibrils revealed by antibodies from phage display

Hilal Lashuel, Patrick Droste

Biomed Central Ltd2015