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Re-Evaluation of the Structural Organization of Neuritic Plaques in Alzheimer's Disease

Eliezer Masliah M.D., Margaret Mallory B.S., Thomas Deerinck B.S., Richard Deteresa B.S., Steve Lamont Ph.D., Aida Miller M.D., Robert D. Terry M.D., Bridget Carragher Ph.D., Mark Ellisman Ph.D.
DOI: http://dx.doi.org/10.1097/00005072-199311000-00009 619-632 First published online: 1 November 1993


We re-examined the relationship among synaptic pathology, subcellular abnormalities within neurites in the plaques and β-amyloid deposits of Alzheimer's disease (AD) using laser confocal imaging and computer-aided serial section reconstruction techniques. Analysis of serial optical sections of neuritic plaques double-immunolabeled for anti-β-amyloid/anti-tau-2 revealed that 35% of this type of plaque contained a dense amyloid core with clusters of peripheral abnormal neurites. The other 65% were without a dense core and were mainly composed of abundant abnormal neuritic clusters with bundles of amyloid distributed throughout the neuritic plaque. While two-dimensional (2-D) analysis of the plaques has suggested that neurites are distributed in the plaque periphery with β-amyloid localized in its center, serial section analysis showed the opposite arrangement can also be true. Three-dimensional (3-D) reconstructions of serial optical sections showed that the tau-positive tortuous axons clustered in the neuritic plaques were often continuous with synaptophysin-positive distended terminals. Analysis of electron micrographs from serial sections showed continuity among the different segments of the neurites. Further analysis of the computer generated 3-D reconstructed neuritic plaques (both from serial electron micrographs and serial optical sections), viewed as continuous rotating loops, confirmed that a great majority of the plaque volume was occupied by the clustered and continuous abnormal neurites, while the amyloid fibrils were compressed and displaced to the periphery of the plaque. The 3-D imaging of the neuritic plaques in AD suggests a more widespread and active neuritic damage than that predicted from 2-D observations. This more complete view supports a theory in which synapto-axonal damage plays an important role in the pathogenesis of the plaque.

Key Words
  • Alzheimer's disease
  • Laser confocal imaging
  • Neuritic plaque
  • Synaptophysin
  • Tau
  • Three-dimensional reconstruction