Plaque-induced Abnormalities in Neurite Geometry in Transgenic Models of Alzheimer Disease: Implications for Neural System Disruption

J Neuropathol Exp Neurol. 2001 Aug;60(8):753-8. doi: 10.1093/jnen/60.8.753.

Abstract

Neurites that pass through amyloid-beta deposits in Alzheimer disease (AD) undergo 3 changes: they develop phosphorylated tau immunoreactivity; the density of SMI-32-positive dendrites diminishes; and they also develop a marked alteration in their geometric features, changing from being nearly straight to being quite curvy. The extent to which the latter 2 phenomena are related to phosphorylated tau is unknown. We have now examined whether amyloid-beta deposits in APP695Sw transgenic mice, which have only rare phosphorylated tau containing neurites. develop these changes. We found that dendritic density is diminished within the boundaries of amyloid-beta plaques, with the greatest loss (about 80%, p < 0.001) within the boundaries of thioflavine S cores. Remaining dendrites within plaques develop substantial morphological alterations quantitatively similar to those seen in AD. A statistically significant but smaller degree of change in geometry was seen in the immediate vicinity around plaques, suggesting a propagation of cytoskeletal disruption from the center of the plaque outward. We examined the possible physiological consequences of this change in dendritic geometry using a standard cable-theory model. We found a predicted delay of several milliseconds in about one quarter of the dendrites passing through a thioflavine S plaque. These results are consistent with previous observations in AD, and suggest that thioflavine S-positive amyloid-beta deposits have a marked effect on dendritic microarchitecture in the cortex, even in the relative absence of phosphorylated tau alterations.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Action Potentials
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Benzothiazoles
  • Brain / metabolism
  • Brain / pathology
  • Dendrites / metabolism
  • Dendrites / pathology
  • In Vitro Techniques
  • Mice
  • Mice, Transgenic
  • Microscopy, Confocal
  • Models, Neurological
  • Neurites / pathology*
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology*
  • Reaction Time
  • Thiazoles / metabolism

Substances

  • Amyloid beta-Peptides
  • Benzothiazoles
  • Thiazoles
  • thioflavin T