Plaque-induced neurite abnormalities: implications for disruption of neural networks in Alzheimer's disease

Abstract

The brains of Alzheimer's disease patients contain extracellular Abeta amyloid deposits (senile plaques). Although genetic evidence causally links Abeta deposition to the disease, the mechanism by which Abeta disrupts cortical function is unknown. Using triple immunofluorescent confocal microscopy and three-dimensional reconstructions, we found that neuronal processes that cross through an Abeta deposit are likely to have a radically changed morphology. We modeled the electrophysiological effect of this changed morphology and found a predicted delay of several milliseconds over an average plaque. We propose that this type of delay, played out among thousands of plaques throughout neocortical areas, disrupts the precise temporal firing patterns of action potentials, contributing directly to neural system failure and dementia.

Figure 1

(a) Curvature of dendrites was defined as the inverse of the curvature radius (C_i). For each dendrite, a mean C value then was determined with the following equation: C = (1/N) Σ⋅C_i, where N is the number of equidistant points along the dendrite. (b) The ratio (R_o) of the end to end distance (d) to the curvilinear length (L) was calculated for each dendrite (R_o = d/L). (c) The width of each dendrite was determined from the average of the sum of all widths along the dendrite (W = (1/N) Σ⋅w_i).

Figure 2

Dendrites in AD were classified by the presence of Aβ deposits and Alz-50 immunoreactivity. (a) An example of a projection of a three-dimensional triple-labeled plaque (Aβ in green, Alz-50 in red, and SMI32 in blue). (b) The area containing the Aβ deposit is outlined to show examples of dendrites. (c) Neurite segments are classified as being outside or inside Aβ deposits and by whether they are Alz-50-immunoreactive. (Bar = 20 μm.)

Figure 3

Distribution of dendrite curvature inside versus outside of Aβ deposits. (a) Dendrites in non-AD control cases are straight and have no significant changes in their curvature when they traverse Aβ deposits. (b) Alz-50 immunoreactive dendrites have a nearly 4-fold increase in curvature compared with dendrites from controls. There is no additional change in their curvature as they pass through Aβ deposits. (c) Alz-50-negative dendrites also have altered morphology in AD cases, but only when they traverse Aβ deposits. Dendrites have a 3-fold increase in curvature inside Aβ deposits as compared with dendrites from control cases. By contrast, there is no increase in curvature of Alz-50-negative dendrites outside of Aβ deposits as compared with dendrites from control cases.

Figure 4

Changes in dendritic morphology in AD could lead to delays in dendritic spike timing. Shown is the percentage of dendrites that would have an increase of at least 30% in dendritic spike timing >100 μm, the size of an average plaque. Dendrites from non-AD cases, 2%; Alz-50-negative dendrites that do not traverse Aβ deposits, 3%; Alz-50-negative dendrites that traverse Aβ deposits, 45%; Alz-50-immunoreactive dendrites that do not traverse Aβ deposits, 73%; and Alz-50-immunoreactive dendrites that traverse Aβ deposits, 79%.