Plaque-induced abnormalities in neurite geometry in transgenic models of Alzheimer disease: Implications for neural system disruption

Neurites that pass through amyloid-beta deposits in Alzheimer disease (AD) undergo 3 changes: they develop phosphorylated tau immunoreactivity the den sity of SMI-32-positive dendrites diminishes and they also develop a marked alteration in their geometric features, changing from being nearly straigh t to being quite curvy. The extent to which the latter 2 phenomena are rela ted to phosphorylated tau is unknown. We have now examined whether amyloid- beta deposits in APP695Sw transgenic mice, which have only rare phosphoryla ted 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 thioflavi ne S cores. Remaining dendrites within plaques develop substantial morpholo gical alterations quantitatively similar to those seen in AD. A statistical ly significant but smaller degree of change in geometry was seen in the imm ediate vicinity around plaques, suggesting a propagation of cytoskeletal di sruption from the center of the plaque outward. We examined the possible ph ysiological consequences of this change in dendritic geometry using a stand ard cable-theory model. We found a predicted delay of several milliseconds in about one quarter of the dendrites passing through a thioflavine S plaqu e. These results are consistent with previous observations in AD, and sugge st that thioflavine S-positive amyloid-beta deposits have a marked effect o n dendritic microarchitecture in the cortex, even in the relative absence o f phosphorylated tau alterations.