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 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.
Le
R
R
Department of Neurology, Massachusetts General Hospital, Charlestown, USA.
Cruz
L
L
Urbanc
B
B
Knowles
R B
RB
Hsiao-Ashe
K
K
Duff
K
K
Irizarry
M C
MC
Stanley
H E
HE
Hyman
B T
BT
D000200:Action Potentials; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D052160:Benzothiazoles; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008959:Models, Neurological; D016501:Neurites / Q000473:pathology*; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology*; D011930:Reaction Time; D013844:Thiazoles / Q000378:metabolism
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D013844:Thiazoles; C009462:thioflavin T