title: Plaque-induced abnormalities in neurite geometry in transgenic models of Alzheimer disease: implications for neural system disruption.
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.
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Charlestown, USA.
authors.forename: R
authors.initials: R
authors.lastname: Le
authors.forename: L
authors.initials: L
authors.lastname: Cruz
authors.forename: B
authors.initials: B
authors.lastname: Urbanc
authors.forename: R B
authors.initials: RB
authors.lastname: Knowles
authors.forename: K
authors.initials: K
authors.lastname: Hsiao-Ashe
authors.forename: K
authors.initials: K
authors.lastname: Duff
authors.forename: M C
authors.initials: MC
authors.lastname: Irizarry
authors.forename: H E
authors.initials: HE
authors.lastname: Stanley
authors.forename: B T
authors.initials: BT
authors.lastname: Hyman
mesh_terms: 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
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D013844:Thiazoles; C009462:thioflavin T