Despite extensive deposition of putatively neurotoxic amyloid-␤ (A␤) protein in the brain, it has not been possible to demonstrate an association of A␤ deposits with neuronal loss in Alzheimer's disease (AD), and neuronal loss is minimal in transgenic mouse models of AD. Using triple immunostaining confocal microscopy and analyzing the images with the cross-correlation density map method from statistical physics, we directly compared A␤ deposition, A␤ morphology, and neuronal architecture. We found dramatic, focal neuronal toxicity associated primarily with thioflavin S-positive fibrillar A␤ deposits in both AD and PSAPP mice. These results, along with computer simulations, suggest that A␤ develops neurotoxic properties in vivo when it adopts a fibrillar ␤-pleated sheet conformation.T he primary pathologic features of Alzheimer's disease (AD) are amyloid deposition, neurofibrillary tangle formation, and neuronal loss. There is substantial indirect evidence implicating amyloid-␤ (A␤) protein in the pathological cascade leading to neuronal loss in AD (1). Presenilin-1 (PS1), presenilin-2, and amyloid precursor protein (APP) mutations causing familial AD and the apolipoprotein E 4 allele risk factor for AD all increase plasma, fibroblast, or brain levels of A␤ or A␤x-42͞43 in AD and transgenic mice (2-10). However, paradoxically, in human AD, the total amount of extracellular A␤ has little or no correlation with the amount of neuronal loss, which exceeds 50% in vulnerable regions of the cortex (11-13). Although quantitative stereological studies of neuron number in CA1 of APP23 (APPSw overexpressing) mice show a small decrement in neuronal number, no neuronal loss was detected in APP23 mice in the cortex (despite high levels of amyloid deposits) or in the hippocampus or cortex of PDAPP (APP V717F ), Tg2576 (APP KM670Ϫ1NL ), and PSAPP (APPSw ϫ PS1 M146L ) mice (14-17), arguing that, in contrast to in vitro data, A␤ deposits are not neurotoxic in vivo.A␤ deposits have a variety of morphologies, reflecting different amounts of fibrillar, ␤-pleated sheet conformation, ranging from ''diffuse'' deposits with little ␤-pleated sheet to dense core compact deposits that can be stained with dyes such as thioflavin S (ThioS) or Congo red; the extent of associated gliosis and synaptic loss is associated with the morphology of the A␤ deposits. We now test the hypothesis that only a subset of A␤ deposits is biologically toxic. In our approach we adopt a statistical physics method, i.e., the density map method, which is typically used in condensed matter physics to study local molecular organization, and which we have recently applied successfully to study the microcolumnar structure in brains of AD patients and patients with Lewy body dementia (18). We generalize the density map method to study the relationship between two different populations and then apply this method, which we call the cross-correlation density map (CCDM) method, to study the local neuronal organization surrounding A␤-immunoreactive deposits. We find evidence...

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.