Neurotoxic effects of thioflavin S-positive amyloid deposits in transgenic mice and Alzheimer's disease

Abstract

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...

Age-related reduction in microcolumnar structure in area 46 of the rhesus monkey correlates with behavioral decline

“…Other methods that look at positional organization of neurons related to pathological conditions include early work by Benes and Bird (24), in which they applied computerassisted stereomorphometric analyses to neuron (x,y) locations and found that the anterior cingulate cortex of schizophrenic patients may contain aggregates of neurons, particularly in layer II. Also, Urbanc et al (25) used a crosscorrelation density-map method to study spatial relationships between the position and morphology of plaques with changes in neuronal architecture and revealed a focal neuronal toxicity associated with thioflavin S-positive plaque deposits in both AD and transgenic mice. Others, such as Casanova and Buxhoeveden, developed a method to quantify individually identified microcolumns, applying it to different human brain disorders (e.g., autism) (9)(10)(11)27), ʈ and to identify microcolumnar organization across species (28)(29).…”

Topological analyses in APP/PS1 mice reveal that astrocytes do not migrate to amyloid-β plaques

“…We next investigated whether the small repulsive force detected between astrocytes and plaques, strong enough to cause the nearest astrocytes to move a few microns, would disturb g(r) at heavier plaque loads. Whereas in APP/PS1 mice the percentage of brain covered by thioflavin or methoxy-labeled plaques can reach 1%, in humans it ranges between 0.8-6.0%, with an average of around 3% (11,12).…”

Two-photon imaging of synaptic plasticity and pathology in the living mouse brain

“…Fibrillar amyloid (A␤) deposition, one of the hallmarks of AD, is commonly associated with dystrophic neurites [41][42][43] and aberrant sprouting, [44][45][46][47] as well as increased curvature of dendritic processes. [48][49][50] However, only A␤ deposition in certain areas but not others correlates well with the degree of cognitive dysfunction. 46,[51][52][53][54][55] Furthermore, in transgenic mouse models of AD it has been shown that cognitive dysfunction may occur even before plaque deposition.…”