Congo red and thioflavin‐T analogs detect Aβ oligomers

Abstract

Several small molecule ligands for amyloid‐β (Aβ) fibrils deposited in brain have been developed to facilitate radiological diagnosis of Alzheimer’s disease (AD). Recently, the build‐up of Aβ oligomers (AβO) in brain has been recognized as an additional hallmark of AD and may play a more significant role in early stages. Evidence suggests that quantitative assessment of AβO would provide a more accurate index of therapeutic effect of drug trials. Therefore, there is an urgent need to develop methods for efficient identification as well as structural analysis of AβO. We found that some well established amyloid ligands, analogs of Congo red and thioflavin‐T (ThT), bind AβO with high affinity and detect AβO in vitro and in vivo. Binding studies revealed the presence of binding sites for Congo red‐ and thioflavin‐T‐analogs on AβO. Furthermore, these ligands can be used for imaging intracellular AβO in living cells and animals and as positive contrast agent for ultrastructural imaging of AβO, two applications useful for structural analysis of AβO in cells. We propose that by improving the binding affinity of current ligands, in vivo imaging of AβO is feasible by a ‘signal subtraction’ procedure. This approach may facilitate the identification of individuals with early AD.

Atorvastatin prevents amyloid-β peptide oligomer-induced synaptotoxicity and memory dysfunction in rats through a p38 MAPK-dependent pathway

“…It has been found that AβOs are highly neurotoxic and kill hippocampal neurons at nanomolar concentrations [27] . AβOs accumulate at synaptic sites [36] , where they bind to postsynaptic density complexes with a high affinity [14,37] and disrupt synaptic plasticity [38,39] . This provides strong evidence for direct AβO toxicity to post-synaptic components, a possible physical basis of synaptic dysfunction in AD.…”

Vitamin D-binding protein interacts with Aβ and suppresses Aβ-mediated pathology

“…The SPR protocol for the study of real-time direct binding of Ab and DBP was essentially similar to that described previously 47,48 and was performed using a Biacore X-100 (GE Healthcare). The CM5 sensor chip (GE Healthcare) was preactivated by a mixture of N-hydroxysuccinimide and N-ethyl-N'-(dimethylaminopropyl) carbodiimide.…”

Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1ΔE9 mouse model of Alzheimer's disease

“…First, we assessed the areas and distribution of aggregate positives with BSB, a derivative of Congo Red that is more prone to stain oligomers than fibrils. 29 Brain sections from wild-type mice, APP-PS1 control, APP-PS1 lithium-and APP-PS1 rosiglitazone-treated mice were stained with BSB and analyzed for area fraction and plaque density (Figure 8a-f). This analysis showed a reduction in the positive area of BSB staining in the hippocampus by both treatments (Figure8h).…”

“…24,26,27 BSB ([(trans,trans)-1-Bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)-styrylbenzene) staining was performed as described earlier. 28,29 Briefly, the mounted sections were dehydrated and rehydrated in graded ethanol solutions, stained with BSB solution (200 mM) in 50% ethanol for 30 min, washed with saturated solution of lithium carbonate, differentiated with 50% ethanol and covered using a fluorescentmounting medium.…”