Journal
MOLECULAR PHARMACEUTICS
Volume 9, Issue 3, Pages 458-469Publisher
AMER CHEMICAL SOC
DOI: 10.1021/mp2005627
Keywords
phosphorus dendrimers; beta-amyloid; MAP-Tau protein; fibril formation; amyloid peptide; aggregation; ThT assay; ThS assay; cytotoxicity
Funding
- project Biological Properties and Biomedical Applications of Dendrimers
- Foundation for Polish Science
- European Regional Development Found
- EU
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Alzheimer's disease (AD) is characterized by pathological aggregation of beta-amyloid peptides and MAP-Tau protein. beta-Amyloid (A beta) is a peptide responsible for extracellular Alzheimer's plaque formation. Intracellular MAP-Tau aggregates appear as a result of hyperphosphorylation of this cytoskeletal protein. Small, oligomeric forms of A beta are intermediate products that appear before the amyloid plaques are formed. These forms are believed to be most neurotoxic. Dendrimers are highly branched polymers, which may find an application in regulation of amyloid fibril formation. Several biophysical and biochemical methods, like circular dichroism (CD), fluorescence intensity of thioflavin T and thioflavin S, transmission electron microscopy, spectrofluorimetry (measuring quenching of intrinsic peptide fluorescence) and MTT-cytotoxicity assay, were applied to characterize interactions of cationic phosphorus-containing dendrimers of generation 3 and generation 4 (CPDG3, CPDG4) with the fragment of amyloid peptide (A beta(1-28)) and MAP-Tau protein. We have demonstrated that CPDs are able to affect beta-amyloid and MAP-Tau aggregation processes. A neuro-2a cell line (N2a) was used to test cytotoxicity of formed fibrils and intermediate products during the A beta(1-28) aggregation. It has been shown that CPDs might have a beneficial effect by reducing the system toxicity. Presented results suggest that phosphorus dendrimers may be used in the future as agents regulating the fibrilization processes in Alzheimer's disease.
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