Tetracycline and its Analogues as Drugs Against Protein Aggregation and Amyloid Formation

Beeg, Marten (2010). Tetracycline and its Analogues as Drugs Against Protein Aggregation and Amyloid Formation. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000f22d

Abstract

With more than 20 million cases worldwide, Alzheimer’s disease (AD) is now the most common neurodegenerative disease. The two defining features of this disease are extracellular plaques and intracellular neurofibrillary tangles.

Although no AD treatment is available, researchers are making encouraging progress, including the use of small compounds which interact with amyloid-β (AB) and affect its self aggregation. Tetracyclines (TCs) are thought to have an anti-amyloidogenic effect on Aβ peptides. But the inconsistency of results in literature prompted us to further investigate the behaviour of various fragments of Aβ (Aβ1-40; Aβ1-42; guest-host-peptide Aβ 14-24) which were synthesised as depsi-peptides, in the presence of TCs. Due to their superior solubility the depsi-peptides allowed us to prepare reliable and seed-free stock solutions with reproducible properties. These allowed the preparation of different well-characterised Aβ1-42 species (initial state, oligomers, and fibrils), and to investigate the binding of Aβ ligands (Aβ monomers or TCs) to them or to study the modulation of the kinetics of fibril formation in the absence or presence of TCs, by Surface Plasmon Resonance (SPR), Circular Dichroism (CD) or Thioflavine-T (ThT) fluorescence.

Binding of Aβ1-42 monomers to immobilised fibrils could be well described by the “Dock and Lock” mechanism. TCs do not bind to the prepared Aβ species nor do they alter the highly reproducible kinetics of fibril formation or disaggregated preformed amyloidogenic structures. Consistent with the inactivity of TCs against amyloid β-sheet structures the treatment of APP/PS1tg mice with doxycycline (DC) after plaque formation did not change the plaque load in this mouse model compared to the control mice. These findings suggest that toxic Ap species other than these considered in this study or the common neuroprotection seen for TCs might be responsible for the positive effects in-vivo in previously reported studies.

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