Alzheimer's Drug PBT2 Interacts with the Amyloid β 1-42 Peptide Differently than Other 8-Hydroxyquinoline Chelating Drugs

The though Alzheimer's disease (AD) was first described over a century ago, it remains the leading cause of age-related dementia. Innumerable changes have been linked to the pathology of AD; however, there remains much discord regarding which might be the initial cause of the disease. The amyloid cascade hypothesis proposes that the amyloid beta (A beta) peptide is central to disease pathology, which is supported by elevated A beta levels in the brain before the development of symptoms and correlations of amyloid burden with cognitive impairment. The metals hypothesis proposes a role for metal ions such as iron, copper, and zinc in the pathology of AD, which is supported by the accumulation of these metals within amyloid plaques in the brain. Metals have been shown to induce aggregation of A beta, and metal ion chelators have been shown to reverse this reaction in vitro. 8-Hydroxyquinoline-based chelators showed early promise as anti-Alzheimer's drugs. Both 5-chloro-7-iodo-8-hydroxyquinoline (CQ) and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline (PBT2) underwent unsuccessful clinical trials for the treatment of AD. To gain insight into the mechanism of action of 8HQs, we have investigated the potential interaction of CQ, PBT2, and 5,7-dibromo-8-hydroxyquinoline (B2Q) with Cu(II)-bound A beta(1-42) using X-ray absorption spectroscopy (XAS), high energy resolution fluorescence detected (HERFD) XAS, and electron paramagnetic resonance (EPR). By XAS, we found CQ and B2Q sequestered similar to 83% of the Cu(II) from A beta(1-42), whereas PBT2 sequestered only similar to 59% of the Cu(II) from A beta(1-42), suggesting that CQ and B2Q have a higher relative Cu(II) affinity than PBT2. From our EPR, it became clear that PBT2 sequestered Cu(II) from a heterogeneous mixture of Cu(II)A beta(1-42) species in solution, leaving a single Cu(II)A beta(1-42) species. It follows that the Cu(II) site in this Cu(II)A beta(1-42) species is inaccessible to PBT2 and may be less solvent-exposed than in other Cu(II)A beta(1-42) species. We found no evidence to suggest that these 8HQs form ternary complexes with Cu(II)A beta(1-42).

Automated summary

Alzheimer's disease is a major cause of age-related dementia with an unclear initial cause. The amyloid cascade hypothesis suggests that the amyloid beta peptide plays a central role in disease pathology, while the metals hypothesis proposes a role for metal ions in Alzheimer's pathology.