PAmyloid aggregation blockers

Alternate strategies to reduce the Ab plaque load include: (1) inhibition of the formation of Ab dimers and their aggregation into b-pleated sheets; and (2) clearing of Ab deposits by immune surveillance. Only small molecule-based strategies will be reviewed here; however, both passive and active immunization strategies to facilitate brain Ab clearance, e.g., AN-1792, have shown success in animal models. Clinical exposure with AN-1792 resulted in significant adverse events with second-generation vaccines, e.g., AAB001, under evaluation.

Ab polymerization is dependent on pH, temperature, and time, with a number of cofactors, e.g., heparin sulfates, glycosaminoglycans, and metals (e.g., Cu2 +, Zn2 +, Fe3 +, Al3 +), modulating the process. Linear peptides, 5-7 amino acids in length, corresponding to the central hydrophobic region of the Ab sequence inhibit Ab fibril formation. Specifically, peptides with a proline residue preclude b-sheet formation as well as those that contain Phe in the second and Leu in the third position.47 No peptide-based inhibitors of Ab aggregation are in clinical trials.

Metal chelators have also been targeted, as metal ions form intermolecular bridges with the histidine residues of adjacent Ab peptides and can stabilize aggregates. Clioquinol (PBT-1: 34), an antimalarial agent, selectively chelates Zn2 + and Cu2 +, avoiding nonspecific depletion of tissue metal ions.48 It reduced brain Ab deposition in genetically engineered mice and increased the fraction of solubilized Ab, thus reducing the total brain Ab burden. Whether increased soluble Ab is a positive event is controversial as soluble Ab has toxic effects. Additionally, the safety profile of clioquinol is questionable as it reduces vitamin B12, an action that may be related to subacute myelooptic neuropathy seen in patients taking clioquinol as an antimalarial. Nonetheless, clioquinol advanced to clinical trials, with patients being supplemented with vitamin B12 and folic acid. In a 36-week phase II dose escalation study in AD patients, clioquinol lowered plasma Ab42 levels, improving performance on the ADAS-cog in severely affected patients, although the behavioral improvement was not apparent at the 6-month time point.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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