Amyloid-like plaques are characteristic lesions defining the neuropathology of
Alzheimer's disease (AD). The size and density of these plaques are closely associated with
cognitive decline. To combat this disease, the few
therapies that are available rely on drugs that increase neurotransmission; however, this approach has had limited success as it has simply slowed an imminent decline and failed to target the root cause of AD.
Amyloid-like deposits result from aggregation of the Aβ
peptide, and thus, reducing
amyloid burden by preventing Aβ aggregation represents an attractive approach to improve the therapeutic arsenal for AD. Recent studies have shown that the
natural product curcumin is capable of crossing the blood-brain barrier in the CNS in sufficient quantities so as to reduce
amyloid plaque burden. Based upon this bioactivity, we hypothesized that
curcumin presents molecular features that make it an excellent lead compound for the development of more effective inhibitors of Aβ aggregation. To explore this hypothesis, we screened a library of
curcumin analogs and identified structural features that contribute to the anti-oligomerization activity of
curcumin and its analogs. First, at least one enone group in the spacer between aryl rings is necessary for measureable anti-Aβ aggregation activity. Second, an unsaturated
carbon spacer between aryl rings is essential for inhibitory activity, as none of the saturated
carbon spacers showed any margin of improvement over that of native
curcumin. Third, methoxyl and
hydroxyl substitutions in the meta- and para-positions on the aryl rings appear necessary for some measure of improved inhibitory activity. The best lead inhibitors have either their meta- and para-substituted methoxyl and
hydroxyl groups reversed from that of
curcumin or methoxyl or
hydroxyl groups placed in both positions. The simple substitution of the para-hydroxy group on
curcumin with a methoxy substitution improved inhibitor function by 6-7-fold over that measured for
curcumin.