Development of a new distyrylbenzene-derivative amyloid-ß-aggregation and fibril formation inhibitor.

Several new amyloid-ß (Aß) aggregation inhibitors were synthesized according to our theory that a hydrophilic moiety could be attached to the Aß-recognition unit for the purpose of preventing amyloid plaque formation. A distyrylbenzene-derivative, DSB(EEX)(3), which consider the Aß recognition unit (DSB, 1,4-distyrylbenzene) and expected to bind to amyloid fibrils (ß-sheet structure), was combined with the hydrophilic aggregation disrupting element (EEX) (E, Glu; X, 2-(2-(2-aminoethoxy)ethoxy)acetic acid). This DSB(EEX)(3) compound, compared to several others synthesized similarly, was found to be the most active for reducing Aß toxicity toward IMR-32 human neuroblastoma cells. Moreover, its inhibition of Aß-aggregation or fibril formation was directly confirmed by transmission electron microscopy and atomic force microscopy. These results suggest that the Aß aggregation inhibitor DSB(EEX)(3) disrupts clumps of Aß protein and is a likely candidate for drug development to treat Alzheimer's disease.

Butyrylcholinesterase inhibitors ameliorate cognitive dysfunction induced by amyloid-ß peptide in mice.

The cholinesterase inhibitor, rivastigmine, ameliorates cognitive dysfunction and is approved for the treatment of Alzheimer's disease (AD). Rivastigmine is a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE); however, the impact of BuChE inhibition on cognitive dysfunction remains to be determined. We compared the effects of a selective BuChE inhibitor, N1-phenethyl-norcymserine (PEC), rivastigmine and donepezil (an AChE-selective inhibitor) on cognitive dysfunction induced by amyloid-ß peptide (Aß(1-40)) in mice. Five-week-old imprinting control region (ICR) mice were injected intracerebroventricularly (i.c.v.) with either Aß(1-40) or the control peptide Aß(40-1) on Day 0, and their recognition memory was analyzed by a novel object recognition test. Treatment with donepezil (1.0mg/kg), rivastigmine (0.03, 0.1, 0.3mg/kg) or PEC (1.0, 3.0mg/kg) 20min prior to, or immediately after the acquisition session (Day 4) ameliorated the Aß(1-40) induced memory impairment, indicating a beneficial effect on memory acquisition and consolidation. In contrast, none of the investigated drugs proved effective when administrated before the retention session (Day 5). Repeated daily administration of donepezil, rivastigmine or PEC, on Days 0-3 inclusively, ameliorated the cognitive dysfunction in Aß(1-40) challenged mice. Consistent with the reversal of memory impairments, donepezil, rivastigmine or PEC treatment significantly reduced Aß(1-40) induced tyrosine nitration of hippocampal proteins, a marker of oxidative damage. These results indicate that BuChE inhibition, as well as AChE inhibition, is a viable therapeutic strategy for cognitive dysfunction in AD.