Withanolide A and asiatic acid modulate multiple targets associated with amyloid-beta precursor protein processing and amyloid-beta protein clearance.

Alzheimer's disease (AD) is a progressive, neurodegenerative disease histochemically characterized by extracellular deposits of amyloid beta (Abeta) protein and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. AD is considered to be a complex, multifactorial syndrome, with numerous causal factors contributing to its pathogenesis. Thus, for any novel therapeutic molecule to have a "disease-modifying" effect on AD, it must be able to modulate multiple, synergistic targets simultaneously. In this context, we have studied two compounds of plant origin [withanolide A (1) and asiatic acid (2)] for their potential activities against multiple targets associated with Abeta pathways (BACE1, ADAM10, IDE, and NEP). BACE1 is a rate-limiting enzyme in the production of Abeta from amyloid-beta precursor protein (AbetaPP), while ADAM10 is involved in non-amyloidogenic processing of AbetaPP. IDE and NEP are two of the prominent enzymes involved in effectively degrading Abeta. It was found that both 1 and 2 significantly down-regulated BACE1 and also up-regulated ADAM10 in primary rat cortical neurons. In addition, 1 significantly up-regulated IDE levels, which may help in degrading excess Abeta from the AD brain. On the basis of the data obtained, the two multifunctional compounds may prove valuable in developing novel, effective therapeutics for the prevention and treatment of AD-associated amyloid pathology.