Withanolide a and asiatic acid modulate multiple targets associated with amyloid-β precursor protein processing and amyloid-β protein clearance

Sachin P. Patil, Sarah Maki, Santosh A. Khedkar, Alan C. Rigby, Christina Chan

Research output: Contribution to journalArticle

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Abstract

Alzheimer's disease (AD) is a progressive, neurodegenerative disease histochemically characterized by extracellular deposits of amyloid beta (Aβ) 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 Aβ pathways (BACE1, ADAM10, IDE, and NEP). BACE1 is a rate-limiting enzyme in the production of Aβ from amyloid-β precursor protein (AβPP), while ADAM10 is involved in non-amyloidogenic processing of AβPP. IDE and NEP are two of the prominent enzymes involved in effectively degrading Aβ. 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 Aβ 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.

LanguageEnglish (US)
Pages1196-1202
Number of pages7
JournalJournal of Natural Products
Volume73
Issue number7
DOIs
StatePublished - Jul 23 2010

Profile

Withanolides
Amyloid beta-Protein Precursor
Amyloid beta-Peptides
Alzheimer Disease
Processing
Amyloid
tau Proteins
Neurofibrillary Tangles
Neurodegenerative diseases
Enzymes
Neurodegenerative Diseases
Pathology
Therapeutics
Neurons
asiatic acid
Rats
Brain
Deposits
Molecules

ASJC Scopus subject areas

  • Complementary and alternative medicine
  • Molecular Medicine
  • Organic Chemistry
  • Analytical Chemistry
  • Pharmaceutical Science
  • Pharmacology
  • Drug Discovery

Cite this

Withanolide a and asiatic acid modulate multiple targets associated with amyloid-β precursor protein processing and amyloid-β protein clearance. / Patil, Sachin P.; Maki, Sarah; Khedkar, Santosh A.; Rigby, Alan C.; Chan, Christina.

In: Journal of Natural Products, Vol. 73, No. 7, 23.07.2010, p. 1196-1202.

Research output: Contribution to journalArticle

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