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.

    Original languageEnglish (US)
    Pages (from-to)1196-1202
    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
    Acids
    Supravalvular Aortic Stenosis
    Enzymes
    Accessory Nerve
    tau Proteins
    Neurofibrillary Tangles
    Amyloid
    Neurodegenerative Diseases
    Pathology
    Neurons
    Brain
    Bis(4-Methyl-1-Homopiperazinylthiocarbonyl)disulfide
    Staphylococcal Pneumonia
    Nitrogenase
    Submandibular Gland
    Deposits

    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

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

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

    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.",
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