Inhibition of serine palmitoyltransferase reduces Aβ and tau hyperphosphorylation in a murine model: a safe therapeutic strategy for Alzheimer's disease

Hirosha Geekiyanage, Aditi Upadhye, Christina Chan

    Research output: Contribution to journalArticle

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    Abstract

    The contribution of the autosomal dominant mutations to the etiology of familial Alzheimer's disease (AD) is well characterized. However, the molecular mechanisms contributing to sporadic AD are less well understood. Increased ceramide levels have been evident in AD patients. We previously reported that increased ceramide levels, regulated by increased serine palmitoyltransferase (SPT), directly mediate amyloid β (Aβ) levels. Therefore, we inhibited SPT in an AD mouse model (TgCRND8) through subcutaneous administration of L-cylcoserine. The cortical Aβ42 and hyperphosphorylated tau levels were down-regulated with the inhibition of SPT/ceramide. Positive correlations were observed among cortical SPT, ceramide, and Aβ42 levels. With no evident toxic effects observed, inhibition of SPT could be a safe therapeutic strategy to ameliorate the AD pathology. We previously observed that miR-137, -181c, -9, and 29a/b post-transcriptionally regulate SPT levels, and the corresponding miRNA levels in the blood sera are potential diagnostic biomarkers for AD. Here, we observe a negative correlation between cortical Aβ42 and sera Aβ42, and a positive correlation between cortical miRNA levels and sera miRNA levels suggesting their potential as noninvasive diagnostic biomarkers.

    Original languageEnglish (US)
    Pages (from-to)2037-2051
    Number of pages15
    JournalNeurobiology of Aging
    Volume34
    Issue number8
    DOIs
    StatePublished - Aug 2013

    Profile

    Serine C-Palmitoyltransferase
    Amyloid
    Alzheimer Disease
    Inhibition (Psychology)
    Ceramides
    MicroRNAs
    Serum
    Biological Markers
    Poisons
    Pathology
    Mutation

    Keywords

    • Alzheimer's disease
    • Amyloid beta
    • Inhibition
    • MicroRNA
    • Serine palmitoyltransferase
    • Tau hyperphosphorylation

    ASJC Scopus subject areas

    • Clinical Neurology
    • Neuroscience(all)
    • Aging
    • Developmental Biology
    • Geriatrics and Gerontology

    Cite this

    Inhibition of serine palmitoyltransferase reduces Aβ and tau hyperphosphorylation in a murine model : a safe therapeutic strategy for Alzheimer's disease. / Geekiyanage, Hirosha; Upadhye, Aditi; Chan, Christina.

    In: Neurobiology of Aging, Vol. 34, No. 8, 08.2013, p. 2037-2051.

    Research output: Contribution to journalArticle

    Geekiyanage, Hirosha; Upadhye, Aditi; Chan, Christina / Inhibition of serine palmitoyltransferase reduces Aβ and tau hyperphosphorylation in a murine model : a safe therapeutic strategy for Alzheimer's disease.

    In: Neurobiology of Aging, Vol. 34, No. 8, 08.2013, p. 2037-2051.

    Research output: Contribution to journalArticle

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