Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer's disease neurons: Implications for mitochondrial dysfunction and neuronal damage

Maria Manczak, P (Hemachandra) Reddy

    Research output: Contribution to journalArticle

    137 Citations (Scopus)

    Abstract

    We recently reported increased mitochondrial fission and decreased fusion, increased amyloid beta (Aβ) interaction with the mitochondrial fission protein Drp1, increased mitochondrial fragmentation, impaired axonal transport of mitochondria and synaptic degeneration in neurons affected by AD. In the present study, we extended our previous investigations to determine whether phosphorylated tau interacts with Drp1 and to elucidate mitochondrial damage in the progression of AD. We also investigated GTPase activity, which is critical for mitochondrial fragmentation, in postmortem brain tissues from patients with AD and brain tissues from APP, APP/PS1 and 3XTg.AD mice. Using co-immunoprecipitation and immunofluorescence analyses, for the first time, we demonstrated the physical interaction between phosphorylated tau and Drp1. Mitochondrial fission-linked GTPase activity was significantly elevated in the postmortem frontal cortex tissues from AD patients and cortical tissues from APP, APP/PS1 and 3XTg.AD mice. On the basis of these findings, we conclude that Drp1 interacts with Aβ and phosphorylated tau, likely leading to excessive mitochondrial fragmentation, and mitochondrial and synaptic deficiencies, ultimately possibly leading to neuronal damage and cognitive decline. Treatment designed to reduce the expression of Drp1, Aβ and/or phosphorylated tau may decrease the interaction between Drp1 and phosphorylated tau and the interaction between Drp1 and Aβ, conferring protection to neurons from toxic insults of excessive Drp1, Aβ and/or phosphorylated tau.

    Original languageEnglish (US)
    Article numberdds072
    Pages (from-to)2538-2547
    Number of pages10
    JournalHuman Molecular Genetics
    Volume21
    Issue number11
    DOIs
    StatePublished - Jun 2012

    Fingerprint

    Mitochondrial Dynamics
    Mitochondrial Proteins
    Alzheimer Disease
    Neurons
    GTP Phosphohydrolases
    Nerve Degeneration
    Axonal Transport
    Poisons
    Brain
    Frontal Lobe
    Immunoprecipitation
    Amyloid
    Fluorescent Antibody Technique
    Mitochondria

    ASJC Scopus subject areas

    • Genetics
    • Genetics(clinical)
    • Molecular Biology

    Cite this

    Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer's disease neurons : Implications for mitochondrial dysfunction and neuronal damage. / Manczak, Maria; Reddy, P (Hemachandra).

    In: Human Molecular Genetics, Vol. 21, No. 11, dds072, 06.2012, p. 2538-2547.

    Research output: Contribution to journalArticle

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