Small molecules as therapeutic drugs for Alzheimer's disease

Darryll M.A. Oliver, P. Hemachandra Reddy

    Research output: Contribution to journalReview article

    15 Scopus citations

    Abstract

    Mitochondrial dysfunction is a central protagonist of Alzheimer's disease (AD) pathogenesis. Mitochondrial dysfunction stems from various factors including mitochondrial DNA damage and oxidative stress from reactive oxygen species, membrane and ionic gradient destabilization, and interaction with toxic proteins such as amyloid beta (Aβ). Therapeutic drugs such as cholinesterase and glutamate inhibitors have proven to improve synaptic neurotransmitters, but do not address mitochondrial dysfunction. Researchers have demonstrated that oxidative damage may be reduced by increasing endogenous antioxidants, and/or increasing exogenous antioxidants such as vitamin C & E, beta-carotene and glutathione. Nonetheless, as AD pathology intensifies, endogenous antioxidants are overwhelmed, and exogenous antioxidants are unable to reach neuronal mitochondria as they are blocked by the blood brain barrier. Current therapeutic methods however include novel usage of lipophilic phosphonium cation bound to antioxidants, to effect neuronal mitochondria targeted activity. Mitochondria targeted MitoQ, MitoVitE, MitoTempo, MitoPBN and MCAT concentrate within mitochondria where they scavenge free-radicals, and augment mitochondrial dysfunction. Additional molecules include Szeto-Schiller (SS) peptides which target stability of the inner mitochondrial membrane, and DDQ molecule capable of improving bioenergetics and reduce mitochondrial fragmentation. This article discusses advantages and disadvantages of small molecules, their ability to mitigate Aβ induced damage, and ability to ameliorate synaptic dysfunction and cognitive loss.

    Original languageEnglish (US)
    Pages (from-to)47-62
    Number of pages16
    JournalMolecular and Cellular Neuroscience
    Volume96
    DOIs
    StatePublished - Apr 2019

    Keywords

    • Aging
    • Alzheimer's disease
    • Disease
    • Huntington's disease
    • Mitochondria-targeted molecules
    • Mitochondrial dysfunction
    • Mitophagy and mitochondrial dynamics
    • Oxidative stress
    • Parkinson

    ASJC Scopus subject areas

    • Molecular Biology
    • Cellular and Molecular Neuroscience
    • Cell Biology

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