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Publication - Dr James Hodge

    Alzheimer’s Disease Associated Genes Ankyrin and Tau Cause Shortened Lifespan and Memory Loss in Drosophila

    Citation

    Higham, J, Malik, BR, Buhl, E, Dawson, J, Ogier, AS, Lunnon, K & Hodge, J, 2019, ‘Alzheimer’s Disease Associated Genes Ankyrin and Tau Cause Shortened Lifespan and Memory Loss in Drosophila’. Frontiers in Cellular Neuroscience, vol 13.

    Abstract

    Alzheimer's disease (AD) is the most common form of dementia and is characterized by intracellular neurofibrillary tangles of hyperphosphorylated Tau, including the 0N4R isoform and accumulation of extracellular amyloid beta (Aβ) plaques. However, less than 5% of AD cases are familial, with many additional risk factors contributing to AD including aging, lifestyle, the environment and epigenetics. Recent epigenome-wide association studies (EWAS) of AD have identified a number of loci that are differentially methylated in the AD cortex. Indeed, hypermethylation and reduced expression of the
    Ankyrin 1 (
    ANK1) gene in AD has been reported in the cortex in numerous different post-mortem brain cohorts. Little is known about the normal function of ANK1 in the healthy brain, nor the role it may play in AD. We have generated
    Drosophila models to allow us to functionally characterize
    Drosophila Ank2, the ortholog of human
    ANK1 and to determine its interaction with human Tau and Aβ. We show expression of human Tau 0N4R or the oligomerizing Aβ 42 amino acid peptide caused shortened lifespan, degeneration, disrupted movement, memory loss, and decreased excitability of memory neurons with co-expression tending to make the pathology worse. We find that
    Drosophila with reduced neuronal
    Ank2 expression have shortened lifespan, reduced locomotion, reduced memory and reduced neuronal excitability similar to flies overexpressing either human Tau 0N4R or Aβ42. Therefore, we show that the mis-expression of
    Ank2 can drive disease relevant processes and phenocopy some features of AD. Therefore, we propose targeting human ANK1 may have therapeutic potential. This represents the first study to characterize an AD-relevant gene nominated from EWAS.

    Full details in the University publications repository