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Title: From chromatin to protein synthesis : the role of glutamate, amyloid beta and tau in Alzheimer's disease
Author: Maina, Mahmoud Bukar
ISNI:       0000 0004 6422 9525
Awarding Body: University of Sussex
Current Institution: University of Sussex
Date of Award: 2017
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Alzheimer's disease (AD) is the most common form of dementia, which is characterised by extracellular Aβ plaques and intracellular neurofibrillary tangles, comprised of fibrils of Aβ42 and tau protein, respectively. A species of tau protein localised to the nucleus has been discovered, but its role in AD is still unclear. Glutamate excitotoxicity, oxidative stress, DNA damage, alteration of the chromatin and nucleolar stress are key features of AD. The early stages of the disease are characterised by minimal neurodegeneration and altered protein synthesis machinery. The culprit (s) and molecular link between these changes and the role of nuclear tau are unclear. This work utilised glutamate stress and Aβ42 oligomers to investigate the involvement of nuclear tau in the chromatin alteration, nucleolar dysfunction, and downstream protein synthesis impairment that occurs in AD. This revealed that glutamate stress in SHSY5Y neuroblastoma cells results in oxidative stress, a nuclear upsurge of phosphorylated tau and delocalisation of nucleolar tau, alongside, DNA damage, heterochromatin loss, nucleolar stress and protein synthesis inhibition, partly through eIF2α phosphorylation. Likewise, short incubation of SHSY5Y cells with Aβ42 oligomers led to significant oxidative stress, with gradual accumulation of nucleolar stress, which resulted in altered transcription and processing of 45S pre-rRNA and decrease in protein synthesis, without DNA damage. Although both glutamate and Aβ ultimately decreased protein synthesis, Aβ incubation led to an increase in heterochromatin formation and a reduction in RNA synthesis without DNA damage, pointing to a different mechanism of toxicity by the Aβ and glutamate stress. To characterise a nuclear role for tau, this work localised tau in the nucleolus and heterochromatin in the SHSY5Y cells and the human brain, where it associates with TIP5 - a key player in heterochromatin formation. Accordingly, tau knockdown destabilises the heterochromatin and increases rDNA transcription, indicating that tau is essential for silencing of the rDNA and heterochromatin stability, similar to TIP5. Overall, this thesis provides evidence that implicates glutamate and Aβ toxicity in some of the changes that occur in the disease and specifically implicates Aβ42 as a key culprit that drives changes in the early stage of the disease. It also reveals a new role for tau in the nucleus and points to its pathological involvement in AD.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QP0551 Proteins ; amino acids ; etc. ; RC0523 Alzheimer's disease