The involvement of Aβ42 and tau in nucleolar and protein synthesis machinery dysfunction

Maina, Mahmoud B, Bailey, Laura J, Doherty, Aidan J and Serpell, Louise C (2018) The involvement of Aβ42 and tau in nucleolar and protein synthesis machinery dysfunction. Frontiers in Cellular Neuroscience, 12 (220). pp. 1-13. ISSN 1662-5102

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Abstract

Alzheimer’s disease (AD) is the most common form of dementia and is distinguished from other dementias by observation of extracellular Amyloid-b (Ab) plaques and intracellular neurofibrillary tangles, comprised of fibrils of Ab and tau protein, respectively. At early stages, AD is characterized by minimal neurodegeneration, oxidative stress, nucleolar stress, and altered protein synthesis machinery. It is generally believed that Ab oligomers are the neurotoxic species and their levels in the AD brain correlate with the severity of dementia suggesting that they play a critical role in the pathogenesis of the disease. Here, we show that the incubation of differentiated human neuroblastoma cells (SHSY5Y) with freshly prepared Ab42 oligomers initially resulted in oxidative stress and subtle nucleolar stress in the absence of DNA damage or cell death. The presence of exogenous Ab oligomers resulted in altered nuclear tau levels as well as phosphorylation state, leading to altered distribution of nucleolar tau associated with nucleolar stress. These markers of cellular dysfunction worsen over time alongside a reduction in ribosomal RNA synthesis and processing, a decrease in global level of newly synthesized RNA and reduced protein synthesis. The interplay between Ab and tau in AD remains intriguing and Ab toxicity has been linked to tau phosphorylation and changes in localization. These findings provide evidence for the involvement of Ab42 effects on nucleolar tau and protein synthesis machinery dysfunction in cultured cells. Protein synthesis dysfunction is observed in mild cognitive impairment and early AD in the absence of significant neuronal death.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
School of Life Sciences > Neuroscience
School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups: Dementia Research Group
Depositing User: Louise Serpell
Date Deposited: 13 Aug 2018 13:51
Last Modified: 02 Jul 2019 14:51
URI: http://sro.sussex.ac.uk/id/eprint/77778

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