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The involvement of Aß42 and tau in nucleolar and protein synthesis machinery dysfunction
journal contribution
posted on 2023-06-09, 14:30 authored by Mahmoud MainaMahmoud Maina, Laura BaileyLaura Bailey, Aidan DohertyAidan Doherty, Louise SerpellLouise SerpellAlzheimer’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.
History
Publication status
- Published
File Version
- Published version
Journal
Frontiers in Cellular NeuroscienceISSN
1662-5102Publisher
Frontiers MediaExternal DOI
Issue
220Volume
12Page range
1-13Department affiliated with
- Biochemistry Publications
Research groups affiliated with
- Dementia Research Group Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2018-08-13First Open Access (FOA) Date
2018-08-13First Compliant Deposit (FCD) Date
2018-08-10Usage metrics
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