期刊
PROGRESS IN NEUROBIOLOGY
卷 168, 期 -, 页码 104-127出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pneurobio.2018.05.001
关键词
p53; A beta; Tau; Oxidative stress; Neuronal apoptosis; Alzheimer's disease
资金
- Croatian Science Foundation [IP-2014-09-9730, IP-11-2013-1615]
- European Union through the European Regional Development Fund, Operational Programme Competitiveness and Cohesion [KK.01.1.1.01.0007]
- NIH [P50 AG005138]
Alzheimer's disease (AD), the most common progressive neurodegenerative disorder, is characterized by severe cognitive decline and personality changes as a result of synaptic and neuronal loss. The defining clinicopathological hallmarks of the disease are deposits of amyloid precursor protein (APP)-derived amyloid-beta peptides (A beta) in the brain parenchyma, and intracellular aggregates of truncated and hyperphosphorylated tau protein in neurofibrillary tangles (NFT). At the cellular and molecular levels, many intertwined pathological mechanisms that relate A beta and tau pathology with a transcription factor p53 have been revealed. p53 is activated in response to various stressors that threaten genomic stability. Depending on damage severity, it promotes neuronal death or survival, predominantly via transcription-dependent mechanisms that affect expression of apoptosis-related target genes. Levels of p53 are enhanced in the AD brain and maintain sustained tau hyperphosphorylation, whereas intracellular All directly contributes to p53 pool and promotes downstream p53 effects. The review summarizes the role of p53 in neuronal function, discusses the interactions of p53, tau, and A beta in the normal brain and during the progression of AD pathology, and considers the impact of the most prominent hereditary risk factors of AD on p53/tau/A beta interactions. A better understanding of this intricate interplay would provide deeper insight into AD pathology and might offer some novel therapeutic targets for the improvement of treatment options. In this regard, drugs and natural compounds targeting the p53 pathway are of growing interest in neuroprotection as they may represent promising therapeutic approaches in the prevention of oxidative stress-dependent pathological processes underlying AD.
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