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The interactions of p53 with tau and Aß represent potential therapeutic targets for Alzheimer’s disease

Jazvinšćak Jembrek, Maja; Slade, Neda; Hof, Patrick R.; Šimić, Goran (2018) The interactions of p53 with tau and Aß represent potential therapeutic targets for Alzheimer’s disease. Progress in Neurobiology, 168 . pp. 104-127. ISSN 0555-4047

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Abstract

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-β peptides (Aβ) 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 Aβ 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, predomimantly 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 Aβ 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 Aβ 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/Aβ 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 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. Keywords: p53, Aβ, tau, oxidative stress, neuronal apoptosis, Alzheimer's disease

Item Type: Article
Additional Information: This work was supported in part by the Croatian Science Foundation under the projects IP-2014-09-9730 to MJJ and GS, and IP-11-2013-1615 to MJJ and NS. GS is also supported by the European Union through the European Regional Development Fund, Operational Programme Competitiveness and Cohesion, grant agreement no. KK.01.1.1.01.0007, CoRE - Neuro. PRH is supported in part by NIH grant P50 AG005138.
Uncontrolled Keywords: p53; Aβ; Tau; Oxidative stress; Neuronal apoptosis; Alzheimer's disease
Subjects: BIOMEDICINE AND HEALTHCARE
BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences
BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences > Neuroscience
BIOMEDICINE AND HEALTHCARE > Clinical Medical Sciences
BIOMEDICINE AND HEALTHCARE > Clinical Medical Sciences > Neurology
Divisions: Division of Molecular Medicine
Projects:
Project titleProject leaderProject codeProject type
Hiperfosforilacija, agregacija i transsinaptički prijenos tau proteina u Alzheimerovoj bolesti: analiza likvora i ispitivanje potencijalnih neuroprotektivnih spojeva-ALZTAUPROTECTGoran ŠimićIP-2014-09-9730HRZZ
Otkrivanje novih proteinskih interakcija kao podloga za nove pristupe liječenju melanoma čovjeka-ProNetMelNeda SladeIP-2013-11-1615HRZZ
Depositing User: Maja Jazvinšćak Jembrek
Date Deposited: 20 Nov 2019 14:46
Last Modified: 25 Nov 2019 00:15
URI: http://fulir.irb.hr/id/eprint/5093
DOI: 10.1016/j.pneurobio.2018.05.001

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