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

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, 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 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 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.

Molecular crosstalk between cancer and neurodegenerative diseases

“…Unlike the role of p53 in cancer, the level and activity of p53 in neurodegenerative diseases have been shown to be substantially increased [93][94][95]. Brains of AD patients and model mice showed increased levels of p53 [96][97][98][99] and apoptotic neuronal cell death [100][101][102].…”

Current status and potential role of circular RNAs in neurological disorders

“…For example, several miRNAs play critical roles in regulation of β‐site amyloid precursor protein‐cleaving enzyme 1 (BACE1) levels, which mediates the rate‐limiting step for Aβ generation. Reduction in BACE1 has been reported as an effective strategy for prevention of Aβ aggregation (Jazvinscak Jembrek et al ). MiR‐107 and miR‐188‐3p, which both targeted the 3’‐untranslated region of BACE1 mRNA, were decreased in patients with AD.…”

Continuous tracking of startled Drosophila as an alternative to the negative geotaxis climbing assay

“…In addition, under neurodegenerative conditions, p53 increases oxidative stress by activation of pro-oxidant genes and repression of antioxidant genes (Chatoo, Abdouh, & Bernier, 2010). There is growing evidence for cooperation between Ab and p53 in the progression of Alzheimer's disease (Jazvin s cak Jembrek, Slade, Hof, & Simi c, 2018). Therefore, p53 is a potential target for treating various neurodegenerative disorders (Chang et al, 2012;Culmsee & Mattson, 2005), but little work has been done in vivo.…”