Δ133p53α-mediated inhibition of astrocyte senescence and neurotoxicity as a possible therapeutic approach for neurodegenerative diseases.

Abstract

Non-neuronal glial cells in the brain, such as astrocytes, play essential roles in maintaining the functional integrity of neuronal cells. A growing body of evidence suggests that cellular senescence of astrocytes, characterized by loss of proliferative potential and secretion of neurotoxic cytokines, makes significant contribution to neurotoxicity in Alzheimer's disease and a wide range of other neurodegenerative diseases. This review discusses the beneficial effects of Δ133p53α, a natural p53 protein isoform that inhibits p53-mediated cellular senescence, thereby protecting astrocytes from senescence, highlights its potential as a therapeutic target, and underscores the need for continued research in this area. Both in senescent human astrocytes in culture, whether induced by replicative exhaustion, irradiation or exposure to amyloid-β, and in brain tissues with increased senescent astrocytes from patients with Alzheimer's disease, the expression levels of endogenous Δ133p53α protein were consistently and significantly reduced. The lentiviral vector-driven expression of Δ133p53α protected cultured human astrocytes from cellular senescence and neurotoxic secretory phenotype, leading to their cellular reprogramming to a neuroprotective state associated with neurotrophic growth factors. We thus propose that Δ133p53α is worth testing as a therapeutic target that can be enhanced in a wide range of neurodegenerative diseases with accumulated senescent astrocytes, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and chronic traumatic encephalopathy due to traumatic brain injury. We hypothesize that a Δ133p53α-mediated cellular reprogramming approach and a senolytic or senomorphic approach, both targeting non-neuronal cells, may be complementary with each other, and may cooperate with neuron-protecting or amyloid-β-targeting therapies currently in use.