Neuroprotective Effects of Phosphodiesterase Inhibitors on Sestrin-2 (SESN2) Expression and Autophagy in Alzheimer's Disease Model
Abstract
OBJECTIVE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and the accumulation of amyloid-beta (Aβ) peptides. The neuroprotective protein sestrin-2 (SESN2) has been implicated in the cellular response to oxidative stress and autophagy, processes that are disrupted in AD. This study explores the effects of phosphodiesterase inhibitors (PDEIs) roflumilast (RF), rolipram (ROL), and tadalafil (TAD) on SESN2 expression and autophagy in Aβ25-35-treated hippocampal neuron (HT-22) cell cultures.
METHODS: The HT-22 cells were exposed to 5 μM Aβ25-35 for 32 hours to induce AD-like pathology. Concurrently, cells were treated with PDEIs (ROL: 10 μM, TAD: 1.53 nM, RF: 5 μM). The SESN2, autophagy-related proteins (ATG5, beclin-1 (BECN1), LC3II), adenosine monophosphate-activated protein kinase (AMPK), and mTOR expression levels were analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot techniques.
RESULTS: The Aβ25-35 exposure significantly increased SESN2 expression and altered the levels of autophagy-related proteins, resulting in decreased active AMPK (phosphorylated (p)-AMPK) and increased active mTOR (phosphorylated (p)-mTOR). Treatment with PDEIs reduced the elevated SESN2 expression and modulated autophagy-related protein levels, enhancing ATG5, BECN1, and LC3II expression. The PDEIs also restored p-AMPK levels and reduced p-mTOR expression in Aβ25-35-treated cells.
CONCLUSION:…
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