Phycocyanobilin Attenuates Oligomerized Amyloid β-Induced Neuronal Senescence Through SIRT1-Associated Mechanisms

Background/Objectives: Alzheimer’s disease (AD) is associated with amyloid-β (Aβ)-induced neuronal injury, oxidative stress, inflammatory activation, and cellular senescence. Phycocyanobilin (PCB), an algae nutritive compound, has shown neuroprotective potential, but whether it attenuates Aβ-induced neuronal senescence remains unclear. This study investigated the protective effects of PCB against Aβ1–42 oligomer-induced senescence-like alterations in SH-SY5Y cells and examined the involvement of sirtuin 1 (SIRT1) signaling. Methods: Differentiated SH-SY5Y cells were pretreated with PCB (50 μmol/L) in the presence or absence of EX527 (10 μmol/L) for 24 h, followed by exposure to Aβ1–42 oligomers (20 μmol/L) for an additional 24 h. Cell viability, lactate dehydrogenase (LDH) release, senescence-associated β-galactosidase (SA-β-gal) staining, senescence-associated heterochromatin foci (SAHF)-associated di-/tri-methylated histone H3 lysine 9 (H3K9me2/3) fluorescence, senescence-associated secretory phenotype (SASP)-related cytokines, phosphorylated histone H2AX (γ-H2AX) accumulation, Ki67 expression, p53/p21/p16 signaling, and silent information regulator 1 (SIRT1) expression and activity were assessed using cell counting kit-8 assay, LDH assay, enzyme-linked immunosorbent assay, immunofluorescence staining, quantitative real-time PCR analysis, Western blotting, and fluorometric enzymatic activity assay. Results: Aβ1–42 oligomers reduced cell viability, increased LDH release, promoted SA-β-gal positivity, enhanced H3K9me2/3 and γ-H2AX signals, elevated IL-1β, IL-6, and IL-8 levels, suppressed Ki67 expression, and upregulated p53, p21, and p16. PCB pretreatment markedly attenuated these cytotoxic, senescence-associated inflammatory, and DNA damage-related responses while restoring SIRT1 mRNA, protein expression, and enzymatic activity. EX527 partially reversed these protective effects. Conclusions: PCB attenuates Aβ1–42 oligomer-induced neuronal senescence-like alterations, at least partly through SIRT1-associated regulation, supporting its potential as a naturally derived anti-senescent neuroprotective compound for AD-related neuronal aging.