Variecolactone, a Natural PDE4 Inhibitor from Marine-Derived Talaromyces sp. ZSD-1, Alleviates Amyloid-β Accumulation and mtDNA Dyshomeostasis via cAMP-PKA-CREB Signaling Pathway

= 2.302 μM) with minimal activity against other PDE subtypes. Further mechanical investigation revealed that VLT treatment elevated cAMP and p-CREB levels, reduced amyloid-β (Aβ) accumulation, promoted synaptic function, and ameliorated mitochondrial fragmentation, along with mtDNA homeostasis in the AD cell model. Moreover, under conditions of mtDNA depletion or Drp1 overexpression, VLT exerted neuroprotective effects and maintained mtDNA homeostasis via the cAMP-PKA-CREB signaling pathway. These results demonstrate that PDE4 inhibition by VLT represents a promising therapeutic strategy for AD and related neurodegenerative disorders.