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

Overview

1. Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570225, China; (T.F.); (Y.S.); (Z.Y.); (J.Z.); (L.H.)

Abstract

Alzheimer’s disease (AD) is characterized by amyloid-β deposition, neuroinflammation, and mitochondrial dysfunction. Phosphodiesterase 4 (PDE4), a key regulator of cyclic nucleotides in neurons, represents a promising therapeutic target for AD. In this study, we performed a PDE4 inhibition-guided screen of an in-house marine natural product library derived from marine fungi, leading to the identification of a sesterterpenoid variecolactone (VLT) as a potent PDE4 inhibitor. VLT exhibited selective PDE4D inhibition (IC50 = 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.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• rcsb.org/pdb/home, at PDB; found in the text, “2.10. Molecular Docking”

Data Availability Statement

The data presented in this study is available within the article or Supplementary Materials.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Recorded: type, language, journal, volume, issue, pages, dates, 7 authors, 5 keywords, 16 MeSH terms, 3 funders, 49 references, 1 RRID.

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This paper

Fu, T., Shi, Y., Yang, Z., Zhou, J., Huang, L., Fu, Y., & Xiong, W. (2026). Variecolactone, a Natural PDE4 Inhibitor from Marine-Derived <i>Talaromyces</i> sp. ZSD-1, Alleviates Amyloid-β Accumulation and mtDNA Dyshomeostasis via cAMP-PKA-CREB Signaling Pathway. Biomolecules, 16(4), 570. https://doi.org/10.3390/biom16040570

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