K34 (3,3″-Dihydroxy-6′-desmethyl Terphenyllin) Promotes Hemoglobin-Supported H2O2 Decomposition and Attenuates Neurodegenerative Phenotypes in APP/PS1 Mice with Focal GiD

Hydrogen peroxide (H2O2) contributes to oxidative stress in Alzheimer’s disease (AD), yet conventional antioxidants that directly scavenge H2O2 have shown limited therapeutic efficacy. Here, we investigated K34 (3,3″-dihydroxy-6′-desmethyl terphenyllin), a catechol-bearing para-terphenyl isolated from the marine fungus Penicillium janthinellum 168CLC-17.1, as an indirect H2O2-decomposing agent. Complementary cell-free assays showed that K34 promoted peroxidase-dependent H2O2 decomposition, including Hb-supported H2O2 decomposition, while molecular docking predicted a plausible binding pose near the Hbβ heme pocket. In amyloid-β42 (Aβ42)-stimulated primary astrocytes, K34 reduced intracellular H2O2. In APPswe/PSEN1dE9 (APP/PS1) mice subjected to focal GFAP-inducible diphtheria toxin receptor (fGiD), systemic K34 attenuated memory impairment, preserved NeuN-positive neurons, reduced GFAP immunoreactivity, and improved hippocampal spike probability. K34 also exhibited low passive blood–brain barrier (BBB) permeability and limited inhibition of five major cytochrome P450 (CYP) isoforms under the tested conditions. These findings extend Hb-supported H2O2 decomposition to a structurally distinct marine natural product and support further evaluation of K34 as an antioxidant scaffold for modulating oxidative stress-associated neurodegenerative phenotypes.