title: A carboxylated Zn-phthalocyanine inhibits fibril formation of Alzheimer's amyloid β peptide.
abstract: Amyloid β (Aβ), a 39-42 amino acid peptide derived from amyloid precursor protein, is deposited as fibrils in Alzheimer's disease brains, and is considered to play a major role in the pathogenesis of the disease. We have investigated the effects of a water-soluble Zn-phthalocyanine, ZnPc(COONa)₈, a macrocyclic compound with near-infrared optical properties, on Aβ fibril formation in vitro. A thioflavin T fluorescence assay showed that ZnPc(COONa)₈ significantly inhibited Aβ fibril formation, increasing the lag time and dose-dependently decreasing the plateau level of fibril formation. Moreover, it destabilized pre-formed Aβ fibrils, resulting in an increase in low-molecular-weight species. After fibril formation in the presence of ZnPc(COONa)₈, immunoprecipitation of Aβ₁₋₄₂ using Aβ-specific antibody followed by near-infrared scanning demonstrated binding of ZnPc(COONa)₈ to Aβ₁₋₄₂. A study using the hydrophobic fluorescent probe 8-anilino-1-naphthalenesulfonic acid showed that ZnPc(COONa)8 decreased the hydrophobicity during Aβ₁₋₄₂ fibril formation. CD spectroscopy showed an increase in the α helix structure and a decrease in the β sheet structure of Aβ₁₋₄₀ in fibril-forming buffer containing ZnPc(COONa)₈. SDS/PAGE and a dot-blot immunoassay showed that ZnPc(COONa)₈ delayed the disappearance of low-molecular-weight species and the appearance of higher-molecular-weight oligomeric species of Aβ₁₋₄₂. A cell viability assay showed that ZnPc(COONa)₈ was not toxic to a neuronal cell line (A1), but instead protected A1 cells against Aβ₁₋₄₂-induced toxicity. Overall, our results indicate that ZnPc(COONa)₈ binds to Aβ and decreases the hydrophobicity, and this change is unfavorable for Aβ oligomerization and fibril formation.
authors.affiliation: Department of Laboratory Medicine, Shimane University School of Medicine, Izumo, Japan.
authors.forename: Shatera
authors.initials: S
authors.lastname: Tabassum
authors.forename: Abdullah M
authors.initials: AM
authors.lastname: Sheikh
authors.forename: Shozo
authors.initials: S
authors.lastname: Yano
authors.forename: Takafumi
authors.initials: T
authors.lastname: Ikeue
authors.forename: Makoto
authors.initials: M
authors.lastname: Handa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nagai
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D054833:Isoindoles; D009942:Organometallic Compounds / Q000494:pharmacology*; D017967:Zinc Compounds
chemical_list: D016229:Amyloid beta-Peptides; D007211:Indoles; D054833:Isoindoles; D009942:Organometallic Compounds; D017967:Zinc Compounds; C052159:Zn(II)-phthalocyanine
keywords: Alzheimer's disease; amyloid β peptide; fibril formation; near infrared; phthalocyanine