ABSTRACT
Aß accumulation plays a central role in the pathogenesis of Alzheimer's disease (AD). Recent studies suggest that the process of Aß nucleated polymerization is essential for Aß fibril formation, pathology spreading and toxicity. Therefore, targeting this process represents an effective therapeutic strategy to slow or block disease progression. To discover compounds that might interfere with the Aß seeding capacity, toxicity and pathology spreading, we screened a focused library of FDA-approved drugs in vitro using a seeding polymerization assay and identified small molecule inhibitors that specifically interfered with Aß seeding-mediated fibril growth and toxicity. Mitoxantrone, bithionol and hexachlorophene were found to be the strongest inhibitors of fibril growth and protected primary cortical neuronal cultures against Aß-induced toxicity. Next, we assessed the effects of these three inhibitors in vivo in the mThy1-APPtg mouse model of AD (8-month-old mice). We found that mitoxantrone and bithionol, but not hexachlorophene, stabilized diffuse amyloid plaques, reduced the levels of Aß42 oligomers and ameliorated synapse loss, neuronal damage and astrogliosis. Together, our findings suggest that targeting fibril growth and Aß seeding capacity constitutes a viable and effective strategy for protecting against neurodegeneration and disease progression in AD.
Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/drug effects , Nerve Degeneration/drug therapy , Nerve Degeneration/physiopathology , Neuroprotective Agents/pharmacology , Peptide Fragments/drug effects , Alzheimer Disease/pathology , Amyloid beta-Peptides/toxicity , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Bithionol/pharmacokinetics , Bithionol/pharmacology , Cells, Cultured , Cerebral Cortex/drug effects , Cerebral Cortex/pathology , Cerebral Cortex/physiopathology , Disease Models, Animal , Drug Evaluation, Preclinical , Female , Gliosis/drug therapy , Gliosis/pathology , Gliosis/physiopathology , Hexachlorophene/pharmacokinetics , Hexachlorophene/pharmacology , Humans , Mice, Inbred C57BL , Mice, Transgenic , Mitoxantrone/pharmacokinetics , Mitoxantrone/pharmacology , Nerve Degeneration/pathology , Neurons/drug effects , Neurons/pathology , Neurons/physiology , Neuroprotective Agents/pharmacokinetics , Peptide Fragments/toxicity , Plaque, Amyloid/drug therapy , Plaque, Amyloid/pathology , Plaque, Amyloid/physiopathology , RatsABSTRACT
A liquid chromatographic method is described for determining bithionol sulfoxide and its metabolites, bithionol and bithionol sulfone, in milk. Samples are treated with HCl to precipitate proteins and to permit extraction of bithionol sulfoxide in nonionized form. Tetrahydrofuran is added to the organic phase to facilitate extraction in diethyl ether; the dried residue is dissolved in chloroform, hexane, and sodium hydroxide and subjected to LC analysis. Residues of bithionol sulfoxide and its 2 metabolites were determined in milk of lactating cows. Holstein-Friesian dairy cows were administered a single oral dose of bithionol sulfoxide (50 mg/kg). Milk samples were analyzed with a reliable detection level of 0.025 microgram/mL for each compound. Residues of bithionol sulfoxide and bithionol were detected during 30 and 16 milkings, respectively; bithionol sulfone was never present at detectable levels.
