Amyloid Modifier SERF1a Accelerates Alzheimer's Amyloid-ß Fibrillization and Exacerbates the Cytotoxicity.

Alzheimer's disease (AD) is a devastating, progressive neurodegenerative disease affecting the elderly in the world. The pathological hallmark senile plaques are mainly composed of amyloid-ß (Aß), in which the main isoforms are Aß40 and Aß42. Aß is prone to aggregate and ultimately forms amyloid fibrils in the brains of AD patients. Factors that alter the Aß aggregation process have been considered to be potential targets for treatments of AD. Modifier of aggregation 4 (MOAG-4)/small EDRK-rich factor (SERF) was previously selected from a chemical mutagenesis screen and identified as an amyloid modifier that promotes amyloid aggregation for α-synuclein, huntingtin, and Aß40. The interaction and effect of yeast ScSERF on Aß40 were previously described. Here, we examined the human SERF1a effect on Aß40 and Aß42 fibrillization by the Thioflavin T assay and found that SERF1a accelerated Aß fibrillization in a dose-dependent manner without changing the fibril amount and without incorporation. By Fourier transform infrared spectroscopy (FTIR) and transmission electron microscopy (TEM), we found that SERF1a altered the secondary structures and the morphology of Aß fibrils. The electrospray ionization mass spectrometry (ESI-MS) and analytical ultracentrifugation (AUC) results showed that SERF1a binds to Aß in a 1:1 stoichiometry. Moreover, the NMR study showed that SERF1a interacts with Aß via its N-terminal region. Cytotoxicity assay demonstrated that SERF1a enhanced toxicity of Aß intermediates, and the effect can be rescued by SERF1a antibody. Overall, our study provides the underlying molecular mechanism for the SERF1a effect on Aß fibrillization and facilitates the therapeutic development of AD.

Structural Switching of a Distorted Trigonal Metal-Organic Cage to a Tetragonal Cage and Singlet Oxygen Mediated Oxidations.

Construction of metal-organic cages with unique architecture and guest binding abilities is highly desirable. Herein, we report the synthesis of a distorted trigonal cage (1) from a twisted tetratopic ligand (L) and a PdII acceptor. Surprisingly, 1 exhibited a complete structural reorganization of its building units in the presence of C70 and C60 to form guest-encapsulated tetragonal cages, (C70 )2 @2 and (C60 )2 @2, respectively. These guest-bound cages were found to be potential 1 O2 generators, with the former effectively catalyzing two different varieties of 1 O2 -mediated oxidation reactions.