Insights into the Impact of a Membrane-Anchoring Moiety on the Biological Activities of Bivalent Compounds As Potential Neuroprotectants for Alzheimer’s Disease

Bivalent compounds anchoring in different manners to the membrane were designed and biologically characterized to understand the contribution of the anchor moiety to their biological activity as neuroprotectants for Alzheimer’s disease. Our results established that the anchor moiety is essential, and we identified a preference for diosgenin, as evidenced by <b>17MD</b>. Studies in primary neurons and mouse brain mitochondria also identified <b>17MD</b> as exhibiting activity on neuritic outgrowth and the state 3 oxidative rate of glutamate while preserving the coupling capacity of the mitochondria. Significantly, our studies demonstrated that the integrated bivalent structure is essential to the observed biological activities. Further studies employing bivalent compounds as probes in a model membrane also revealed the influence of the anchor moiety on how they interact with the membrane. Collectively, our results suggest diosgenin to be an optimal anchor moiety, providing bivalent compounds with promising pharmacology that have potential applications for Alzheimer’s disease

Additional file 1: Figure S1. of Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex

Representative western blot and quantification analysis of brain homogenates found the DLP1 and OPA1 protein levels were unchanged in Mfn2 cKOmice (8 weeks of age) compared to control mice in both the hippocampus and the cortex. GAPDH was used as an internal loading control (N = 3/group, data represent mean ± SEM, Student’s t-test, *P < 0.05). Figure S2. Nissl staining of the entire cortex showing neuronal layers I-VI (upper panels) and higher magnification of area encompassing layers III/IV (lower panels). Dashed line represents lower boundary of cortical neurons. Cortical shrinkage is apparent, neuronal layers become less distinct, and nuclei become disfigured and less uniform with age in the cKOmice. Figure S3. Quantification of the immunostaining of (A) GFAP, (B) IBA-1 and (C) MAP2 in the CA1 regions of the Mfn2 cKO mice at different ages (8–28 weeks) compared to control mice at 28 weeks of age (Data represent mean ± SEM, Student’s t-test, *P < 0.05). (PDF 427 kb