title: Bivalent Compound 17MN Exerts Neuroprotection through Interaction at Multiple Sites in a Cellular Model of Alzheimer's Disease.
abstract: Multiple pathogenic factors have been suggested to play a role in the development of Alzheimer's disease (AD). The multifactorial nature of AD also suggests the potential use of compounds with polypharmacology as effective disease-modifying agents. Recently, we have developed a bivalent strategy to include cell membrane anchorage into the molecular design. Our results demonstrated that the bivalent compounds exhibited multifunctional properties and potent neuroprotection in a cellular AD model. Herein, we report the mechanistic exploration of one of the representative bivalent compounds, 17MN, in MC65 cells. Our results established that MC65 cells die through a necroptotic mechanism upon the removal of tetracycline (TC). Furthermore, we have shown that mitochondrial membrane potential and cytosolic Ca2+ levels are increased upon removal of TC. Our bivalent compound 17MN can reverse such changes and protect MC65 cells from TC removal induced cytotoxicity. The results also suggest that 17MN may function between the Aβ species and RIPK1 in producing its neuroprotection. Colocalization studies employing a fluorescent analog of 17MN and confocal microscopy demonstrated the interactions of 17MN with both mitochondria and endoplasmic reticulum, thus suggesting that 17MN exerts its neuroprotection via a multiple-site mechanism in MC65 cells. Collectively, these results strongly support our original design rationale of bivalent compounds and encourage further optimization of this bivalent strategy to develop more potent analogs as novel disease-modifying agents for AD.
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Jeremy E
authors.initials: JE
authors.lastname: Chojnacki
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Wade
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Saathoff
authors.affiliation: Department of Medicine, Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University, Richmond, VA, USA.|Biochemistry, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Lesnefsky
authors.affiliation: Department of Medicine, Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Shijun
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D003474:Curcumin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C000608788:17MN compound; D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D002784:Cholesterol; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D003474:Curcumin; D002118:Calcium
keywords: Alzheimer’s disease; bivalent compound; calcium; mitochondria; multifunctional; neuroprotection