title: Oral TNFα Modulation Alters Neutrophil Infiltration, Improves Cognition and Diminishes Tau and Amyloid Pathology in the 3xTgAD Mouse Model.
abstract: Cytokines such as TNFα can polarize microglia/macrophages into different neuroinflammatory types. Skewing of the phenotype towards a cytotoxic state is thought to impair phagocytosis and has been described in Alzheimer's Disease (AD). Neuroinflammation can be perpetuated by a cycle of increasing cytokine production and maintenance of a polarized activation state that contributes to AD progression. In this study, 3xTgAD mice, age 6 months, were treated orally with 3 doses of the TNFα modulating compound isoindolin-1,3 dithione (IDT) for 10 months. We demonstrate that IDT is a TNFα modulating compound both in vitro and in vivo. Following long-term IDT administration, mice were assessed for learning & memory and tissue and serum were collected for analysis. Results demonstrate that IDT is safe for long-term treatment and significantly improves learning and memory in the 3xTgAD mouse model. IDT significantly reduced paired helical filament tau and fibrillar amyloid accumulation. Flow cytometry of brain cell populations revealed that IDT increased the infiltrating neutrophil population while reducing TNFα expression in this population. IDT is a safe and effective TNFα and innate immune system modulator. Thus small molecule, orally bioavailable modulators are promising therapeutics for Alzheimer's disease.
authors.affiliation: P2D Bioscience, Inc., Cincinnati, Ohio, United States of America.
authors.forename: S Prasad
authors.initials: SP
authors.lastname: Gabbita
authors.affiliation: Veterans Administration-Greater Los Angeles Healthcare System, Los Angeles, California, United States of America.
authors.forename: Ming F
authors.initials: MF
authors.lastname: Johnson
authors.affiliation: Veterans Administration-Greater Los Angeles Healthcare System, Los Angeles, California, United States of America.
authors.forename: Naomi
authors.initials: N
authors.lastname: Kobritz
authors.affiliation: Veterans Administration-Greater Los Angeles Healthcare System, Los Angeles, California, United States of America.
authors.forename: Pirooz
authors.initials: P
authors.lastname: Eslami
authors.affiliation: Veterans Administration-Greater Los Angeles Healthcare System, Los Angeles, California, United States of America.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Poteshkina
authors.affiliation: University of North Carolina Wilmington, Department of Chemistry and Biochemistry, Wilmington, North Carolina, United States of America.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Varadarajan
authors.affiliation: University of North Carolina Wilmington, Department of Chemistry and Biochemistry, Wilmington, North Carolina, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Turman
authors.affiliation: P2D Bioscience, Inc., Cincinnati, Ohio, United States of America.
authors.forename: Frank
authors.initials: F
authors.lastname: Zemlan
authors.affiliation: Veterans Administration-Greater Los Angeles Healthcare System, Los Angeles, California, United States of America; University of California Los Angeles, David Geffen School of Medicine, Los Angeles, California, United States of America.
authors.forename: Marni E
authors.initials: ME
authors.lastname: Harris-White
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D003071:Cognition / Q000145:classification*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D054833:Isoindoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects*; D010641:Phenotype; D055503:Protein Multimerization / Q000187:drug effects; D017433:Protein Structure, Secondary / Q000187:drug effects; D012449:Safety; D012995:Solubility; D013854:Thioamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D013871:Thiones / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016875:tau Proteins / Q000737:chemistry*
chemical_list: D054833:Isoindoles; D013854:Thioamides; D013871:Thiones; D014409:Tumor Necrosis Factor-alpha; D016875:tau Proteins; C000608222:isoindolin-1,3-dithione