RESEARCH ARTICLE Oral TNFαModulation Alters Neutrophil Infiltration, Improves Cognition and Diminishes Tau and Amyloid Pathology in the 3xTgAD Mouse Model

Cytokines such as TNFα can polarize microglia/macrophages into different neuroinflamma-tory types. Skewing of the phenotype towards a cytotoxic state is thought to impair phagocy-tosis 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, 3xTgADmice, age 6 months, were treated orally with 3 doses of the TNFαmodulating compound isoindolin-1,3 dithione (IDT) for 10 months. We demonstrate that IDT is a TNFαmodulating 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 3xTgADmouse 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