Indoleamine 2,3-Dioxygenase: The Key to Pathogenesis and Treatment of Alzheimer’s and Related Neurodegenerative Diseases

Several neurodegenerative brain diseases (primarily Huntington’s, Parkinson’s, and ALS) have distinctive differences but they share similar, incurable pathologies with Alzheimer’s disease. These pathologies have mechanisms in common that involve oxidant stress. More than 20 years ago, research identified indoleamine 2,3-dioxygenase (IDO) as a significant site of oxygen toxicity resulting in convulsions. More recently, (IDO1), the rate-limiting enzyme of the kynurenine pathway in brain and some other tissues was identified as an eclectic, immunoregulatory agent including maternal T-cell tolerance. IDO1 is currently known to be a complex biomolecule with the catalytic activity of an enzyme and a coenzyme-like heme iron component that responds to changes in oxidant stress and equips it to function in a highly-regulated manner. Thus, IDO1 is known to perform non-enzyme functions that include reprogramming the expression profiles of immune cells with roles in autoimmune diseases, chronic inflammation, pregnancy, and cancer. I propose that brain IDO1, functioning as a highly-regulated enzyme of the kynurenine pathway, and as a sensor of and responder to oxidant stress, is deeply involved in the mechanisms leading to neurodegenerative brain diseases, and Alzheimer’s serves as a representative, basic, mechanistic example. Following this connection offers new hope for elucidating the mechanisms of neurodegenerative brain diseases and for discovering treatments and cures.