Neurobiology of Disease, Volume 156, August 2021,
Sporadic late-onset Alzheimer's disease (AD) is the most frequent cause of dementia associated with aging. Due to the progressive aging of the population, AD is becoming a healthcare burden of unprecedented proportions. Twenty years ago, it was reported that some indole molecules produced by the gut microbiota possess essential biological activities, including neuroprotection and antioxidant properties. Since then, research has cemented additional characteristics of these substances, including anti-inflammatory, immunoregulatory, and amyloid anti-aggregation features. Herein, we summarize the evidence supporting an integrated hypothesis that some of these substances can influence the age of onset and progression of AD and are central to the symbiotic relationship between intestinal microbes and the brain. Studies have shown that some of these substances' activities result from interactions with biologically conserved pathways and with genetic risk factors for AD. By targeting multiple pathologic mechanisms simultaneously, certain indoles may be excellent candidates to ameliorate neurodegeneration. We propose that management of the microbiota to induce a higher production of neuroprotective indoles (e.g., indole propionic acid) will promote brain health during aging. This area of research represents a new therapeutic paradigm that could add functional years of life to individuals who would otherwise develop dementia.
Aging; Alzheimer Disease; Amyloid Precursor Protein; Animal; Animals; Antiinflammatory Activity; Antineoplastic Activity; Aromatic Hydrocarbon Receptor; Autacoid; Brain; Brain-Gut Axis; C Reactive Protein; Decarboxylation; Dendritic Cell; Gastrointestinal Microbiome; Gene Expression Profiling; Genetic Risk; Genetics; Glucose Homeostasis; Halogenation; High Performance Liquid Chromatography; Human; Humans; Immunomodulation; Immunoreactivity; Immunoregulation; Indole Derivative; Indoles; Inducible Nitric Oxide Synthase; Inflammation Mediators; Intermittent Fasting; Intestine Flora; Liver Metabolism; Metabolism; Methylation; Mitochondrial Biogenesis; Neuroprotection; Nitric Oxide Synthase; Nuclear Magnetic Resonance Spectroscopy; Oxidative Stress; Physiology; Protein Expression; Regulatory T Lymphocyte; Review; Risk Factor; Short Chain Fatty Acid; Sporogenesis; Symbiont; Global