Role of Neuroprotective Indoles in Delaying the Onset of Cognitive Decline

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PROJECT SUMMARY/ABSTRACT This proposal is focused on an emerging hypothesis, developed by us, that age-related changes in the level of certain neuroprotective molecules, produced by the microbiota, can influence the onset and/or rate of progression of mild cognitive decline (MCI) due to Alzheimer’s disease (AD). We and others demonstrated that small molecules related to indole substances, derived from intestinal bacteria, act systemically through diverse pathways to promote cellular protection and reduce inflammation. Over two decades ago, we showed for the first time, that some of these indoles have several beneficial effects on biological systems, including neuroprotection. In addition, these substances have several properties that are important to AD therapeutics. 1) They are neuroprotective; 2) They prevent the aggregation of amyloid into toxic forms and 3) They were shown (by others) to have anti-inflammatory properties. Studies from several independent investigators have confirmed and expanded our initial findings and showed that bacteria-derived indoles extend lifespan and health-span of diverse organisms, including rotifers, Drosophila melanogaster, and mice. It has been proposed that age-associated shifts in the microbiota contributes to age-related infirmity, including the development of age-related neurodegenerative disease. The identities of the bacterial molecules mediating multiple effects of the microbiota on the brain are not fully defined. In humans, high serum levels of indole-3-propionic acid, for example, were tightly linked to a decreased incidence of diabetes mellitus type 2. However, there is limited information available regarding the levels of these substances and the onset of age-related neurodegenerative disorders such as MCI and AD. Wide-scale profiling technologies, including metabolomics, open the door for novel discoveries related to the pathogenesis of age-related neurodegenerative diseases. By applying metabolomics, we propose to investigate whether the levels of these small molecules in the serum influence the age of onset and rates of progression of MCI due to AD. Serum samples will be obtained at several time intervals during the active study period. Our results will be supplemented and compared with samples from normal controls, subjects with MCI (converters and non-converters) obtained two AD Centers with which we established collaborative arrangements. Using a metabolomics approach and computerized algorithms, we will seek correlative interactions between serum levels of neuroprotective indoles and the incidence of MCI as well as between these and the rate of cognitive decline and brain atrophy, over time. This is an exploratory set of projects, designed to obtain preliminary data for larger mechanistic studies and therapeutic interventions.