There are currently no effective treatments for Alzheimer's Disease (AD), a progressive disease that destroys memory and cognitive function. In the US, there are 5.3 million people afflicted with AD. The classical pathology of AD consists of two associated features, the occurrence of extracellular amyloid beta plaques and intercellular neurofibrillary tangles consisting of phosphorylated tau protein. The overproduction and aggregation of amyloid beta leads to neuronal cell death and loss of cognitive function, however, therapeutics directed at clearance or prevention of aggregation have been largely unsuccessful. In addition to cognitive decline and neuronal loss, synaptic dysfunction and inflammation, have been directly linked with AD-dependent transcriptional alterations. The mechanisms leading to altered chromatin and transcriptional states in AD remain a major gap in the molecular etiology of the disease. Here, we propose to investigate a promising link between bacterially-derived metabolites and epigenetic dysregulation in the brain of those suffering from AD. Enzyme-catalyzed histone modifications (e.g. (de)acetylation, (de)phosphorylation, and (de)methylation) result in a unique set of chemical ?marks? that regulate chromatin function through mechanisms that remain a focus of intense study. The combinatorial nature of these posttranslational modifications (PTMs) give rise to a histone ?code? or ?language?, which is interpreted by enzyme complexes to mediate transcriptional responses and to alter the functional state of chromatin. There is accumulating evidence that gut microbiome derived metabolites can influence chromatin states indirectly or directly by modulating the levels of substrates and inhibitors of chromatin modifying enzymes, such as acetyltransferases, deacetylases, methyltransferases, and demethylases. To investigate this hypothesis we will i.) Determine if trimethylamine oxide (TMAO, bacterially-derived) alone drives the epigenetic states observed in mice harboring choline-consuming gut microbiota, ii.) Determine the mechanism by which TMAO induces specific alteration to the PTM state of histone H3, and iii.) Determine whether hippocampi from human AD brains display histone PTM profiles that correlate with plasma levels of TMAO.
There are currently no effective treatments for AD, which underscores the need for novel insights into the molecular etiology of the disease. This proposal investigates a promising and novel link between bacterially-derived metabolites and epigenetic dysregulation in the AD brain. The results of this work will provide new avenues for therapeutically-relevant research AD and AD related diseases.
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