Targeting conserved diet-responsive transcriptional networks in neurons to slow neurodegeneration in Alzheimer's disease

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PROJECT SUMMARY/ ABSTRACT Alzheimer’s disease (AD) is a chronic neurodegenerative disorder and the most common cause of dementia amongst subjects over the age of 65. Despite identifying some of the genetic risk factors for AD, therapeutics to treat AD have been unsuccessful. A potential reason for this is that aging, the most significant risk factor for AD, has not been considered. Dietary restriction (DR) is one of the most robust interventions to slow aging and the onset of age-related diseases, including AD. However, the underlying mechanisms by which DR protects against AD are unknown. We propose to use D. melanogaster to investigate the conserved links between diet and AD for the following reasons: 1) their excellent track record for elucidating the biology of aging, neurodegenration and DR, 2) their amenability to genetic manipulation, 3) the availability of established genetic models for understanding aging and AD pathology, 4) their fast generation time and short lifespan, and 5) they share many biological processes and signaling pathways with mammals. The overall goals of this proposal are to understand the mechanisms by which DR influences AD pathology and neurodegeneration. We have observed that DR significantly improves survival and reduces the functional decline in tauopathy models of AD in flies. Importantly, our proteomic analysis suggests that mutant Tau affects the proteome of flies in a fashion that is similar to the effect of a high-nutrient diet. A comparison of our proteomic analysis from a fly tauopathy model with proteomic data from human AD brains identified 47 common genes. We also demonstrate that modulating two of the transcriptional regulators and their downstream genes modulate neurodegeneration in Tau mutant flies. Based on our preliminary data, our central hypothesis is that nutrient-dependent transcriptional networks in the brain influence neurodegeneration in pathogenic tau and AD models. We will test our hypothesis by pursuing the following specific aims. In Aim 1, we characterize the transcriptional targets altered in both fly tauopathy model and human AD for changes in neurodegeneration and lifespan in Tau and Aβ fly models of AD. In Aim 2, we characterize candidate transcriptional regulators for changes in neurodegeneration and lifespan in fly models of AD. In Aim 3, we identify the mechanisms by which nutrient-responsive transcriptional networks inhibit neurodegeneration. We focus on diet's impact on metabolism, oxidative stress, heterochromatin loss, and abortive neuronal cell-cycle activation, given that these processes are known to affect AD and aging. This research is significant, as we expect it to reveal common genetic mechanisms across species, novel targets, and lifestyle changes that slow the onset and progression of AD and related tauopathy.