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 Aß 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.