Neural Aging and Ab Toxicity Assessments, a Fly Pharmacology-Molecular AD Model
Abstract:
Human studies have shown that the progressive accumulation of protein aggregates (Aß42) is key a factor in
the development of neurodegenerative disorders, including Alzheimer’s disease (AD). As a result, a significant
portion of AD research has since focused on the origin and cytotoxic effects that Aß42 has on the maintenance,
stress responses and functional decline of neurons. However, geroscience studies have highlighted other
metabolic, proteolytic, stress response and cell signaling pathways are also closely linked to aging and
neurodegenerative processes. It has emerged that AD risk factors include chronic activation of innate immunity
(inflammaging) and impaired proteolytic clearance. In addition, AD associated processes like NFkb signaling
and APP processing are also involved with neural development and synaptic remodeling. This indicates that a
less focus more nuanced geroscience based approach to study AD and potential therapies is required. Our work
on gerontology has largely focused on the role of autophagy using an aging Drosophila model. We found that
the autophagic capacity of neurons is directly correlated with aggregate formation, stress responses and
longevity profiles of Drosophila. Using a fly aging model, we have identified dietary (intermittent fasting, IF) and
drug treatment regimens that promote autophagic and neuronal function. This is in part by restoring more youthful
gene expression and transcriptional drift variance (TDV) profiles in aged neural tissues. Of particular mechanistic
importance was the profound age-related dysregulation of proteolytic components, which was largely
suppressed by IF. We developed a second Drosophila model, examining traumatic brain injury (TBI). Using
standardized conditions, TBI-treated flies showed conserved pathway changes (autophagy, NFkb), behavioral
defects (locomotion, sleep) and molecular alterations known to occur in human trauma patients and in rodent
models. We find that aging and the genetic background of adult flies alters TBI responses, as does select drug
(J147) or IF treatment. The goal of this application is to take an integrated approach using an AD Drosophila
model to examine the impact that in vivo aggregate formation (Aß42-Arctic) has on the aging or traumatized CNS.
The central hypothesis of this proposal is that common protective molecular pathways can be identified using
animal models and these unique mechanistic insights can be exploited to develop new therapeutic treatments
for complex aging and neurodegenerative disorders. Specific Aim 1 will determine the impact that tissue specific
production of Aß42-Arctic has on the neural aging and TBI dependent phenotypes and longevity profiles of adult
Drosophila. In Specific Aim 2, we will use our Drosophila neural aging, trauma and AD models to determine the
effectiveness of select diets (IF) and compounds (J147) to delay or suppress phenotypes associated many
neural degenerative disorders. Findings from this proposal will be the foundation for future gerosciene studies
examining the conserved mechanisms of neural aging and the identification of neuroprotective treatments.