PROJECT SUMMARY: Poor sleep has been identified as a major behavioral risk factor for Alzheimer's disease
and related dementias (ADRDs) as well as a possible pathogenic factor driving disease progression. However,
the molecular mechanisms linking healthy sleep to healthy brain aging remain elusive. Furthermore, we are yet
to identify any drug that promotes healthy sleep or slows the progression of Alzheimer's disease. This is largely
because the molecular mechanisms which govern both processes are yet to be fully understood. This project
proposes to investigate the mechanisms that link sleep/wake regulation to Alzheimer's disease pathophysiology.
To improve drug discovery for ADRDs, our lab has focused on targeting both age-associated and neuron-specific
toxicities simultaneously. To this end, I established a drug screening pipeline to identify small molecules that
delay aging and protect against neuronal cell death; we refer to these drugs as GeroNeuroProtectors (GNP).
Using this pipeline, I identified CX08005 – an inhibitor of protein tyrosine phosphatase 1B (PTP1B) – as a
candidate GNP which extends lifespan in C. elegans and protects hippocampal neurons from Alzheimer's
disease-associated oxidative cell death. Notably, in addition to its anti-aging and neuroprotective effects, I find
that CX08005 consolidates fragmented sleep/wake patterns in aged Drosophila. Thus, CX08005 may serve as
a useful pharmacological tool to investigate the mechanisms that link sleep/wake regulation to Alzheimer's
pathophysiology. In the proposed project, I will test the hypothesis that PTP1B activity is a central driver of
Alzheimer's disease related sleep fragmentation and neurodegeneration. During the K99 phase, I will determine
whether PTP1B inhibition improves Alzheimer's disease-associated outcomes and characterize the mechanisms
of PTP1B signaling in modulating Alzheimer's disease related sleep disturbance. Aim 1 will determine whether
PTP1B inhibition by CX08005 improves sleep/wake patterns, neuropathology, and cognitive performance in AD
mouse models. Since the mechanisms of PTP1B-mediated geroneuroprotection are unknown, Aim 2 will apply
CRISPR screening and tissue clearing and whole-brain labeling technologies to identify the genetic targets and
brain regions modulated by CX08005 then determine which genes modulate sleep and lifespan. A portion of
both aims will carry over into the independent R00 phase of the award. This work will lay the foundational
groundwork necessary for future studies to investigate the translational potential of targeting protein
phosphorylation and sleep to treat Alzheimer's disease and related dementias. The successful execution of the
proposed training plan will prepare me to lead an independent research program.