Alzheimer’s disease (AD) is a complex, multifactorial disease with a significant health and financial societal
impact as there are no drugs that effectively counteract the disease. AD is characterized by impaired synaptic
plasticity leading to defective hippocampal-dependent memory, which has been found to appear long before the
buildup of amyloid plaques and neuronal cell death. This observation suggests that interventions targeting
biological pathways that regulate synaptic plasticity may provide a way to slow down, arrest, and/or prevent the
progression of neurodegenerative processes. The objective of this proposal is to identify first-in-class small
molecules with dual target activity that enhance synaptic plasticity. In preliminary studies, we discovered that
two distinct molecular targets, phosphodiesterase 5 (PDE5) and histone acetyltransferase (HAT) are crucial in
synaptic plasticity. We developed small molecule PDE5 inhibitors and HAT activators that are able to rescue
impaired synaptic plasticity in mouse hippocampal slices. In a proof-of-concept study, we demonstrated that a
combination treatment with a PDE5 inhibitor and a HAT activator produces a 6-fold higher rescue of synaptic
plasticity compared to treatment with the two compounds alone. These findings indicate that modulating these
two targets involved in AD provides a more effective treatment than a single-target therapy. In this proposal, we
plan to test the hypothesis that modulating PDE5 and HAT activity via a newly synthesized single molecule will
result in a novel AD treatment. The multi-target directed ligand approach will be used to attain a PDE5
inhibitor/HAT activator drug molecule. This approach has emerged as a beneficial strategy for the treatment of
complex diseases and presents several advantages with respect to combination therapy, including increased
therapeutic efficacy, reduced drug-drug interactions, and simplified drug regimen. Specifically, we will test our
hypothesis via the following specific aims: 1) design and synthesis of a library of new dual-target molecules with
HAT and PDE5 activity, 2) elucidate the pharmacokinetic/pharmacodynamic properties of our newly synthesized
dual-target molecules in vitro and in vivo, and 3) assess synaptic plasticity in mouse hippocampal slices derived
from a genetically modified mouse model of amyloid deposition treated with our newly synthesized dual-target
ligands. These aims will be addressed through a combination of medicinal chemistry approaches for generating
new chemical entities, and biochemical and electrophysiological techniques for testing the biological activity of
these new dual target molecules in vitro as well as assessing their in vivo efficacy. Results from these
experiments will provide crucial insights into an alternative and novel therapeutic approach for treating AD based
on cleverly modulating two molecular targets known to play a significant role in the etiopathology of this disease.
