Glycolysis and Alzheimer?s Disease - Project Summary
Alzheimer's disease (AD) is a devastating disease with no disease-modifying therapies. A key
contributing factor to AD is impaired glucose metabolism. However, it is unknown how glucose
metabolism contributes to neurodegeneration in AD. Our recent work demonstrated that we could
enhance glycolysis via an existing drug, terazosin (TZ). This drug is an alpha-1 antagonist, but it also
binds to and enhances activity of phosphoglycerate kinase-1 (PGK1), the first ATP-generating step of
glycolysis. Excitingly, our preliminary data from the Truven database of Medicare claims suggest that
patients taking TZ are protected from developing AD relative to those taking tamsulosin, another
alpha-1 antagonist that does not bind PGK1. Additionally, our review of the Alzheimer's Disease
Neuroimaging initiative (ADNI) indicates that patients taking TZ have slower progression on FDG-PET
and on cognitive impairment, compared to those taking tamsulosin. In this proposal, our goal is to test
TZ target engagement and efficacy in animal models of AD. To our knowledge, no drug for AD directly
engages PGK1 or metabolism and mitigates protein aggregation; thus, this mechanism is entirely
novel for AD. Our overall hypothesis is that TZ is protective in rodent models of AD. In Aim 1, we will
quantify TZ target engagement in rodent AD models. We will administer TZ orally for six-months to
transgenic tau (P301S) and amyloid (5XFAD) mice relevant for human AD, along with littermate and
vehicle controls. We will evaluate blood and brain metabolomics and [ATP], as well as in vivo magnetic
resonance spectroscopy (MRS). In Aim 2, we will evaluate whether improving glycolysis mitigate
neurodegeneration in rodent AD models. We will use the same mice as in Aim 1 and evaluate
cognitive function via novel-object recognition, spatial working memory, and interval timing assays. We
will also perform immunohistochemistry, ELISA, and western blot to assess tau/amyloid pathology.
These studies will elucidate the basic principles of how TZ enhances brain energetics, and affects
neurodegeneration. These fundamental mechanisms could be highly relevant for inspiring novel
disease-modifying therapies in AD and related dementias.