ABSTRACT
Metabolic disorders (i.e. obesity, prediabetes or type 2 diabetes), often resulting from poor diet, is a significant
risk factor for Alzheimer’s disease (AD). Several common neurodegenerative mechanisms in these two
conditions have been identified, including oxidative stress, mitochondrial dysfunction, and inflammation.
Changes in metabolism and mitochondrial bioenergetics may be at the heart of both metabolic disorders and
AD but may be affecting men and women differently. Although AD treatments exist, none are very effective,
and certainly no drugs are sex-specific, creating a significant unmet medical need. Interestingly, several clinical
trials testing nilotinib, a repurposed leukemia drug, have shown promise for use in treating AD and other
neurodegenerative diseases. In addition to attenuating hallmark pathology, we recently demonstrated that
nilotinib improves mitochondrial function and bioenergetics in cultured cells from the 3xTg-AD mouse model for
AD. In this study, our specific objective is to use a high fat diet (HFD) to model metabolic disease in 3xTg-AD
mice and evaluate sex-differences associated with bioenergetic, cognitive, and neuropathological outcomes,
as well as whether nilotinib can improve them. The rationale for the proposed work is further supported by a
recent phase II study conducted by our collaborator, Dr. Scott Turner, that showed 12 months of treatment with
nilotinib, at 150 mg/day for 26 weeks followed by 300 mg/day for 26 weeks was safe, tolerable, and effective in
patients with mild to moderate AD. Here, we hypothesize that nilotinib will improve mitochondrial bioenergetics,
enhance cognitive function, and reduce biomarkers of AD pathology in a sex-dependent manner in 3xTg-AD
mice subjected to a HFD. In Aim 1, we will determine whether in vivo treatment (100 or 250 mg/kg for 2
months) with nilotinib improves mitochondrial function and bioenergetics in 3xTg-AD mice in the absence and
presence of HFD-induced metabolic disease. In Aim 2, we will investigate whether in vivo treatment with
nilotinib can reverse cognitive-behavioral deficits in 3xTg-AD mice in the absence and presence of metabolic
disease. Finally, in Aim 3, we will characterize the effects of in vivo treatment with nilotinib on AD-associated
neuropathology in 3xTg-AD mice in the absence and presence of metabolic disease. The mechanisms by
which nilotinib may improve outcomes in vivo, as well as patient populations for whom nilotinib treatment may
be safe and effective (i.e., based on sex and comorbid metabolic disease, present in 80% of AD patients),
have yet to be adequately explored in rodent models prior to the commencement of the drug’s phase III trial.
We expect that a HFD will result in a wider range of bioenergetic, cognitive, and neuropathological
consequences in female AD mice as compared to males. Overall, we expect nilotinib will improve
mitochondrial function, ATP levels, AD-associated neuropathology, and cognition in 3xTg AD mice, including
those subjected to a HFD.
