Evaluation of a specific LXR/PPAR agonist for treatment of Alzheimer's disease

Project Summary
Alzheimer's disease (AD) is the sixth leading cause of death in United States, yet this indication
lacks truly effective therapeutics to mitigate this disease. To develop novel and effective
therapies, a novel (partial) Liver-X-receptor (LXR) β and peroxisomal proliferator activating–
gamma (PPARγ) nuclear receptor agonist (AU403) that has selective amino acid interactions in
the receptor ligand-binding domain was developed. Preliminary data suggest AU403 may
reduce AD-related pathologies, including amyloid accumulation, behavioral deficits and
neurodegeneration (reduced neuronal plasticity). The goal of this current application is to further
test and develop AU403 in preparation to submit an SBIR/STTR or NIH BPN program. Five
aims are proposed to achieve this goal. Aim 1: Tests our in silico design that AU403 and AU403
methyl ester (me) selectively induce robust LXRβ activity. This aim will focus upon establishing
EC50, LD50 and other measurable parameters of AU403 and AU403me. Aim 2 will determine
the oral and IV absorption and distribution kinetics of AU403 and AU403me. The current aim
will determine the minimal dose of AU403 and AU403me in the brain by lcms. The values will
be compared to values in aim 1 for the EC50 for understanding the dose that induces LXRβ
activity. Aim3 will evaluate the safety of AU403 in primary human hepatocytes and in vivo. We
will measure in this aim the ability for AU403 to induce Liver CYP enzyme induction and
expression as well as measure toxicity markers for liver and heart. Completion of the first 3 aims
from the R61 portion of the grant will progress the program towards the R33 portion of the grant.
The R33 portion of the grant has 2 aims which will test the efficacy of AU403 or AU403 me in
the 5xFAD mouse model. Aim 4 we will test that oral administration of AU403 is efficacious in
the ApoE4 x Abeta or ApoE4xTau Alzheimer's Disease animal models . This aim will determine
the minimal concentration of AU403 to reduce pathology in preventative model (3-6 months in
age) and Treatment model (9-12 months in age). Aim 5 will determine the impact of Au403 on
neuro-energy regulatory pathways. The impact of AU403 on brain energy regulatory pathways,
will be assessed by an untargeted approach to evaluate brain metabolomics in conjunction with
transcriptome analysis using the Alzheimer's disease neuroinflammatory pathway. The results
of these studies are expected to confirm AU403 as a potential treatment for AD and ultimately
support efforts to submit an IND application and initiate Phase I clinical trials testing AU403.

Grant Number: 5R33NS126618-03
NIH Institute/Center: NIH
Principal Investigator: Rajesh Amin