051: Drug Discovery of PPAR (Peroxisome Proliferator Activated Receptor) Agonists as Promising Treatment for Alzheimer's Disease

Statement of Purpose: Alzheimer's disease (AD) continues to be a significant problem facing the aging population, and mortality rates indicate unmet medical needs. Clinically used pharmaceuticals on the market sadly only delay the symptoms for 6-12 months, while doing nothing to reverse the progression of the disease. There is a critical need to develop new targeted drug discovery molecules to better treat this unmet need.

Description of Methods & Materials: We have developed a new class of novel molecular targets using in silico technologies that bind within the desired target receptor with high selectivity. This novel class of compounds has a different mechanism of action than current AD drugs on the market, and offers a very promising new direction for future treatment. Our main objective is to evaluate the drugs effect on the AF-2 binding domain of specific PPAR receptors. Of the three PPAR receptors (Alpha, delta and gamma), gamma has been the most exclusively studied due to the long use of Thiazolidinedione drugs such as Rosiglitazone and Pioglitazone for the management of diabetes. PPAR-alpha is the most abundant nuclear receptor expressed in the brain, and this receptor regulates the expression of genes involved with amyloid precursor protein by activating alpha-secretase enzyme which enhances degradation. It also down regulates beta-secretase (BACE-1) which is the main enzyme responsible for amyloid-beta peptide release in AD patients. The first phase of the project required in silico technologies such as Molecular Operating Environment, MOE, to simulate binding within the AF-2 binding domain of the PPAR-alpha and delta receptor. The 10 best molecules evaluated in phase one were then moved on to phase two which was chemical synthesis. Molecules were synthesized and analyzed using NMR, MS, and IR technologies and then freeze-dried down to a powder to be analyzed against PPARgc1a antibodies in neuroblastoma and glial cells using western blot, ELISA technologies and finally in vitro analysis of neuroinflammatory markers in AD induced mice. Neuroinflammatory markers analyzed were interleukin 6, 1A, 1-beta, TNF-alpha, and NFkB.

Data & Results: Analysis of data of first and second generation compounds has shown improved cellular neurotransmission, decreased neuroinflammation expression, and improved memory both in vitro and in vivo with only a 30 day treatment in an AD animal model. Future research will focus on improving binding to PPAR receptors through chemical functional group modification.

Interpretation, Conclusion or Significance: So far, no drug on the market has shown a reversal in AD pathologies, only to slow the progression of the disease. This data so far has shown a promising start for future for the AD pathology where we can actually reverse AD pathologies.

Disclosures: We do not disclose any conflicts of interest.