PPARδ/Ɣ current NIH proposal:
Funded NIH-R15, R43, R44
Selective PPARδ/Ɣ agonist improves behavioral deficits and synaptic plasticity in a model of Alzheimer’s disease
The continuous increase incidences of Alzheimer’s disease (AD) with the increasing aged population and mortality rate indicates the urgent need for establishing novel molecular targets for therapeutic potential. Many reports verify direct pathological links such as increased amyloid beta, plaque formation and Tau mediated tangles between AD and diabetes, which highlights the contribution of diabetes to the development of AD.
Figure 1 PPARs mechanism of action for mitigating Alzheimer’s disease.
Thiazolidinediones (TZDs) such as rosiglitazone (rosi) and pioglitazone (pio) are known as insulin sensitizing peroxisomal proliferator activating receptor gamma (PPARg) agonists. TZDs have also been recognized as promising agents for improving cognition in patients with AD because they reduce amyloid and tau pathologies and improve memory impairments in diabetic mice (Figure 1). However, these agonists display poor blood-brain barrier permeability resulting in inadequate bio-availability in the brain and thus requiring high dosing with chronic time frames. Furthermore, these dosing levels are associated with several adverse effects including an increased incidence of myocardial infarction. Furthermore, there lacks a significant knowledge base for identifying molecular targets that brain-specific PPAR activation influences to improve memory in AD.
The innovation of our proposed research is based upon the development of novel selective PPARg/δ modulators (partial agonists) to better understand how central PPAR activation alters memory deficits in animal models of AD. (Figure 2) Our compounds were computationally designed to influence partial activation of PPARg activity by interaction with selective amino acids in the PPARg ligand binding domain. We have modified these compounds to also display enhanced blood-brain barrier (BBB) permeability, thus requiring lower concentrations to promote protection against AD. Evaluation of our lead compound, compound 9, by in vitro promoter activity and in vivo analysis has revealed that it lacks the life threatening adverse effects of traditional PPARg agonists in db/db mice. We expect that further evaluation of these compounds will lead to increased knowledge base for identifying molecular targets that will ameliorate memory deficits associated with AD.
Fig. 2 Docking images of AU9 compared to a full PPARg agonist (Pio.). AU9 serves as a partial PPARƔ agonist by avoiding forming interactions with Tyr-473 in the AF2 ligand binding domain.
A primary cause for progression of AD is the accumulation of amyloid beta peptide (Aβ) in the brain. Aβ is formed by the cleaving of the amyloid precursor protein by the protease, BACE1 (β-secretase). Thus, investigation into BACE-1 inhibition is a leading target for therapeutic potential. Recently TZDs have been found to attenuate BACE-1 expression. Further investigation into the consequences of increased Ab upon memory at the neuronal level revealed reduced neurotrophins such as brain-derived neurotrophic factor (BDNF) which mediates memory formation by inducing spine formation, post synaptic receptor expression and neurogenesis.
Our very exciting findings offer that centrally administered rosi intracerebroventricularly (ICV) (published in Neurobiology of Aging) as well as compound 9 significantly improve memory impairment and synaptic plasticity in db/db (type 2 diabetic) mice and more recently in 3xTgAD mice. Furthermore, we also found that central PPARƔ activation by rosi (ICV) and compound 9 (orally) induce postsynaptic receptor expression. Most unexpectedly, we observed significantly improved expression of brain neurotrophins including brain derived neurotrophic factor (BDNF) in db/db mice and 3xTgAD mice which helps explain the increase in the glutaminergic receptor expression, improved synaptic plasticity (LTP) and behavioral deficits. The full manuscript has been submitted in a special report of PPARs in the journal Cells (MDPI). The initial study was supported by an NIH-R15 NIHR15AG048643 grant. We then worked with a biotech company thus allowing us to be supported by an 1R43AG065069-01. After completion of this grant in 2021, we were recently informed by NIH that our phase 2, R44-AG065069-03A1 has been accepted and are waiting for NIH on the start date.