Therapeutic Advantages of Dual Targeting of PPAR-δ and PPAR-γ in an Experimental Model of Sporadic Alzheimer's Disease.

Abstract

Background: Alzheimer's disease (AD) is associated with progressive impairments in brain responsiveness to insulin and insulin-like growth factor (IGF). Although deficiencies in brain insulin and IGF could be ameliorated with trophic factors such as insulin, impairments in receptor expression, binding, and tyrosine kinase activation require alternative strategies. Peroxisome proliferator-activated receptor (PPAR) agonists target genes downstream of insulin/IGF stimulation. Furthermore, their anti-oxidant and anti-inflammatory effects address other pathologies contributing to neurodegeneration.

Objectives: The goal of this research was to examine effects of dual delivery of L165, 041 (PPAR-δ) and F-L-Leu (PPAR-γ) agonists for remediating in the early stages of neurodegeneration.

Model: Experiments were conducted using frontal lobe slice cultures from an intracerebral Streptozotocin (i.c. STZ) rat model of AD.

Results: PPAR-δ+ PPAR-γ agonist treatments increased indices of neuronal and myelin maturation, and mitochondrial proliferation and function, and decreased neuroinflammation, AβPP-Aβ, neurotoxicity, ubiquitin, and nitrosative stress, but failed to restore choline acetyl transferase expression and adversely increased HNE(lipid peroxidation) and acetylcholinesterase, which would have further increased stress and reduced cholinergic function in the STZ brain cultures.

Conclusion: PPAR-δ + PPAR-γ agonist treatments have substantial positive early therapeutic targeting effects on AD-associated molecular and biochemical brain pathologies. However, additional or alternative strategies may be needed to optimize disease remediation during the initial phases of treatment.