Therapeutic Advantages of Dual Targeting of PPAR-δ and PPAR-γ in an Experimental Model of Sporadic Alzheimer’s Disease
Journal Title: Journal of Parkinson’s Disease and Alzheimer’s Disease - Year 2018, Vol 5, Issue 1
Abstract
Background: Alzheimer’s disease (AD) is associated with progressive impairments in brain responsiveness to insulin and insulinlike 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 t
Authors and Affiliations
De la Monte SM
Keywords
Related Articles
- EP ID EP496818
- DOI 10.13188/2376-922X.1000025
- Views 131
- Downloads 0
Alzheimer’s Disease: AdultOnset of Inborn Error of Methionine Metabolism
The cause and treatment of Alzheimer’s Disease remains obscure. It could arise from adult onset of an inborn error of metabolism of the essential amino acid methionine expressed through an alternate biochemical pathway f...
Dihydrolipoic Acid Conjugated Carbon Dots Accelerate Human Insulin Fibrillation
Protein fibrillation is believed to play an important role in the pathology and development of several human diseases, such as Alzheimer’s disease, Parkinson’s disease, and type 2 diabetes. Carbon dots (CDs), as a new ty...
Brain Health as a Key Concept in the Development of Strategies for Delaying Age- Related Cognitive Decline and Alzheimer’s Disease
The rapid growth of the elderly population is accompanied by a continuous increase in the incidence of neurodegenerative diseases. This demographic change has financial, social and cultural consequences although it also...
Sporadic Parkinsonism-Dementia Complex of Rhode Island with Unusually Abundant Glial TDP-43 Immunoreactivity
Background: Parkinson’s disease can overlap with other forms of neurodegeneration; however its co-occurrence with both frontotemporal lobar degeneration and motor neuron disease is distinctly rare although characteristic...
Lessons from a Rare Familial Dementia: Amyloid and Beyond
Here we review the similarities between a rare inherited disorder, familial British dementia (FBD), and the most common of all late-life neurological conditions, Alzheimer’s diseases (AD). We describe the symptoms, patho...