Abstract
The molecular mechanisms underlying the pathophysiology of Alzheimer's disease (AD) are still not fully understood. In AD, Wnt/beta-catenin signaling has been shown to be downregulated while the peroxisome proliferator-activated receptor (PPAR) gamma (mARN and protein) is upregulated. Certain neurodegenerative diseases share the same Wnt/beta-catenin/PPAR gamma profile, such as bipolar disorder and schizophrenia. Conversely, other NDs share an opposite profile, such as amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, multiple sclerosis, and Friedreich's ataxia. AD is characterized by the deposition of extracellular Abeta plaques and the formation of intracellular neurofibrillary tangles in the central nervous system (CNS). Activation of Wnt signaling or inhibition of both glycogen synthase kinase-3beta and Dickkopf 1, two key negative regulators of the canonical Wnt pathway, are able to protect against Abeta neurotoxicity and to ameliorate cognitive performance in AD patients. Although PPAR gamma is upregulated in AD patients, and despite the fact that it has been shown that the PPAR gamma and Wnt/beta catenin pathway systems work in an opposite manner, PPAR gamma agonists diminish learning and memory deficits, decrease Abeta activation of microglia, and prevent hippocampal and cortical neurons from dying. These beneficial effects observed in AD transgenic mice and patients might be partially due to the anti-inflammatory properties of PPAR gamma agonists. Moreover, activation of PPAR alpha upregulates transcription of the alpha-secretase gene and represents a new therapeutic treatment for AD. This review focuses largely on the behavior of two opposing pathways in AD, namely Wnt/beta-catenin signaling and PPAR gamma. It is hoped that this approach may help to develop novel AD therapeutic strategies integrating PPAR alpha signaling.
Highlights
Alzheimer disease (AD) represents the most common form of neurodegenerative dementia
peroxisome proliferator-activated receptor (PPAR) gamma expression is high in AD, PPAR gamma agonists have been used in AD for both humans and animal models and have been shown to induce beneficial effects (Combs et al, 2000; Sastre et al, 2003; Camacho et al, 2004; D’Abramo et al, 2005; Pedersen et al, 2006; Risner et al, 2006; Escribano et al, 2010)
Upregulation of Adam 10 signaling represents an interesting therapeutic strategy against overproduction of Abeta. These findings suggest PPAR alpha could be a therapeutic target for reducing Abeta burden in AD (Corbett et al, 2015), especially as PPAR alpha exerts powerful anti-inflammatory effects and Wnt/beta-catenin activation upregulates PPAR alpha expression (Kozinski and Dobrzyn, 2013)
Summary
Alzheimer disease (AD) represents the most common form of neurodegenerative dementia. Activation of the Wnt pathway by Wnt-3a prevents the Abeta-induced toxic effects, induces a decrease in GSK-3beta and tau phosphorylation and increases the level of cytoplasmic beta-catenin (Alvarez et al, 2004). Activation of the Wnt pathway via Wnt ligands or inhibition of key negative regulators of the Wnt pathway, such as DKK-1 and GSK-3beta, are able to protect against Abeta neurotoxicity and to ameliorate cognitive performance in AD patients (Alvarez et al, 2004; Rosi et al, 2010; Shruster et al, 2011; Clevers and Nusse, 2012; Maguschak and Ressler, 2012a,b; Purro et al, 2012; Vargas et al, 2014). The rationale that leads to the use of PPAR gamma agonists to treat AD would seem to merit discussion
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