Alzheimer Disease: Crosstalk between the Canonical Wnt/Beta-Catenin Pathway and PPARs Alpha and Gamma

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.

Keywords: Alzheimer disease; PPAR alpha; PPAR gamma; Wnt/beta-catenin; glycogen synthase kinase-3beta; lithium; riluzole.

Figure 1

A schematic model of the Wnt/beta-catenin pathway. In the Wnt “on state” (right part), Wnt binds both Fzd and LRP5/6 receptors to initiate LRP phosphorylation as well as Dsh/Fzd internalization. Dsh membrane translocation leads to dissociation of the axin/APC/GSK-3β complex. Beta-catenin phosphorylation is inhibited and it accumulates in the cytosol. The cytosolic beta-catenin translocates to the nucleus and binds to TCF/LEF factors. This results in the Wnt-responsive gene transcription. In Wnt “off state” (left part), Dsh dissociates from Fzd and Axin. APC and axin complex with GSK-3β. Beta-catenin is phosphorylated, dissociates from GSK-3β, migrates to the cytosol and is destroyed in the proteasome. Abbreviations: APC, adenomatous polyposis coli; Dsh, Disheveled; Fzd, Frizzled; GSK-3β, glycogen synthase kinase-3beta; LRP5/6, low density lipoprotein receptor-related protein 5/6; TCF/LEF, T-cell factor /lymphoid enhancer factor.

Figure 2

A schematic model of the Wnt/beta-catenin pathway in Alzheimer disease. In AD, the “on state” of canonical Wnt/beta-catenin pathway is interrupted at two potential levels. Firstly, extracellular Aβ activates DKK1 which inhibits the interaction between Wnt and LRP 5/6. Binding of Wnt to Fzd is suppressed and Dsh dissociates from Fzd/Axin and migrates to the cytosol. The recruitment of the destruction complex to the plasma membrane is suppressed. Inactivation of Dsh leads to stimulation of GSK-3β. Thus, APC and AXIN interact with GSK-3β and beta-catenin (Wnt “off state”). Beta-catenin is phosphorylated by GSK-3β. The destruction complex AXIN/APC/GSK-3β is activated and enhances the destruction process of beta-catenin in the proteasome. Secondly, PPAR gamma which is activated by agonists can inhibit the beta-catenin/TCF/LEF complex in the nucleus, thus inhibiting the transcription of Wnt target genes. Amyloid precursor protein (APP) can be cut into various fragments by α, β, and γ secretases. PPAR α activates the transcription of α secretase. Abbreviations APC, adenomatous polyposis coli; Dsh, Disheveled; Fzd, Frizzled; GSK-3β, glycogen synthase kinase-3beta; LRP5/6, low density lipoprotein receptor-related protein 5/6; TCF/LEF, T-cell factor /lymphoid enhancer factor; sAPPα, soluble APPα ectodomain; sAPPβ, soluble APPβ ectodomain; APP, Amyloid precursor protein; α, β, and γ, α, β, and γ secretases; Aβ, amyloid β peptide; DKK1, Dickkopf-related protein1.