Is Alzheimer's Disease related to Metabolic Syndrome? A Wnt Signaling Conundrum

Is Alzheimer’s Disease related to Metabolic Syndrome?
A Wnt Signaling Conundrum

Juvenal A. Ríos, Pedro Cisternas, Marco Arrese, Salesa
Barja and Nibaldo C. Inestrosa

Abstract

Alzheimer's disease (AD) is the most common cause of dementia, affecting more than 36 million people worldwide. AD is characterized by a progressive loss of cognitive functions. For years, it has been thought that age is the main risk factor for AD. Recent studies suggest that life style factors, including nutritional behaviors, play a critical role in the onset of dementia. Evidence about the relationship between nutritional behavior and AD includes the role of conditions such as obesity, hypertension, dyslipidemia and elevated glucose levels. The coexistence of some of these cardio-metabolic risk factors is generally known as metabolic syndrome (MS). Some clinical studies support the role of MS in the onset of AD. However, the cross-talk between the molecular signaling implicated in these disorders is unknown. In the present review, we focus on the molecular correlates that support the relationship between MS and the onset of AD. We also discuss relevant issues such as the role of leptin, insulin and renin-angiotensin signaling in the brain and the possible role of Wnt signaling in both MS and AD. We discuss the evidence supporting the use of ob/obmice, high-fructose diets, aortic coarctation-induced hypertension and Octodon degus, which spontaneously develops β-amyloid deposits and metabolic derangements, as suitable animal models to address the relationships between MS and AD. Finally, we examine emergent data supporting the role of Wnt signaling in the modulation of AD and MS, implicating this pathway as a therapeutic target in both conditions.

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New Review !!!! Brain metabolite clearance: impact on Alzheimer’s disease

Brain metabolite clearance: impact on Alzheimer’s disease

Juan M. Zolezzi and 

Nibaldo C. Inestrosa

Abstract

Alzheimer’s Disease (AD) is a complex neurodegenerative disorder often associated with aging and characterized by several critical molecular changes that take place in the brain. Among the molecular hallmarks of AD, increased levels of amyloid β-peptide (Aβ) and the subsequent Aβ-derived damage are the most well-studied factors; however, despite the large amounts of effort and resources devoted to the study of AD and AD pathophysiology, the scientific community still awaits therapeutic alternatives capable of ensuring a better outcome for AD patients. In 2012, Cramer et al. (Science 335:1503-1506 2012) astonished the scientific community by rescuing behavioral and cognitive impairments in AD mouse models via oral administration of bexarotene, a drug used to treat some types of skin cancer. Moreover, these authors demonstrated that bexarotene, a retinoid X receptor (RXR) agonist, exerts major effects on Aβ levels, mainly through increased apolipoprotein E (ApoE) expression. Apart from the valid questions addressed in Cramer’s work, only a few attempts have been made to explain the effects of bexarotene. Most of these explanations have been solely based on the ability of bexarotene to reduce Aβ levels and not on the mechanisms that lead to such a reduction. Although it is well known that an imbalance in the Aβ production/excretion rate is the basis of increased Aβ levels in AD, no further explanations have been proposed to address the potential involvement of the blood-brain barrier (BBB), a critical Aβ-clearance structure, in the bexarotene-mediated effects. Moreover, no attempt has been made to explain how the different effects observed after bexarotene administration are connected to each other. Based on current information and on our own experience with nuclear receptors (NR), we offer new perspectives on the mechanisms of bexarotene action, which should help to improve our knowledge of NRs.

Neuroprotection by Wnt signaling against Amyloid-beta peptide

New Article with drawings: Wnt Signaling in Skeletal Muscle Dynamics: Myogenesis, Neuromuscular Synapse and Fibrosis

Wnt Signaling in Skeletal Muscle Dynamics: Myogenesis, Neuromuscular Synapse and Fibrosis

Pedro Cisternas, 

Juan P. Henriquez, 

Enrique Brandan, 

Nibaldo C. Inestrosa

Abstract

The signaling pathways activated by Wnt ligands are related to a wide range of critical cell functions, such as cell division, migration, and synaptogenesis. Here, we summarize compelling evidence on the role of Wnt signaling on several features of skeletal muscle physiology. We briefly review the role of Wnt pathways on the formation of muscle fibers during prenatal and postnatal myogenesis, highlighting its role on the activation of stem cells of the adult muscles. We also discuss how Wnt signaling regulates the precise formation of neuromuscular synapses, by modulating the differentiation of presynaptic and postsynaptic components, particularly regarding the clustering of acetylcholine receptors on the muscle membrane. In addition, based on previous evidence showing that Wnt pathways are linked to several diseases, such as Alzheimer's and cancer, we address recent studies indicating that Wnt signaling plays a key role in skeletal muscle fibrosis, a disease characterized by an increase in the extracellular matrix components leading to failure in muscle regeneration, tissue disorganization and loss of muscle activity. In this context, we also discuss the possible cross-talk between the Wnt/β-catenin pathway with two other critical profibrotic pathways, transforming growth factor β and connective tissue growth factor, which are potent stimulators of the accumulation of connective tissue, an effect characteristic of the fibrotic condition. As it has emerged in other pathological conditions, we suggests that muscle fibrosis may be a consequence of alterations of Wnt signaling activity.

New paper with drawings: Canonical Wnt Signaling New Paper with drawings!: Protects Hippocampal Neurons from Aβ Oligomers: Role of Non-Canonical Wnt-5a/Ca2+ in Mitochondrial Dynamics

Canonical Wnt Signaling Protects Hippocampal Neurons from Aβ Oligomers: Role of Non-Canonical Wnt-5a/Ca2+ in Mitochondrial Dynamics

Carmen Silva-Alvarez1, Macarena Arrazola2, Juan A. Godoy1, Daniela Ordenes1 and Nibaldo C. Inestrosa1, 2*
1Cell and Molecular Biology, Pontifical Catholic University of Chile, Chile
2Cell and Molecular Biology, Pontifical Catholic University of Chile, Chile

Alzheimer´s disease (AD) is the most common type of age-related dementia. The disease is characterized by a progressive loss of cognitive abilities, severe neurodegeneration, synaptic loss and mitochondrial dysfunction. The Wnt signaling pathway participates in the development of the central nervous system and growing evidence indicates that Wnts also regulate the function of the adult nervous system. We report here, that indirect activation of canonical Wnt/β-catenin signaling using Bromoindirubin-30-Oxime (6-BIO), an inhibitor of glycogen synthase kinase-3β, protects hippocampal neurons from amyloid-β (Aβ) oligomers with the concomitant blockade of neuronal apoptosis. More importantly, activation with Wnt-5a, a non-canonical Wnt ligand, results in the modulation of mitochondrial dynamics, prevents changes induced by Aβ oligomers in mitochondrial fission-fusion dynamics and modulates Bcl-2 increases induced by oligomers. The canonical Wnt-3a ligand neither the secreted Frizzled-Related Protein (sFRP), a Wnt scavenger, did not prevent these effects. In contrast, some of the Aβ oligomer effects were blocked by Ryanodine. We conclude that canonical Wnt/β-catenin signaling controls neuronal survival, and that non-canonical Wnt/Ca2+ signaling controls mitochondrial dysfunction. To our knowledge, this is the first report showing that activation of non-canonical Wnt-5a/Ca2+signaling prevents Aβ oligomer neurotoxicity. Since mitochondrial dysfunction is present in neurodegenerative diseases, the therapeutic possibilities of the activation of Wnt signaling are evident.

New model for new ideas

Is the evolution baby !

New drawing model of a Signaling by Graphique-science

A couple of weeks ago, I was looking for a new design of drawings. So now, here is my new style of creations !!. More definition and more design with a new concept. Enjoy !  I will accept observations !.