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.

New Article with drawings: Wnt-5a increases NO and modulates NMDA receptor in rat hippocampal neurons

Wnt-5a increases NO and modulates NMDA receptor in rat hippocampal neurons

Francisco J. Muñoz^a, b, 

Juan A. Godoy^a, 

Waldo Cerpa^c, 

Inés M. Poblete^a, d, 

Juan Pablo Huidobro-Toro^a,d, 

Nibaldo C. Inestrosa^a, e

Abstract

Wnt signaling has a crucial role in synaptic function at the central nervous system. Here we evaluate whetherWnts affect nitric oxide (NO) generation in hippocampal neurons. We found that non-canonical Wnt-5atriggers NO production; however, Wnt-3a a canonical ligand did not exert the same effect. Co-administration of Wnt-5a with the soluble Frizzled related protein-2 (sFRP-2) a Wnt antagonist blocked the NO production.Wnt-5a activates the non-canonical Wnt/Ca²⁺ signaling through a mechanism that depends on Ca²⁺ release from Ryanodine-sensitive internal stores. The increase in NO levels evoked by Wnt-5a promotes the insertion of the GluN2B subunit of the NMDA receptor (NMDAR) into the neuronal cell surface. To the best of our knowledge, this is the first time that Wnt-5a signaling is related to NO production, which in turn increases NMDARs trafficking to the cell surface.

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.

Neurogenesis Re-Loaded !!

Neurogenesis in the Sub-Granular Zone (SGZ) of the hippocampus Reloaded!!. This drawing was created in comparison with one of my firsts design in the neurogenesis. Thanks to the creativity and patience to make everyday a nice work !

(Hace un tiempo había realizado este dibujo pero sin los conocimientos que he ido adquiriendo en el tiempo. Hoy año 2013 Graphique-science esta a la vanguardia!!!)

Cat brain !

The dark side of the brain !!

Is the first publication of the year. So, we can start with a classic image and with a phrase of Elbert Hubband:
"The brain is a commodity used to fertilize ideas.”

microglia a l'attaque !

The Microglia participate in the defense of the immune system in the brain, protecting us of any threat by the release of cytokines, chemokines, proteins, etc. So, prepare you to die when a microglia is activated!.

Tripartite synapse

tripartite synapse between neurons and astrocytes !

Identification of Inhibitory Synapses

Conversation between Per Andersen and John Eccles in Canberra, about the identification of a new type of interneuron with new properties. The cite is a extract of "The History of Neuroscience in Autobiography" VOLUME 4, Edited by Larry R. Squire.

Cajal rules!

Santiago Ramón y Cajal rules!!!!!!

His pioneering investigations of the microscopic structure of the brain were original: he is considered by many to be the father of modern neuroscience. He was skilled at drawing, and hundreds of his illustrations of brain cells are still used for educational purposes today!!!

BBB in a neurodegenerative condition

What's happen when the Brain Blood Barrier (BBB) is in neurodegenerative condition ???. Graphique Science bring to you the model of the BBB in Alzheimer Disease!

Cerebro murino / murine brain