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 Review with drawings: Alzheimer’s disease: relevant molecular and physiopathological events affecting amyloid-β brain balance and the putative role of PPARs.

Alzheimer’s disease: relevant molecular and physiopathological events affecting amyloid-β brain balance and the putative role of PPARs.

Juan M. Zolezzi, Sussy Bastías-Candia, Manuel J. Santos and Nibaldo C. Inestrosa

New Review !! "Signaling pathway cross talk in Alzheimer’s disease"

Signaling pathway cross talk in Alzheimer’s disease

Juan A Godoy¹, Juvenal A Rios¹, Juan M Zolezzi², Nady Braidy³ and Nibaldo C Inestrosa^13*

Abstract

Numerous studies suggest energy failure and accumulative intracellular waste play a causal role in the pathogenesis of several neurodegenerative disorders and Alzheimer’s disease (AD) in particular. AD is characterized by extracellular amyloid deposits, intracellular neurofibrillary tangles, cholinergic deficits, synaptic loss, inflammation and extensive oxidative stress. These pathobiological changes are accompanied by significant behavioral, motor, and cognitive impairment leading to accelerated mortality. Currently, the potential role of several metabolic pathways associated with AD, including Wnt signaling, 5' adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), Sirtuin 1 (Sirt1, silent mating-type information regulator 2 homolog 1), and peroxisome proliferator-activated receptor gamma co-activator 1-α (PGC-1α) have widened, with recent discoveries that they are able to modulate several pathological events in AD. These include reduction of amyloid-β aggregation and inflammation, regulation of mitochondrial dynamics, and increased availability of neuronal energy. This review aims to highlight the involvement of these new set of signaling pathways, which we have collectively termed “anti-ageing pathways”, for their potentiality in multi-target therapies against AD where cellular metabolic processes are severely impaired.

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.

New Article in the cover!: Wnt signaling in the nervous system and in Alzheimer's disease.

Wnt signaling in the nervous system and in Alzheimer's disease.

Inestrosa NC1, Varela-Nallar L.

Abstract

Wnts comprise a large family of proteins that have shown to be part of a signaling cascade that regulates several aspects of development including organogenesis, midbrain development as well as stem cell proliferation. Wnt signaling pathway plays different roles in the development of neuronal circuits and also in the adult brain, where it regulates synaptic transmission and plasticity. It has been also implicated in various diseases including cancer and neurodegenerative diseases, reflecting its relevance in fundamental biological processes. This review summarizes the progress about Wnts function in mature nervous system with a focus on Alzheimer's disease (AD). We discuss the prospects of modulating canonical and non-canonical Wnt signaling as a strategy for neuroprotection. This will include the potential of Wnts to: (i) act as potent regulators of hippocampal synapses and impact in learning and memory; (ii) regulate adult neurogenesis; and finally (iii) control AD pathogenesis.

New article with some drawings .....: Role of Sirt1 During the Ageing Process: Relevance to Protection of Synapses in the Brain

Role of Sirt1 During the Ageing Process: Relevance to Protection of Synapses in the Brain

• Juan A. Godoy, 
• Juan M. Zolezzi, 
• Nady Braidy, 
• Nibaldo C. Inestrosa
• Abstract
• Ageing is a stochastic process associated with a progressive decline in physiological functions which predispose to the pathogenesis of several neurodegenerative diseases. The intrinsic complexity of ageing remains a significant challenge to understand the cause of this natural phenomenon. At the molecular level, ageing is thought to be characterized by the accumulation of chronic oxidative damage to lipids, proteins and nucleic acids caused by free radicals. Increased oxidative stress and misfolded protein formations, combined with impaired compensatory mechanisms, may promote neurodegenerative disorders with age. Nutritional modulation through calorie restriction has been shown to be effective as an anti-ageing factor, promoting longevity and protecting against neurodegenerative pathology in yeast, nematodes and murine models. Calorie restriction increases the intracellular levels of the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD+), a co-substrate for the sirtuin 1 (Sirt1, silent mating-type information regulator 2 homolog 1) activity and a cofactor for oxidative phosphorylation and ATP synthesis. Promotion of intracellular NAD+ anabolism is speculated to induce neuroprotective effects against amyloid-β-peptide (Aβ) toxicity in some models for Alzheimer’s disease (AD). The NAD+-dependent histone deacetylase, Sirt1, has been implicated in the ageing process. Sirt1 serves as a deacetylase for numerous proteins involved in several cellular pathways, including stress response and apoptosis, and plays a protective role in neurodegenerative disorders, such as AD.
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New research Article with drawings: SIRT1 Protects Dendrites, Mitochondria and Synapses from Aβ Oligomers in Hippocampal Neurons

SIRT1 Protects Dendrites, Mitochondria and Synapses from Aβ Oligomers in Hippocampal Neurons

Juan A Godoy¹, ¹Centro de Envejecimiento y Regeneración (CARE); Departamento de Biología Celular, Molecular; Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, ChileClaudio Allard¹, ¹Centro de Envejecimiento y Regeneración (CARE); Departamento de Biología Celular, Molecular; Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, ChileMacarena S Arrázola¹, ²Departamento de Biología, Facultad de Ciencias, Universidad de Tarapacá, Arica, ChileJuan M Zolezzi² and ¹Centro de Envejecimiento y Regeneración (CARE); Departamento de Biología Celular, Molecular; Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, ChileNibaldo C Inestrosa^1*

Aging is a major risk factor in the onset of neurodegenerative diseases, such as Alzheimer’s disease (AD). SIRT1, a β-NAD+-dependent histone deacetylase activity, holds great potential for promoting longevity, preventing against disease and increasing cell survival. We report here, that SIRT1 protects against the damage caused by Aβ oligomers at the level of synaptic contacts, dendritic branching and mitochondrial structure in cultured rat hippocampal neurons. Neurons overexpressing SIRT1 showed increased synaptic contacts, dendritic branching and preserved mitochondrial morphology, suggesting the prevention of the Aβ oligomer-mediated neurodegeneration. Such effects were not observed in neurons overexpressing a dominant negative form of SIRT1. The potential underlying signaling pathways involved in the SIRT1 neuroprotective mechanism are discussed in the context of the peroxisome proliferator-activated receptors (PPARs), peroxisome proliferator activated receptor co-activator 1α (PGC-1α), mTOR, and the Wnt signaling pathway. Our results suggest that SIRT1 modulation might well be a therapeutic agent to protect against neurodegenerative diseases, like AD.

Neuroprotection by Wnt signaling against Amyloid-beta peptide

New Review!! WNT signalling in neuronal maturation and synaptogenesis

WNT signalling in neuronal maturation and synaptogenesis

Silvana B. Rosso1 and Nibald C. Inestros

The Wnt signaling pathway plays a role in the development of the central nervous system (CNS) and growing evidence indicates that Wnts also regulates the structure and function of the adult nervous system. Wnt components are key regulators of a variety of developmental processes, including embryonic patterning, cell specification, and cell polarity. In the nervous system, Wnt signaling also regulates the formation and function of neuronal circuits by controlling neuronal differentiation, axon outgrowth and guidance, dendrite development, synaptic function and neuronal plasticity. Wnt factors can signal through three very well characterized cascades: canonical or β-catenin pathway, planar cell polarity pathway and calcium pathway that control different processes. However, divergent downstream cascades have been identified to control neuronal morphogenesis. In the nervous system, the expression of Wnt proteins is a highly controlled process. In addition, deregulation of Wnt signaling has been associated with neurodegenerative diseases. Here, we will review different aspects of neuronal and dendrite maturation, including spinogenesis and synaptogenesis. Finally, the role of Wnt pathway components on Alzheimer’s disease will be revised.

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.

Review: Wnt Signaling Roles on the Structure and Function of the Central Synapses: Involvement in Alzheimer’s Disease

Review with drawings accepted !  Click Review Here !!

This is a old version of drawings of Graphique-science, but now are coming new versions!

 Wnts compromise a large family of secreted glycoproteins that have shown to be part of the signaling molecules that regulate several aspects of development such as axis formation and midbrain development [1, 2]. In mammals at least 19 Wnt members have been found. The interaction of a Wnt protein with members of the Frizzled (Fz) family of seven-pass transmembrane cell-surface receptors triggers the activation of the Wnt signaling pathway . In human and mice, 10 members of the Fz family have been identified. In addition, receptor-like tyrosine kinase (Ryk) and receptor tyrosine kinase-like orphan receptor (Ror2) have been identified as alternative Wnt receptors [6-8]. Different Wnt signaling cascades are activated downstream the Wnt receptors, identified as Wnt/β-catenin or canonical pathway, and β-catenin-independent or non-canonical pathways. The canonical pathway involves the transcription of Wnt target genes, while activation of non-canonical Wnt pathways may induce either an increase in intracellular calcium concentration or activation of the c-Jun-N-terminal kinase (JNK) cascade.

Alzheimer Disease

The mechanisms involved in the pathogenic changes triggered in Alzheimer’s disease (AD) are not clearly understood, the neuronal dysfunction, which includes oxidative stress, cytoskeletal alterations and synaptic failure are all features that contributes to the progression of the disease.

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!