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.

Drawing: "Wnts in adult brain: from synaptic plasticity to cognitive deficiencies"

Wnts in adult brain: from synaptic plasticity to cognitive deficiencies.

Oliva CA, Vargas JY, Inestrosa NC.

Abstract

During development of the central nervous system the Wnt signaling pathway has been implicated in a wide spectrum of physiological processes, including neuronal connectivity and synapse formation. Wnt proteins and components of the Wnt pathway are expressed in the brain since early development to the adult life, however, little is known about its role in mature synapses. Here, we review evidences indicating that Wnt proteins participate in the remodeling of pre- and post-synaptic regions, thus modulating synaptic function. We include the most recent data in the literature showing that Wnts are constantly released in the brain to maintain the basal neural activity. Also, we review the evidences that involve components of the Wnt pathway in the development of neurological and mental disorders, including a special emphasis on in vivo studies that relate behavioral abnormalities to deficiencies in Wnt signaling. Finally, we include the evidences that support a neuroprotective role of Wnt proteins in Alzheimer's disease. We postulate that deregulation in Wnt signaling might have a fundamental role in the origin of neurological diseases, by altering the synaptic function at stages where the phenotype is not yet established but when the cognitive decline starts.

Mitocondrias y sinapsis / Mitochondrial and synaps

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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Ocelot urban dream?

http://graphiquescience.deviantart.com/art/Ocelot-urban-dream-432249022