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Transthyretin and the brain re-visited: Is neuronal synthesis of transthyretin protective in Alzheimer's disease?
Xinyi Li, Joel N Buxbaum
Molecular Neurodegeneration , 2011, DOI: 10.1186/1750-1326-6-79
Abstract: All amyloid fibrils are similar in appearance, displaying Congophilic, non-branching fibrils 7.5-10 nm in diameter. The twenty nine (thus far) identified human amyloid precursors [1] share no primary sequence and no common conformation although recent biophysical studies suggest the presence of conformationally/energetically similar repeat subunits which determine whether a given protein belongs to the "amylome" [2]. Further it has been suggested that while the precursors represent a variety of folded and unfolded native structures, a combination of primary structural features and level of expression determines the ordering of proteins along a proposed "edge of stability" under in vivo conditions, i.e. there are both qualitative and quantitative factors that influence whether a protein will aggregate in vivo [3,4]. The frequency of many of the amyloidoses increases with aging but their deposition appears to be independent, i.e. each has its own anatomically predisposed site and pattern [5]. Thus, while there are reported instances of mixed precursor deposition, they are relatively uncommon, e.g. [6-9]. Nonetheless the commonality of structure that leads precursor proteins to form fibrils suggests that interaction could occur, perhaps accelerating fibril formation. The example of transthyretin (TTR) and β-amyloid (Aβ) raises the question as to whether the effect may be, in truth, to reduce fibrillogenesis.Wild type and mutant forms of TTR are the precursors in the systemic human diseases, Familial Amyloidotic Polyneuropathy (FAP), Familial Amyloidotic Cardiomyopathy (FAC) and Senile Systemic Amyloidosis (SSA) [10]. In contrast, Alzheimer's disease (AD) is a localized amyloid disease of the brain. AD and the TTR amyloidoses share age dependence and are manifested as both autosomal dominant, mutation-related and sporadic (wild type protein associated) diseases. In the TTR amyloidoses the precursor is synthesized primarily by hepatocytes distant from the main sites of d
The role of microRNAs in regulating neuronal connectivity  [PDF]
Hui Chiu,Amel Alqadah,Chieh Chang
Frontiers in Cellular Neuroscience , 2014, DOI: 10.3389/fncel.2013.00283
Abstract: The assembly of functional neural circuits is critical for complex thoughts, behavior and general brain function. Precise construction of neural circuits requires orderly transition of sequential events from axon outgrowth, pathfinding, branching, to synaptogenesis. Each of these steps is required to be tightly regulated in order to achieve meticulous formation of neuronal connections. MicroRNAs (miRNAs), which silence gene expression post-transcriptionally via either inhibition of translation or destabilization of messenger RNAs, have emerged as key regulators of neuronal connectivity. The expression of miRNAs in neurons is often temporally and spatially regulated, providing critical timing and local mechanisms that prime neuronal growth cones for dynamic responses to extrinsic cues. Here we summarize recent findings of miRNA regulation of neuronal connectivity in a variety of experimental platforms.
Mitochondrial Ca2+ Overload Underlies Aβ Oligomers Neurotoxicity Providing an Unexpected Mechanism of Neuroprotection by NSAIDs  [PDF]
Sara Sanz-Blasco, Ruth A. Valero, Ignacio Rodríguez-Crespo, Carlos Villalobos, Lucía Nú?ez
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002718
Abstract: Dysregulation of intracellular Ca2+ homeostasis may underlie amyloid β peptide (Aβ) toxicity in Alzheimer's Disease (AD) but the mechanism is unknown. In search for this mechanism we found that Aβ1–42 oligomers, the assembly state correlating best with cognitive decline in AD, but not Aβ fibrils, induce a massive entry of Ca2+ in neurons and promote mitochondrial Ca2+ overload as shown by bioluminescence imaging of targeted aequorin in individual neurons. Aβ oligomers induce also mitochondrial permeability transition, cytochrome c release, apoptosis and cell death. Mitochondrial depolarization prevents mitochondrial Ca2+ overload, cytochrome c release and cell death. In addition, we found that a series of non-steroidal anti-inflammatory drugs (NSAIDs) including salicylate, sulindac sulfide, indomethacin, ibuprofen and R-flurbiprofen depolarize mitochondria and inhibit mitochondrial Ca2+ overload, cytochrome c release and cell death induced by Aβ oligomers. Our results indicate that i) mitochondrial Ca2+ overload underlies the neurotoxicity induced by Aβ oligomers and ii) inhibition of mitochondrial Ca2+ overload provides a novel mechanism of neuroprotection by NSAIDs against Aβ oligomers and AD.
Opposing Effects of Sirtuins on Neuronal Survival: SIRT1-Mediated Neuroprotection Is Independent of Its Deacetylase Activity  [PDF]
Jason A. Pfister, Chi Ma, Brad E. Morrison, Santosh R. D'Mello
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0004090
Abstract: Background Growing evidence suggests that sirtuins, a family of seven distinct NAD-dependent enzymes, are involved in the regulation of neuronal survival. Indeed, SIRT1 has been reported to protect against neuronal death, while SIRT2 promotes neurodegeneration. The effect of SIRTs 3–7 on the regulation of neuronal survival, if any, has yet to be reported. Methodology and Principal Findings We examined the effect of expressing each of the seven SIRT proteins in healthy cerebellar granule neurons (CGNs) or in neurons induced to die by low potassium (LK) treatment. We report that SIRT1 protects neurons from LK-induced apoptosis, while SIRT2, SIRT3 and SIRT6 induce apoptosis in otherwise healthy neurons. SIRT5 is generally localized to both the nucleus and cytoplasm of CGNs and exerts a protective effect. In a subset of neurons, however, SIRT5 localizes to the mitochondria and in this case it promotes neuronal death. Interestingly, the protective effect of SIRT1 in neurons is not reduced by treatments with nicotinamide or sirtinol, two pharmacological inhibitors of SIRT1. Neuroprotection was also observed with two separate mutant forms of SIRT1, H363Y and H355A, both of which lack deacetylase activity. Furthermore, LK-induced neuronal death was not prevented by resveratrol, a pharmacological activator of SIRT1, at concentrations at which it activates SIRT1. We extended our analysis to HT-22 neuroblastoma cells which can be induced to die by homocysteic acid treatment. While the effects of most of the SIRT proteins were similar to that observed in CGNs, SIRT6 was modestly protective against homocysteic acid toxicity in HT-22 cells. SIRT5 was generally localized in the mitochondria of HT-22 cells and was apoptotic. Conclusions/Significance Overall, our study makes three contributions - (a) it represents the first analysis of SIRT3–7 in the regulation of neuronal survival, (b) it shows that neuroprotection by SIRT1 can be mediated by a novel, non-catalytic mechanism, and (c) that subcellular localization may be an important determinant in the effect of SIRT5 on neuronal viability.
Aerobic production and utilization of lactate satisfy increased energy demands upon neuronal activation in hippocampal slices and provide neuroprotection against oxidative stress  [PDF]
Avital Schurr,Evelyne Gozal
Frontiers in Pharmacology , 2012, DOI: 10.3389/fphar.2011.00096
Abstract: Ever since it was shown for the first time that lactate can support neuronal function in vitro as a sole oxidative energy substrate, investigators in the field of neuroenergetics have been debating the role, if any, of this glycolytic product in cerebral energy metabolism. Our experiments employed the rat hippocampal slice preparation with electrophysiological and biochemical methodologies. The data generated by these experiments (a) support the hypothesis that lactate, not pyruvate, is the end-product of cerebral aerobic glycolysis; (b) indicate that lactate plays a major and crucial role in affording neural tissue to respond adequately to glutamate excitation and to recover unscathed post-excitation; (c) suggest that neural tissue activation is accompanied by aerobic lactate and NADH production, the latter being produced when the former is converted to pyruvate by mitochondrial lactate dehydrogenase (mLDH); (d) imply that NADH can be utilized as an endogenous scavenger of reactive oxygen species (ROS) to provide neuroprotection against ROS-induced neuronal damage.
Phytoceramide Shows Neuroprotection and Ameliorates Scopolamine-Induced Memory Impairment  [PDF]
Jae-Chul Jung,Yeonju Lee,Sohyeon Moon,Jong Hoon Ryu,Seikwan Oh
Molecules , 2011, DOI: 10.3390/molecules16119090
Abstract: The function and the role phytoceramide (PCER) and phytosphingosine (PSO) in the central nervous system has not been well studied. This study was aimed at investigating the possible roles of PCER and PSO in glutamate-induced neurotoxicity in cultured neuronal cells and memory function in mice. Phytoceramide showed neuro-protective activity in the glutamate-induced toxicity in cultured cortical neuronal cells. Neither phytosphingosine nor tetraacetylphytosphingosine (TAPS) showed neuroproective effects in neuronal cells. PCER (50 mg/kg, p.o.) recovered the scopolamine-induced reduction in step-through latency in the passive avoidance test; however, PSO did not modulate memory function on this task. The ameliorating effects of PCER on spatial memory were confirmed by the Morris water maze test. In conclusion, through behavioral and neurochemical experimental results, it was demonstrated that central administration of PCER produces amelioration of memory impairment. These results suggest that PCER plays an important role in neuroprotection and memory enhancement and PCER could be a potential new therapeutic agent for the treatment of neurodegenerative diseases such as Alzheimer’s disease.
Lithium and neuroprotection: translational evidence and implications for the treatment of neuropsychiatric disorders  [cached]
Diniz BS,Machado Vieira R,Forlenza OV
Neuropsychiatric Disease and Treatment , 2013,
Abstract: Breno Satler Diniz,1 Rodrigo Machado-Vieira,2,3 Orestes Vicente Forlenza2 1Department of Mental Health, National Institute of Science and Technology – Molecular Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil; 2Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, University of Sao Paulo, Sao Paulo, Brazil; 3Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, Bethesda, MD, USA Abstract: In the last two decades, a growing body of evidence has shown that lithium has several neuroprotective effects. Several neurobiological mechanisms have been proposed to underlie these clinical effects. Evidence from preclinical studies suggests that neuroprotection induced by lithium is mainly related to its potent inhibition of the enzyme glycogen synthase kinase-3 (GSK-3 ) and its downstream effects, ie, reduction of both tau protein phosphorylation and amyloid- 42 production. Additional neuroprotective effects include increased neurotrophic support, reduced proinflammatory status, and decreased oxidative stress. More recently, neuroimaging studies in humans have demonstrated that chronic use is associated with cortical thickening, higher volume of the hippocampus and amygdala, and neuronal viability in bipolar patients on lithium treatment. In line with this evidence, observational and case registry studies have shown that chronic lithium intake is associated with a reduced risk of Alzheimer's disease in subjects with bipolar disorder. Evidence from recent clinical trials in patients with mild cognitive impairment suggests that chronic lithium treatment at subtherapeutic doses can reduce cerebral spinal fluid phosphorylated tau protein. Overall, convergent lines of evidence point to the potential of lithium as an agent with disease modifying properties in Alzheimer’s disease. However, additional long-term studies are necessary to confirm its efficacy and safety for these patients, particularly as chronic intake is necessary to achieve the best therapeutic results. Keywords: lithium, Alzheimer’s disease, prevention, GSK-3 , neuroprotection
Yokukansan Inhibits Neuronal Death during ER Stress by Regulating the Unfolded Protein Response  [PDF]
Toru Hiratsuka,Shinsuke Matsuzaki,Shingo Miyata,Mitsuhiro Kinoshita,Kazuaki Kakehi,Shinji Nishida,Taiichi Katayama,Masaya Tohyama
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013280
Abstract: Recently, several studies have reported Yokukansan (Tsumura TJ-54), a traditional Japanese medicine, as a potential new drug for the treatment of Alzheimer's disease (AD). Endoplasmic reticulum (ER) stress is known to play an important role in the pathogenesis of AD, particularly in neuronal death. Therefore, we examined the effect of Yokukansan on ER stress-induced neurotoxicity and on familial AD-linked presenilin-1 mutation-associated cell death.
Mechanisms regulating neuronal excitability and seizure development following mTOR pathway hyperactivation  [PDF]
Candi L. LaSarge,Steve C. Danzer
Frontiers in Molecular Neuroscience , 2014, DOI: 10.3389/fnmol.2014.00018
Abstract: The phosphatidylinositol-3-kinase/phosphatase and tensin homolog (PTEN)-mammalian target of rapamycin (mTOR) pathway regulates a variety of neuronal functions, including cell proliferation, survival, growth, and plasticity. Dysregulation of the pathway is implicated in the development of both genetic and acquired epilepsies. Indeed, several causal mutations have been identified in patients with epilepsy, the most prominent of these being mutations in PTEN and tuberous sclerosis complexes 1 and 2 (TSC1, TSC2). These genes act as negative regulators of mTOR signaling, and mutations lead to hyperactivation of the pathway. Animal models deleting PTEN, TSC1, and TSC2 consistently produce epilepsy phenotypes, demonstrating that increased mTOR signaling can provoke neuronal hyperexcitability. Given the broad range of changes induced by altered mTOR signaling, however, the mechanisms underlying seizure development in these animals remain uncertain. In transgenic mice, cell populations with hyperactive mTOR have many structural abnormalities that support recurrent circuit formation, including somatic and dendritic hypertrophy, aberrant basal dendrites, and enlargement of axon tracts. At the functional level, mTOR hyperactivation is commonly, but not always, associated with enhanced synaptic transmission and plasticity. Moreover, these populations of abnormal neurons can affect the larger network, inducing secondary changes that may explain paradoxical findings reported between cell and network functioning in different models or at different developmental time points. Here, we review the animal literature examining the link between mTOR hyperactivation and epileptogenesis, emphasizing the impact of enhanced mTOR signaling on neuronal form and function.
Spectroscopic Investigations of Pentobarbital Interaction with Transthyretin  [PDF]
Saqer M. Darwish,Jafar Ghithan,Musa M. Abuteir,Mariam Faroun,Mahmoud M. Abu-hadid
Journal of Spectroscopy , 2013, DOI: 10.1155/2013/927962
Abstract: Transthyretin (TTR) aggregation has been characterized to be responsible for several amyloid diseases. Fourier transform infrared (FTIR) spectroscopy, fluorescence, and atomic force microscopy (AFM) are used to investigate secondary structure changes in transthyretin, induced upon thermal denaturation and interaction with pentobarbital. Spectral analysis revealed a strong static quenching of the intrinsic fluorescence of TTR by pentobarbital with a binding constant (K) estimated at . Fourier self-deconvolution (FSD) technique is used to evaluates intensity changes in the spectra of the component bands in the amide I and amide II regions due to the changes in pentobarbital concentration in the protein complex. The increases of the relative intensities of the peaks at 1614?cm?1 and 1507?cm?1 are due to the increase of pentobarbital concentrations which is linked to the formation of oligomers in the protein. 1. Introduction Transthyretin (TTR) is a plasma protein composed of 127-residue subunits mainly composed of β-sheet structures [1]. It is present in both human plasma and cerebrospinal fluid (CSF) with concentrations of (0.1–0.4?mg/mL) in human plasma and (0.017?mg/mL) in CSF [2]. X-ray crystal structure studies have shown that human TTR have a molecular weight of 55?kDa in a tetramer form with four identical subunits [3]. TTR is synthesized by the liver and released in the plasma, while the TTR in CSF is mostly produced by the choroid plexus [4–6]. It is considered to be the primary transporter of thyroid hormones in the form of thyroxine in the CSF and it carries retinol via interaction with the retinol-binding protein (RBP) [7]. Other additional function of TTR has been detected in the development of the central nervous system due to the high concentration during the prenatal and postnatal life [8]. Several research groups have shown cerebral TTR expression to rise during the course of experimental Alzheimer disease (AD) in mice and in response to the intake of some drug or mixtures of compounds such as gingko extracts or dietary fatty acids [9–11]. The process of transthyretin amyloidogenesis or amyloid fibril formation seems to be associated with some amyloid diseases. It is not understood precisely how TTR forms amyloids, but several biophysical studies on wild-type (WT) TTR reveals that tetramer dissociation is rate limiting for amyloidogenesis [12–14]. All amyloid diseases are characterized by misfolded proteins that undergo aggregation causing a deposition of insoluble amyloid fibrils either systemically or in specific organs as the brain
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