Acta Neuropathol. 2010 Nov 14. [Epub ahead of print]
Brain aging and Aβ(1-42) neurotoxicity converge via deterioration in autophagy-lysosomal system: a conditional Drosophila model linking Alzheimer's neurodegeneration with aging.
Department of Neuroscience, Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA.
Abstract
Aging is known to be the most prominent risk factor for Alzheimer's disease (AD); however, the underlying mechanism linking brain aging with AD pathogenesis remains unknown. The expression of human amyloid beta 42 peptide (Aβ(1-42)), but not Aβ(1-40) in Drosophila brain induces an early onset and progressive autophagy-lysosomal neuropathology. Here we show that the natural process of brain aging also accompanies a chronic and late-onset deterioration of neuronal autophagy-lysosomal system. This process is characterized by accumulation of dysfunctional autophagy-lysosomal vesicles, a compromise of these vesicles leading to damage of intracellular membranes and organelles, necrotic-like intraneuronal destruction and neurodegeneration. In addition, conditional activation of neuronal autophagy in young animals is protective while late activation is deleterious for survival. Intriguingly, conditional Aβ(1-42) expression limited to young animals exacerbates the aging process to a greater extent than Aβ(1-42) expression in old animals. These data suggest that the neuronal autophagy-lysosomal system may shift from a functional and protective state to a pathological and deleterious state either during brain aging or via Aβ(1-42) neurotoxicity. A chronic deterioration of the neuronal autophagy-lysosomal system is likely to be a key event in transitioning from normal brain aging to pathological aging leading to Alzheimer's neurodegeneration.PMID: 21076961 [PubMed - as supplied by publisher]
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22.
Proc Natl Acad Sci U S A. 2010 Nov 12. [Epub ahead of print]
Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model.
Department of Cell Biology, Biomedical Research Foundation, Academy of Athens, 115 27 Athens, Greece.
Abstract
Scavenger receptor class B type I (SR-BI) is a high-density lipoprotein receptor that regulates cholesterol efflux from the peripheral tissues to the liver. SR-BI has been identified on astrocytes and vascular smooth muscle cells in Alzheimer's disease brain and has been shown to mediate adhesion of microglia to fibrillar amyloid-β (Aβ). Here we report that SR-BI mediates perivascular macrophage response and regulates Aβ-related pathology and cerebral amyloid angiopathy in an Alzheimer's mouse model. Reduction or deletion of SR-BI gene in heterozygous or homozygous deficient mice (SR-BI(+/-), (-/-)) resulted in a significant increase in perivascular macrophages in the brain. SR-BI deletion had no effect on apolipoprotein E or apolipoprotein AI levels in the mouse brain. Our analysis revealed increased levels of SR-BI expression in the brains of human amyloid precursor protein (Swedish, Indiana) transgenic mice (J20 line). To evaluate the role of SR-BI in Alzheimer's disease pathogenesis, we inactivated one SR-BI allele in J20 transgenic mice. SR-BI reduction in J20/SR-BI(+/-) mice enhanced fibrillar amyloid deposition and cerebral amyloid angiopathy and also exacerbated learning and memory deficits compared with J20 littermates. Immunohistochemical analysis revealed localization of SR-BI on perivascular macrophages in tight association with Aβ deposits. Our data suggest that SR-BI reduction impairs the response of perivascular macrophages to Aβ and enhances the Aβ-related phenotype and cerebral amyloid angiopathy in J20 mice. These results reveal that SR-BI, a scavenger receptor primarily involved in high-density lipoprotein cholesterol transport, plays an essential role in Alzheimer's disease and cerebral amyloid angiopathy.PMID: 21076037 [PubMed - as supplied by publisher]
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23.
J Struct Biol. 2010 Nov 11. [Epub ahead of print]
Hinge-loop mutation can be used to control 3D domain swapping and amyloidogenesis of human cystatin C.
Department of Medicinal Chemistry, Faculty of Chemistry, University of Gdańsk, 80-952 Gdańsk, Poland.
Abstract
Cystatins are natural inhibitors of cysteine proteases, enzymes that are widely distributed in animals, plants, and microorganisms. Human cystatin C (hCC) has been also recognized as an aggregating protein directly involved in the formation of pathological amyloid fibrils, and these amyloidogenic properties greatly increase in a naturally occurring L68Q hCC variant. For a long time only dimeric structure of wild-type hCC has been known. The dimer is created through 3D domain swapping process, in which two parts of the cystatin structure become separated from each other and next exchanged between two molecules. Important role in the domain swapping plays the L1 loop, which connects the exchanging segments and, upon dimerization, transforms from a β-turn into a part of a long β-strand. In the very recently published first monomeric structure of human cystatin C (hCC-stab1), dimerization was abrogated due to clasping of the β-strands from the swapping domains by an engineered disulfide bridge. We have designed and constructed another mutated cystatin C with the smallest possible structural intervention, that is a single-point mutation replacing hydrophobic V57 from the L1 loop by polar asparagine, known as a stabilizer of a β-turn motif. V57N hCC mutant occurred to be stable in its monomeric form and crystallized as a monomer, revealing typical cystatin fold with a five-stranded antiparallel β-sheet wrapped around an α-helix. Here we report a 2.04Å resolution crystal structure of V57N hCC and discuss the architecture of the protein in comparison to chicken cystatin, hCC-stab1 and dimeric hCC.Copyright © 2010 Elsevier Inc. All rights reserved.
PMID: 21074623 [PubMed - as supplied by publisher]
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24.
Behav Brain Res. 2010 Nov 11. [Epub ahead of print]
Inhibition of JNK phosphorylation reverses memory deficit induced by β-amyloid (1-42) associated with decrease of apoptotic factors.
Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Abstract
Alzheimer's disease (AD) is the most common form of dementia that is degenerative and terminal disease. The main reason of the disease is still unknown. β-amyloid (Aβ) plaques are the important hallmarks of memory impairment in patients suffering from AD. Aggregation of these plaques in the hippocampus appears during the development of the disease. One of the prominent factors having crucial impact in this process is MAPK. JNK, as a member of MAPK family has a pivotal role, especially in cell survival. We hypothesized that JNK may have beneficial effect on the process of memory improvement. Hence, we performed Morris water maze to investigate the possible impact of JNK inhibitor on spatial memory in Aβ-injected rats. Our data indicated that intracerebroventricular administration of SP600125, a JNK inhibitor, could significantly decrease escape latency and increase time spent in target quadrant, in treatment group. Furthermore, we evaluated some of the apoptotic factors in the hippocampus of the treated rats. Based on our data, the inhibitor led to the significant decrease in the amount of caspase-3, TUNEL positive cells, cyclooxygenase-2 and increase in Bcl-2/Bax ratio. Given the possible neuroprotective effects of SP600125 on Aβ-induced memory impairment and apoptosis, our results may open a new avenue for the treatment of AD.Copyright © 2010. Published by Elsevier B.V.
PMID: 21074575 [PubMed - as supplied by publisher]
Related citations 25.
J Mol Biol. 2010 Nov 10. [Epub ahead of print]
Inhibiting β-Secretase Activity in Alzheimer's Disease Cell Models with Single-Chain Antibodies Specifically Targeting APP.
Department of Chemical Engineering, Arizona State University, Box 876106, Tempe, AZ 85287-6106, USA.
Abstract
The Amyloid-β (Aβ) peptide is produced from the amyloid precursor protein (APP) by sequential proteolytic cleavage of APP first by β-secretase and then by γ-secretase. β-Site APP cleaving enzyme-1 (BACE-1) is the predominant enzyme involved in β-secretase processing of APP and is a primary therapeutic target for treatment of Alzheimer's disease. While inhibiting BACE-1 activity has obvious therapeutic advantages, BACE-1 also cleaves numerous other substrates with important physiological activity. Thus, blanket inhibition of BACE-1 function may have adverse side effects. We isolated a single-chain variable domain antibody (scFv) from a human-based scFv yeast display library that selectively inhibits BACE-1 activity toward APP by binding the APP substrate at the proteolytic site. We selected the iBSEC1 scFv, since it recognizes the BACE-1 cleavage site on APP but does not bind the adjacent highly antigenic N-terminal of Aβ, and thus it will target APP but not soluble Aβ. When added to 7PA2 cells, a mammalian cell line that overexpresses APP, the iBSEC1 scFv binds APP on the cell surface, reduces toxicity induced by APP overexpression, and reduces both intracellular and extracellular Aβ levels by around 50%. Since the iBSEC1 scFv does not contain the antibody F(c) region, this construct does not pose the risk of exacerbating inflammation in the brain as faced with full-length monoclonal antibodies for potential therapeutic applications.Copyright © 2010. Published by Elsevier Ltd.
PMID: 21073877 [PubMed - as supplied by publisher]
Related citations 26.
Acta Physiol (Oxf). 2010 Nov 12. doi: 10.1111/j.1748-1716.2010.02224.x. [Epub ahead of print]
Estrogen prevents β-amyloid inhibition of sympathetic α7-nAChR-mediated nitrergic neurogenic dilation in porcine basilar arteries.
Department of Pharmacology, Southern Illinois University School of Medicine, P.O. Box 19629, Springfield, IL, 62794-9629, U.S.A. College of Life Science, South China Normal University, Guangzhou 510631, China Department of research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan Tzu Chi College of Technology, Hualien, Taiwan Institute of Life Science, College of Life Sciences and Tzu Chi Center for Vascular Medicine, Tzu Chi University, Hualien, Taiwan.
Abstract
Aim: β-amyloid peptides (Aβs) have been shown to block cerebral nitrergic neurogenic vasodilation by blocking sympathetic α7-nAChRs, and that estrogen prevents Aβ-induced neurotoxicity. We examined whether Aβ inhibition of α7-nAChR-mediated cerebral nitrergic vasodilation was prevented by estrogen. Methods: Effects of Aβ and 17β-estradiol on neurogenic nitrergic vasodilation in isolated porcine basilar arteries were examined using wire-myography. Drug effects on nicotine- and choline-induced calcium influx and inward currents in porcine cultured superior cervical ganglion (SCG) were investigated using confocal microscopy and patch-clamp techniques, respectively. Results: Precontracted endothelium-denuded basilar arteries relaxed exclusively upon transmural nerve stimulation (TNS, 8 Hz), and applications of nicotine (100 μM) or choline (1mM), which was sensitive to nitro-L-arginine (L-NNA, 30 μM) and tetrodotoxin (TTX, 0.3 μM). The relaxation induced by nicotine and choline but not that by TNS was blocked reversibly by Aβ(1-40) in a concentration-dependent manner. Aβ(1-40) also reversibly blocked nicotine- and choline-induced increase of calcium influx and inward currents in the SCG neurons. Aβ inhibition of nicotine- and choline-induced α7-nAChR-mediated nitrergic vasodilation and inward currents was prevented by 17β-estradiol (10 μM), but not by α-estradiol (10 μM) or testosterone (10 μM). Conclusion: These results provide further evidence supporting that Aβ is an antagonist for the α7-nAChR found on postganglionic sympathetic adrenergic nerve terminals originating in the SCG. Aβ can cause constriction of cerebral arteries with possible decreased regional cerebral blood flow by blocking sympathetic nerve-mediated release of NO from the perivascular nitrergic nerves. This effect of Aβ can be prevented by endogenous estrogen but not testosterone.Copyright © 2010 Scandinavian Physiological Society.
PMID: 21073661 [PubMed - as supplied by publisher]
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27.
Eur J Neurosci. 2010 Nov 14. doi: 10.1111/j.1460-9568.2010.07482.x. [Epub ahead of print]
β-Secretase activity in rat astrocytes: translational block of BACE1 and modulation of BACE2 expression.
Bettegazzi B, Mihailovich M, Di Cesare A, Consonni A, Macco R, Pelizzoni I, Codazzi F, Grohovaz F, Zacchetti D.
San Raffaele Scientific Institute, via Olgettina 58, I-20132, Milano, Italy Vita-Salute San Raffaele University, Milano, Italy Italian Institute of Technology, Research Unit of Molecular Neuroscience, Milano, Italy.
Abstract
BACE1 and BACE2 are two closely related membrane-bound aspartic proteases. BACE1 is widely recognized as the neuronal β-secretase that cleaves the amyloid-β precursor protein, thus allowing the production of amyloid-β, i.e. the peptide that has been proposed to trigger the neurodegenerative process in Alzheimer's disease. BACE2 has ubiquitous expression and its physiological and pathological role is still unclear. In light of a possible role of glial cells in the accumulation of amyloid-β in brain, we have investigated the expression of these two enzymes in primary cultures of astrocytes. We show that astrocytes possess β-secretase activity and produce amyloid-β because of the activity of BACE2, but not BACE1, the expression of which is blocked at the translational level. Finally, our data demonstrate that changes in the astrocytic phenotype during neuroinflammation can produce both a negative as well as a positive modulation of β-secretase activity, also depending on the differential responsivity of the brain regions.© 2010 The Authors. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.
PMID: 21073551 [PubMed - as supplied by publisher]
Related citations 28.
Anal Chem. 2010 Nov 12. [Epub ahead of print]
Regenerable and Simultaneous Surface Plasmon Resonance Detection of Aβ(1-40) and Aβ(1-42) Peptides in Cerebrospinal Fluids with Signal Amplification by Streptavidin Conjugated to an N-Terminus-Specific Antibody.
College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan, People's Republic of China 410083, Department of Chemistry and Biochemistry, California State University, Los Angeles, Los Angeles, California 90032, United States, and Molecular Neurology, Huntington Medical Research Institutes, Pasadena, California 91101, United States.
Abstract
A major constituent in the deposit of the brain in a patient with Alzheimer's disease (AD) is the aggregates/fibrils of amyloid-β (Aβ) peptides containing 39-43 amino acids. The total Aβ levels and the concentration ratio between the most abundant Aβ(1-40) peptide and the more aggregation-prone Aβ(1-42) in body fluids (e.g., cerebrospinal fluid or CSF) have been suggested as possible criteria for early diagnosis of AD. By immobilizing capture antibodies specific to the two peptides in separate fluidic channels, surface plasmon resonance (SPR) has been used to quantify Aβ(1-40) and Aβ(1-42) present in CSF samples collected from AD patients and healthy donors. With signal amplification by streptavidin conjugated to an antibody that is selective to the common N-terminus of the Aβ peptides, concentrations as low as 20 pM can be readily measured. The range of Aβ peptide concentrations measurable by this method spans 4 orders of magnitude. The ability of regenerating the sensor surface for repeated measurements not only improves the reproducibility but also enhances the sample throughput. Our data reveal that the ratio of Aβ(1-40) concentration versus Aβ(1-42) concentration in CSF samples from AD patients is almost twice as high as that from healthy persons. In contrast to the commonly used enzyme-linked immunosorbent assay (ELISA), SPR obviates the need of a more expensive and less stable enzyme conjugate and the use of carcinogenic substrate for the signal detection and allows the binding events to be monitored in real time.PMID: 21073166 [PubMed - as supplied by publisher]
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29.
Metallomics. 2010 Nov 1;2(11):741-4. Epub 2010 Oct 21.
Zinc release of Zn₇-metallothionein-3 induces fibrillar type amyloid-β aggregates.
Laboratoire de Chimie de Coordination, Centre National de la Recherche Scientifique, 205 route de Narbonne, 77 Toulouse, France.
Abstract
The reactive oxygen species H₂O₂ promotes the Zn₇-metallothionein-3 induced Aβ(40) aggregation of fibrillar type structures via slow cysteine oxidation and Zn(2+) release, whereas amorphous aggregates are formed by addition of Zn(2+) to Aβ(40).PMID: 21072365 [PubMed - in process]
Related citations30.
Metallomics. 2010 Jul 1;2(7):474-9. Epub 2010 May 26.
Copper(i) and copper(ii) binding to β-amyloid 16 (Aβ16) studied by electrospray ionization mass spectrometry.
Laboratoire d'Electrochimie Physique et Analytique, Station 6, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland. hubert.girault@epfl.ch.
Abstract
Copper-β-amyloid 16 (Aβ16) complexes were investigated by electrospray ionization mass spectrometry (ESI-MS). Copper(i) and (ii) complexes were formed on-line in a microchip electrospray emitter by using a sacrificial copper electrode as the anode in positive ionization mode. In the presence of ascorbic acid in the peptide solution, the amount of Cu(i)-Aβ16 generated electrochemically was even higher. A kinetic model is proposed to account for the generation of copper complexes. The structure of Cu(i)-Aβ16 was investigated by tandem mass spectrometry (MS/MS), and the binding site of Cu(i) to Aβ16 was identified at the His13, His14 residues. Cu(ii)-Aβ16 was also investigated by MS/MS and, based on the unusual observations of a-ions, the two binding residues of His13 and His14 of Aβ16 to Cu(ii) were also confirmed. This approach provides direct information on Cu(i)-Aβ16 complexes generated in solution from metallic copper and gives evidence that both His13 and His14 are involved in the coordination of both Cu(i)- and Cu(ii)-Aβ16 complexes.PMID: 21072347 [PubMed - in process]
Related citations31.
PLoS One. 2010 Nov 3;5(11):e13820.
Lactic Acid induces aberrant amyloid precursor protein processing by promoting its interaction with endoplasmic reticulum chaperone proteins.
Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida, United States of America.
Abstract
BACKGROUND: Lactic acid, a natural by-product of glycolysis, is produced at excess levels in response to impaired mitochondrial function, high-energy demand, and low oxygen availability. The enzyme involved in the production of β-amyloid peptide (Aβ) of Alzheimer's disease, BACE1, functions optimally at lower pH, which led us to investigate a potential role of lactic acid in the processing of amyloid precursor protein (APP).METHODOLOGY/PRINCIPAL FINDINGS: Lactic acid increased levels of Aβ40 and 42, as measured by ELISA, in culture medium of human neuroblastoma cells (SH-SY5Y), whereas it decreased APP metabolites, such as sAPPα. In cell lysates, APP levels were increased and APP was found to interact with ER-chaperones in a perinuclear region, as determined by co-immunoprecipitation and fluorescence microscopy studies. Lactic acid had only a very modest effect on cellular pH, did increase the levels of ER chaperones Grp78 and Grp94 and led to APP aggregate formation reminiscent of aggresomes.
CONCLUSIONS/SIGNIFICANCE: These findings suggest that sustained elevations in lactic acid levels could be a risk factor in amyloidogenesis related to Alzheimer's disease through enhanced APP interaction with ER chaperone proteins and aberrant APP processing leading to increased generation of amyloid peptides and APP aggregates.
PMID: 21072203 [PubMed - in process]PMCID: PMC2972223Free PMC Article
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32.
Biosci Biotechnol Biochem. 2010 Nov 7. [Epub ahead of print]
Selection of Peptide Inhibitors of Soluble Aβ(1-42) Oligomer Formation by Phage Display.
The University of Tokyo, Institute of Industrial Science.
Abstract
There have been many reports suggesting that soluble oligomers of amyloid β (Aβ) are neurotoxins causing Alzheimer's disease (AD). Although inhibition of the soluble oligomerization of Aβ is considered to be effective in the treatment of AD, almost all peptide inhibitors have been designed from the β-sheet structure (H14-D23) of Aβ(1-42). To obtain more potent peptides than the known inhibitors of the soluble-oligomer formation of Aβ(1-42), we performed random screening by phage display. After fifth-round panning of a hepta-peptide library against soluble Aβ(1-42), novel peptides containing arginine residues were enriched. These peptides were found to suppress specifically 37/48 kDa oligomer formation and to keep the monomeric form of Aβ(1-42) even after 24 h of incubation, as disclosed by SDS-PAGE and size-exclusion chromatography. Thus we succeeded in acquiring novel efficient peptides for inhibition of soluble 37/48 kDa oligomer formation of Aβ(1-42).PMID: 21071869 [PubMed - as supplied by publisher]Free Article
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33.
Biosci Biotechnol Biochem. 2010 Nov 7. [Epub ahead of print]
Silymarin Attenuated the Amyloid β Plaque Burden and Improved Behavioral Abnormalities in an Alzheimer's Disease Mouse Model.
Molecular Gerontology, Tokyo Metropolitan Institute of Gerontology.
Abstract
Alzheimer's disease (AD) is characterized by progressive cognitive impairment and the formation of senile plaques. Silymarin, an extract of milk thistle, has long been used as a medicinal herb for liver diseases. Here we report marked suppression of amyloid β-protein (Aβ) fibril formation and neurotoxicity in PC12 cells after silymarin treatment in vitro. In vivo studies had indicated a significant reduction in brain Aβ deposition and improvement in behavioral abnormalities in amyloid precursor protein (APP) transgenic mice that had been preventively treated with a powdered diet containing 0.1% silymarin for 6 months. The silymarin-treated APP mice also showed less anxiety than the vehicle-treated APP mice. These behavioral changes were associated with a decline in Aβ oligomer production induced by silymarin intake. These results suggest that silymarin is a promising agent for the prevention of AD.PMID: 21071836 [PubMed - as supplied by publisher]Free Article
Related citations 34.
Science. 2010 Nov 12;330(6006):918-9.
Medicine. Prion-like behavior of amyloid-beta.
Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
Comment on:PMID: 21071652 [PubMed - in process]
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35.
Exp Gerontol. 2010 Nov 8. [Epub ahead of print]
NOS-mediated morphological and molecular modifications in rats infused with Aβ (1-40), as a model of Alzheimer's disease, in response to a new lipophilic molecular combination codrug-1.
Dipartimento di Scienze del Farmaco, Università G. d'Annunzio, Chieti, Pescara, Italy.
Abstract
Alzheimer's disease is a neurodegenerative pathology due to the presence of β-amyloid plaques at brain level and hippocampus level and associated with the loss of memory speech and learning. At the basis of these effects lie molecular mechanisms which include nitric oxide metabolic pathway, whose involvement in the occurrence of morphological modifications related to such neurodegenerative process is suggested. Current evidences show that the non-steroidal anti-inflammatory drug ibuprofen posses a protective effect against the development of the disease, substantially delaying its onset; furthermore (R)-α-lipoic acid seems to have an antioxidant ameliorating effect on disease progression. Starting from these data, a new lipophilic codrug 1, obtained by joining an antioxidant molecule with an NSAID, has been previously synthesized. Our aim has been to investigate the possible therapeutical effects of codrug 1, compared to ibuprofen, on the molecular events at the basis of behavioural and morphological modifications occurring in Aβ (1-40) infused rat brains. Ibuprofen and codrug 1 seem to protect the subject against memory performance impairment and against behavioural detriment, induced by administration of Aβ (1-40) peptide. Such evidences are supported by morphological and biochemical findings showing Aβ (1-40) to determine cell disorganization, increased number of β-amyloid plaques and capillary vessels dilatation in parallel to increased total and specific NOS activity and to apoptosis occurrence, partly prevented by ibuprofen, more broadly by codrug 1. Such results underline the involvement of nitric oxide metabolic pathway in the events related to the onset of this pathology and suggest codrug 1 as a useful tool to protect the brain against cognitive and behavioural dysfunction, by reducing β-amyloid plaques formation and by inhibiting NOS signalling pathway and apoptosis occurrence.Copyright © 2010. Published by Elsevier Inc.
PMID: 21070848 [PubMed - as supplied by publisher]
Related citations 36.
Int J Clin Pract. 2010 Dec;64(13):1808-12. doi: 10.1111/j.1742-1241.2010.02536.x.
The procognitive effects of leptin in the brain and their clinical implications.
Department of Translational Medicine, John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
Abstract
Background: Leptin is a pleiotropic hormone produced mainly by the adipose tissue. Its most well-known effect is to regulate food intake and energy metabolism within the hypothalamus. More recently, several peripheral and extra-hypothalamic effects have been described, expanding leptin's actions far beyond energy balance. Aims: To review the extra-hypothalamic effects of leptin and their possible clinical implications. Methods: We did a PubMed search using the terms "leptin" AND "brain" AND "neuron" AND "glial", and selected the most relevant articles. Results: In extra-hypothalamic sites, leptin has remarkable effects on neurogenesis, axon growth, synaptogenesis, denditric morphology, development of oligodendroglial cells, neuron excitability, neuroprotection and regulation of beta-amyloid levels. Those effects have been shown to improve cognition and mood in animal models of depression and anxiety. In lean humans, leptin levels have been negatively correlated with the development of Alzheimer's disease. Conclusions: Leptin has extra-hypothalamic effects that may protect the brain against the development of mood and neurodegenerative disorders, such as Alzheimer's disease. Better understanding of those effects may lead to the development of potential leptin-based therapies against such conditions.© 2010 Blackwell Publishing Ltd.
PMID: 21070531 [PubMed - in process]
Related citations 37.
Proteins. 2010 Oct 7. [Epub ahead of print]
A differential association of Apolipoprotein E isoforms with the amyloid-β oligomer in solution.
Department of Biochemistry and Molecular Medicine, University of California Davis, California.
Abstract
The molecular pathogenesis of disorders arising from protein misfolding and aggregation is difficult to elucidate, involving a complex ensemble of intermediates, whose toxicity depends upon their state of progression along distinct processing pathways. To address the complex misfolding and aggregation that initiates the toxic cascade resulting in Alzheimer's disease (AD), we have developed a 2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid spin-labeled amyloid-β (Aβ) peptide to observe its isoform-dependent interaction with the apoE protein. Although most individuals carry the E3 isoform of apoE, ∼15% of humans carry the E4 isoform, which is recognized as the most significant genetic determinant for Alzheimer's. ApoE is consistently associated with the amyloid plaque marker for AD. A vital question centers on the influence of the two predominant isoforms, E3 and E4, on Aβ peptide processing and hence Aβ toxicity. We used electron paramagnetic resonance (EPR) spectroscopy of incorporated spin labels to investigate the interaction of apoE with the toxic oligomeric species of Aβ in solution. EPR spectra of the spin-labeled side chain report on side chain and backbone dynamics as well as the spatial proximity of spins in an assembly. Our results indicate oligomer binding involves the C-terminal domain of apoE, with apoE3 reporting a much greater response through this conformational marker. Coupled with SPR binding measurements, apoE3 displays a higher affinity and capacity for the toxic Aβ oligomer. These findings support the hypothesis that apoE polymorphism and Alzheimer's risk can largely be attributed to the reduced ability of apoE4 to function as a clearance vehicle for the toxic form of Aβ. Proteins 2010. © 2010 Wiley-Liss, Inc.PMID: 21069870 [PubMed - as supplied by publisher]
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38.
J Neural Transm. 2010 Nov 11. [Epub ahead of print]
Increased expression of β amyloid precursor gene in the hippocampus of streptozotocin-induced diabetic mice with memory deficit and anxiety induction.
Department of Pharmacology and Toxicology and Metabolic Diseases Research Laboratory, School of Dentistry, Kyung Hee University, Seoul, 130-701, Korea.
Abstract
Diabetes has been associated with memory and behavioral dysfunctions such as anxiety. However, exact mechanisms of how diabetes affect such changes remain to be characterized. The purpose of present study is to search for streptozotocin-regulated genes in hippocampus of the mice using a differential display PCR technique, in the hope of type I diabetes-related hippocampal gene(s). It has been found that expression of a PCR product was increased by streptozotocin treatment and it was identified as β amyloid precursor protein. These results were further confirmed by performing RT-PCR analysis. In addition, the protein expression of β amyloid precursor protein as evidenced by Western blot analysis was increased in the hippocampus of streptozotocin-induced diabetic mice. To explore if the changes in amyloid β precursor protein could be related with functional changes in the brain regarding memory activity and anxiety, passive avoidance test and elevated plus maze test were performed, respectively. There is significant reduction of memory formation and marked induction of anxiety in the streptozotocin-induced diabetic mice. These results suggest that increase of β amyloid precursor protein may play a role in the memory loss and anxiety induction in type I diabetic mice.PMID: 21069392 [PubMed - as supplied by publisher]
Related citations 39.
J Biol Chem. 2010 Nov 10. [Epub ahead of print]
Effect of tetracyclines on the dynamics of formation and destructuration of {beta}2-microglobulin amyloid fibrils.
Giorgetti S, Raimondi S, Pagano K, Relini A, Bucciantini M, Corazza A, Fogolari F, Codutti L, Salmona M, Mangione P, Colombo L, De Luigi A, Porcari R, Gliozzi A, Stefani M, Esposito G, Bellotti V, Stoppini M.
University of Pavia, Italy;
Abstract
The discovery of methods suitable for the conversion in vitro of native proteins into amyloid fibrils has shed light on the molecular basis of amyloidosis and has provided fundamental tools for drug discovery. We have studied the capacity of a small library of tetracycline analogues to modulate the formation or destructuration of β2-microglobulin fibrils. The inhibition of fibrillogenesis of the wild type protein was first established in the presence of 20% TFE and confirmed under a more physiologic environment including heparin and collagen. The latter conditions were also used to study the highly amyloidogenic variant, Pro32Gly. The NMR analysis showed that doxycycline inhibits β2-microglobulin self-association and stabilizes the native-like species through fast-exchange interactions involving specific regions of the protein. Cell viability assays demonstrated that the drug abolishes the natural cytotoxic activity of soluble β2-microglobulin, further strengthening a possible in vivo therapeutic exploitation of this drug. Doxycycline can disassemble preformed fibrils but the IC50 is five fold higher than that necessary for the inhibition of fibrillogenesis. Fibril destructuration is a dynamic and time dependent process characterized by the early formation of cytotoxic protein aggregates that, in a few hours, convert into non-toxic insoluble material. The efficacy of doxycycline as a drug against DRA would benefit from the ability of the drug to accumulate just in the skeletal system where amyloid is formed. In these tissues the doxycycline concentration reaches values several folds higher than those resulting in inhibition of amyloidogenesis and amyloid destructuration in vitro.PMID: 21068391 [PubMed - as supplied by publisher]Free Article
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40.
J Neurosci. 2010 Nov 10;30(45):14946-54.
Amyloid-independent mechanisms in Alzheimer's disease pathogenesis.
Department of Neuroscience, Lerner Research Institute, Cleveland Clinic, and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, USA. pimplis@ccf.org
Abstract
Despite the progress of the past two decades, the cause of Alzheimer's disease (AD) and effective treatments against it remain elusive. The hypothesis that amyloid-β (Aβ) peptides are the primary causative agents of AD retains significant support among researchers. Nonetheless, a growing body of evidence shows that Aβ peptides are unlikely to be the sole factor in AD etiology. Evidence that Aβ/amyloid-independent factors, including the actions of AD-related genes, also contribute significantly to AD pathogenesis was presented in a symposium at the 2010 Annual Meeting of the Society for Neuroscience. Here we summarize the studies showing how amyloid-independent mechanisms cause defective endo-lysosomal trafficking, altered intracellular signaling cascades, or impaired neurotransmitter release and contribute to synaptic dysfunction and/or neurodegeneration, leading to dementia in AD. A view of AD pathogenesis that encompasses both the amyloid-dependent and -independent mechanisms will help fill the gaps in our knowledge and reconcile the findings that cannot be explained solely by the amyloid hypothesis.PMID: 21068297 [PubMed - in process]
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