Saturday, January 14, 2012

beta amyloid proteins | What is beta amyloid proteins|Papers on beta amyloid proteins|Research on beta amyloid proteins | Publications on beta amyl


1.
Arch Neurol. 2012 Jan;69(1):96-104.

Proteomic changes in cerebrospinal fluid of presymptomatic and affected persons carrying familial Alzheimer disease mutations.

Source

Mary S. Easton Center for Alzheimer's Disease Research, 10911 Weyburn Ave, Ste 200, Los Angeles, CA 90095. jringman@mednet.ucla.edu.

Abstract

OBJECTIVE:

To identify cerebrospinal fluid (CSF) protein changes in persons who will develop familial Alzheimer disease (FAD) due to PSEN1 and APP mutations, using unbiased proteomics.

DESIGN:

We compared proteomic profiles of CSF from individuals with FAD who were mutation carriers (MCs) and related noncarriers (NCs). Abundant proteins were depleted and samples were analyzed using liquid chromatography-electrospray ionization-mass spectrometry on a high-resolution time-of-flight instrument. Tryptic peptides were identified by tandem mass spectrometry. Proteins differing in concentration between the MCs and NCs were identified.

SETTING:

A tertiary dementia referral center and a proteomic biomarker discovery laboratory.

PARTICIPANTS:

Fourteen FAD MCs (mean age, 34.2 years; 10 are asymptomatic, 12 have presenilin-1 [PSEN1 ] gene mutations, and 2 have amyloid precursor protein [APP ] gene mutations) and 5 related NCs (mean age, 37.6 years).

RESULTS:

Fifty-six proteins were identified, represented by multiple tryptic peptides showing significant differences between MCs and NCs (46 upregulated and 10 downregulated); 40 of these proteins differed when the analysis was restricted to asymptomatic individuals. Fourteen proteins have been reported in prior proteomic studies in late-onset AD, including amyloid precursor protein, transferrin, α(1)β-glycoprotein, complement components, afamin precursor, spondin 1, plasminogen, hemopexin, and neuronal pentraxin receptor. Many other proteins were unique to our study, including calsyntenin 3, AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) 4 glutamate receptor, CD99 antigen, di- N-acetyl-chitobiase, and secreted phosphoprotein 1.

CONCLUSIONS:

We found much overlap in CSF protein changes between individuals with presymptomatic and symptomatic FAD and those with late-onset AD. Our results are consistent with inflammation and synaptic loss early in FAD and suggest new presymptomatic biomarkers of potential usefulness in drug development.

PMID:
22232349
[PubMed - in process]
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2.
J Neurochem. 2012 Jan;120 Suppl 1:109-24. doi: 10.1111/j.1471-4159.2011.07475.x. Epub 2011 Nov 28.

The physiology of the β-amyloid precursor protein intracellular domain AICD.

Source

Université de Nice Sophia-Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire UMR6097 CNRS, Equipe labellisée Fondation pour la Recherche Médicale, Sophia-Antipolis, Valbonne, France.

Abstract

J. Neurochem. (2012) 120 (Suppl. 1), 109-124. ABSTRACT: The amyloid-β precursor protein (βAPP) undergoes several cleavages by enzymatic activities called secretases. Numerous studies aimed at studying the biogenesis and catabolic fate of Aβ peptides, the proteinaceous component of the senile plaques that accumulate in Alzheimer's disease-affected brains. Relatively recently, another secretase-mediated β-APP-derived catabolite called APP IntraCellular Domain (AICD) entered the game. Whether AICD corresponded to a biologically inert by-pass product of βAPP processing or whether it could harbor its own function remained questionable. In this study, we review the mechanisms by which AICD is generated and how its production is regulated. Furthermore, we discuss the degradation mechanism underlying its rapid catabolic fate. Finally, we review putative AICD-related functions and more particularly, the numerous studies indicating that AICD could translocate to the nucleus and control at a transcriptional level, the expression of a series ofproteins involved in various functions including the control of cell death and Aβ degradation.

© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

PMID:
22122663
[PubMed - in process]
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3.
J Neurochem. 2012 Jan;120 Suppl 1:46-54. doi: 10.1111/j.1471-4159.2011.07459.x. Epub 2011 Nov 28.

Activation of α-secretase cleavage.

Source

Institute of Pharmacy and Biochemistry, Johannes Gutenberg University Mainz, Johann-Joachim-Becherweg 30, Mainz, Germany.

Abstract

J. Neurochem. (2012) 120 (Suppl. 1), 46-54. ABSTRACT: Alpha-secretase-mediated cleavage of the amyloid precursor protein (APP) releases the neuroprotective APP fragment sαAPP and prevents amyloid β peptide (Aβ) generation. Moreover, α-secretase-like cleavage of the Aβ transporter 'receptor for advanced glycation end products' counteracts the import of blood Aβ into the brain. Assuming that Aβ is responsible for the development of Alzheimer's disease (AD), activation of α-secretase should be preventive. α-Secretase-mediated APP cleavage can be activated via several G protein-coupled receptors and receptor tyrosine kinases. Protein kinase C, mitogen-activated protein kinases, phosphatidylinositol 3-kinase, cAMP and calcium are activators of receptor-induced α-secretase cleavage. Selective targeting of receptor subtypes expressed in brain regions affected by AD appears reasonable. Therefore, the PACAP receptor PAC1 and possibly the serotonin 5-HT(6) receptor subtype are promising targets. Activation of APP α-secretase cleavage also occurs upon blockade of cholesterol synthesis by statins or zaragozic acid A. Under physiological statin concentrations, the brain cholesterol content is not influenced. Statins likely inhibit Aβ production in the blood by α-secretase activation which is possibly sufficient to inhibit AD development. A disintegrin and metalloproteinase 10 (ADAM10) acts as α-secretase on APP. By targeting the nuclear retinoic acid receptor β, the expression of ADAM10 and non-amyloidogenic APP processing can be enhanced. Excessive activation of ADAM10 should be avoided because ADAM10 and also ADAM17 are not APP-specific. Both ADAM proteins cleave various substrates, and therefore have been associated with tumorigenesis and tumor progression.

© 2011 The Author. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

PMID:
21883223
[PubMed - in process]
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4.
Toxicol Sci. 2012 Jan 5. [Epub ahead of print]

Differing effects of toxicants (methylmercury, inorganic mercury, lead, amyloidβ and rotenone) on cultured rat cerebrocortical neurons: Differential expression of Rho proteins associated with neurotoxicity.

Abstract

Methylmercury (MeHg), inorganic mercury (IHg), lead (Pb), amyloid-β peptide (Aβ), and rotenone (RTN) are well-known toxicants. Here, we demonstrate that these 5 toxicants exhibit differing effects on cerebrocortical neurons. The concentration responsible for 30% loss of viability (EC30) values 3 days after exposure were approximately 100 nM for MeHg, IHg, and RTN, and 10 μM for Aβ. Neuritic degeneration and subsequent apoptotic cell death were observed in these toxicant-treated cells. In contrast, the EC30 value 3 days after exposure to Pb was >10 μM. We clarified the differential expression of Rho family proteins (Rac1, Cdc42, and RhoA) upon exposure to these 5 toxicants. Exposure to 100 nM MeHg, IHg, or RTN downregulated the expression of Rac1, related to neuritic extension, but did not affect RhoA, related to retraction. At a higher concentration (1 μM), IHg and RTN also acted through the suppression of Rac1, whereas increased MeHg toxicity was not associated with the expression of Rho family proteins. On the other hand, Pb and Aβ showed no effects on the expression of Rho proteins. Modification of the balance of neuritic extension and retraction by the suppression of Rho A rescued the neurotoxicity of 100 nM MeHg, IHg, and RTN. The results indicate that the imbalance of neuritic extension and retraction by the suppression of Rac1 by 100 nM MeHg, IHg, and RTN causes cerebrocortical neuron axonal degeneration and cell death. By contrast, the neurotoxicities of Pb, Aβ, and MeHg (at higher concentrations) are conferred by other toxic mechanisms.

PMID:
22223485
[PubMed - as supplied by publisher]
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5.
Antioxid Redox Signal. 2012 Jan 5. [Epub ahead of print]

The characterization of the Caenorhabditis elegans mitochondrial thioredoxin system uncovers an unexpected protective role of TRXR-2 in β-amyloidpeptide toxicity.

Source

Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide, Sevilla, Spain; bbcacval@alumno.upo.es.

Abstract

Aim: Functional in vivo studies on the mitochondrial thioredoxin system are hampered by the embryonic or larval lethal phenotypes displayed by murine or Drosophila knock-out models. Thus, the access to alternative metazoan knock-out models for the mitochondrial thioredoxin system is of critical importance. Results: We report here the characterization of the mitochondrial thioredoxin system of Caenorhabditis elegans that is composed of the genes trx-2 and trxr-2. We demonstrate that the proteins TRX-2 and TRXR-2 localize to the mitochondria of several cells and tissues of the nematode and that trx-2 and trxr-2 are upregulated upon induction of the mitochondrial unfolded protein response. Surprisingly, C. elegans trx-2(lof) and trxr-2(null) single and double mutants are viable and display similar growth rates as wild type controls. Moreover, the lack of the mitochondrial thioredoxin system does not affect longevity, ROS production or the apoptotic program. Interestingly, we found a protective role of TRXR-2 in a transgenic nematode model of Alzheimer´s Disease that expresses human β-amyloid peptide and causes an age-dependent progressive paralysis. Hence, trxr-2 downregulation enhanced the paralysis phenotype while a strong decrease of β-amyloid peptide andamyloid deposits occurred when TRXR-2 was overexpressed. Innovation: C. elegans provides the first viable metazoan knock-out model for the mitochondrial thioredoxin system and identifies a novel role of this system in β-amyloid peptide toxicity and Alzheimer´s Disease. Conclusion: The nematode strains characterized in this work make C. elegans an ideal model organism to study the pathophysiology of the mitochondrial thioredoxin system at the level of a complete organism.

PMID:
22220943
[PubMed - as supplied by publisher]
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6.
Neurochem Res. 2012 Jan 5. [Epub ahead of print]

Restraint Stress in Rats Alters Gene Transcription and Protein Translation in the Hippocampus.

Source

Department of Psychiatry, Alzheimer's Disease Research Centre, University of Szeged, Kálvária sgt. 57, 6701, Szeged, Hungary, santha.petra@gmail.com.

Abstract

Stress is a relatively new and emerging risk factor for Alzheimer's disease (AD). Severe stress can alter brain characteristics such as neuronal plasticity, due to changes in the metabolism of cytoskeletal proteins. In this study, male Wistar rats were exposed to restraint stress (RS) for 5 h daily for different time periods. At the end of the exposure periods, the amounts of β-actin, cofilin, amyloid precursor protein (APP) and mitogen-activated protein kinase 1 (MAPK-1) RNAs and proteins were investigated. The mRNA expressions of β-actin, cofilin and MAPK-1 followed U-shaped time course. Acute (3 days) and chronic (21 days) RS caused a fourfold and tenfold increases, respectively, in hippocampal β-actin mRNA expression. In the case of cofilin mRNA expression, elevations were detected in the hippocampus on days 3, 7 and 21. The APP mRNA level was increased on day 21. On protein level, chronic stress elevated the levels of β-actin, cofilin and APP in the hippocampus. These results suggest that stress causes the induction of some genes andproteins that are also elevated in AD selectively in the hippocampal region of the rat brain.

PMID:
22219132
[PubMed - as supplied by publisher]
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7.
PLoS One. 2011;6(12):e28881. Epub 2011 Dec 21.

A Carrier for Non-Covalent Delivery of Functional Beta-Galactosidase and Antibodies against Amyloid Plaques and IgM to the Brain.

Source

Department of Experimental Pathology, Mayo Clinic, Rochester, Minnesota, United States of America.

Abstract

BACKGROUND:

Therapeutic intervention of numerous brain-associated disorders currently remains unrealized due to serious limitations imposed by the blood-brain-barrier (BBB). The BBB generally allows transport of small molecules, typically <600 daltons with high octanol/water partition coefficients, but denies passage to most larger molecules. However, some receptors present on the BBB allow passage of cognate proteins to the brain. Utilizing such receptor-ligand systems, several investigators have developed methods for delivering proteins to the brain, a critical requirement of which involves covalent linking of the target protein to a carrier entity. Such covalent modifications involve extensive preparative and post-preparative chemistry that poses daunting limitations in the context of delivery to any organ. Here, we report creation of a 36-amino acid peptide transporter, which can transport a protein to the brain after routine intravenous injection of the transporter-protein mixture. No covalent linkage of the protein with the transporter is necessary.

APPROACH:

A peptide transporter comprising sixteen lysine residues and 20 amino acids corresponding to the LDLR-binding domain of apolipoprotein E (ApoE) was synthesized. Transport of beta-galactosidase, IgG, IgM, and antibodies against amyloid plques to the brain upon iv injection of the protein-transporter mixture was evaluated through staining for enzyme activity or micro single photon emission tomography (micro-SPECT) or immunostaining. Effect of the transporter on the integrity of the BBB was also investigated.

PRINCIPAL FINDINGS:

The transporter enabled delivery to the mouse brain of functional beta-galactosidase, human IgG and IgM, and two antibodies that labeled brain-associated amyloid beta plaques in a mouse model of Alzheimer's disease.

SIGNIFICANCE:

The results suggest the transporter is able to transport most or all proteins to the brain without the need for chemically linking the transporter to a protein. Thus, the approach offers an avenue for rapid clinical evaluation of numerous candidate drugs against neurological diseases including cancer. (299 words).

PMID:
22216132
[PubMed - in process]
PMCID: PMC3244419
Free PMC Article
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8.
FEBS J. 2011 Dec 23. doi: 10.1111/j.1742-4658.2011.08465.x. [Epub ahead of print]

Mapping out the multi-stage fibrillation of glucagon.

Source

 Interdisciplinary Nanoscience Center, Center for Insoluble Protein Structures, Department of Molecular Biology and Genetics, University of Aarhus, Gustav Wieds Vej 10C, DK-8000 Aarhus C, DENMARK  Department of Biomedicine, Aarhus University, Wilhelm Meyers Alle, DK-8000 Aarhus C, DENMARK  Novo Nordisk A/S, Hagedornsvej 1, DK-2820 Gentofte, DENMARK  Danish Power Systems Ltd., Technical University of Denmark, Kemitorvet, DK-2800 Lyngby, DENMARK.  SciAssist ApS, Wildersgade 26A, DK-1408 Copenhagen K, DENMARK.

Abstract

The 29-residue peptide hormone glucagon forms many different morphological types of amyloid-like fibrils, depending on solvent conditions. Here, we combine time-series far-UV circular dichroism with singular value decomposition (SVD) analysis to reveal six different conformational states populated during fibrillation at 25°C and pH 2.5. The existence of these states is supported by complementary fluorescence and electron microscopy data. This highlights a multitude of structural transitions of glucagon from unordered structure to β-sheets, β-turns and further tertiary level changes. We attribute the observed unusual far-UV CD spectra to tertiary level structural changes during the formation and maturation of fibrils. The fibrillation model for the whole process involves formation of three oligomeric species and two different morphologies of fibrils in the same solution. The visualization of annular pore-like species in the early stages of glucagon fibrillation and the prevalence of such species in the amyloidogenesis of several proteins indicates that they may be a common feature of the fibrillation process. This study gives significant insights on the stepwise conversion of soluble glucagon to its fibrillar state and identifies the importance of fibril twisting for its thermodynamic stabilization. STRUCTUREDDIGITALABSTRACT: Glucagon and Glucagon bind by circular dichroism (View interaction) Glucagon and Glucagon bind by transmission electron microscopy (View interaction) Glucagon and Glucagon bind by fluorescence technology (View interaction).

Journal compilation © 2011 Federation of European Biochemical Societies.

PMID:
22212535
[PubMed - as supplied by publisher]
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9.
J Mol Biol. 2011 Dec 23. [Epub ahead of print]

Amphiphilic Adsorption of Human Islet Amyloid Polypeptide Aggregates to Lipid/Aqueous Interfaces.

Abstract

Many amyloid proteins misfold into β-sheet aggregates upon interacting with biomembranes at the onset of diseases, such as Parkinson's disease and type II diabetes. The molecular mechanisms triggering aggregation depend on the orientation of β-sheets at the cell membranes. However, understanding how β-sheets adsorb onto lipid/aqueous interfaces is challenging. Here, we combine chiral sum frequency generation (SFG) spectroscopy and ab initio quantum chemistry calculations based on a divide-and-conquer strategy to characterize the orientation of human islet amyloidpolypeptides (hIAPPs) at lipid/aqueous interfaces. We show that the aggregates bind with β-strands oriented at 48° relative to the interface. This orientation reflects the amphiphilic properties of hIAPP β-sheet aggregates and suggests the potential disruptive effect on membrane integrity.

Copyright © 2011. Published by Elsevier Ltd.

PMID:
22210153
[PubMed - as supplied by publisher]
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10.
J Mol Biol. 2011 Dec 21. [Epub ahead of print]

Sensitivity of Amyloid Formation by Human Islet Amyloid Polypeptide to Mutations at Residue 20.

Source

Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA.

Abstract

Islet amyloid polypeptide (IAPP, amylin) is responsible for amyloid formation in type 2 diabetes and in islet cell transplants. The only known natural mutation found in mature human IAPP is a Ser20-to-Gly missense mutation, found with small frequency in Chinese and Japanese populations. The mutation appears to be associated with increased risk of early-onset type 2 diabetes. Early measurements in the presence of organic co-solvents showed that S20G-IAPP formed amyloid more quickly than the wild type. We confirm that the mutant accelerates amyloid formation under a range of conditions including in the absence of co-solvents. Ser20 adopts a normal backbone geometry, and the side chain makes no steric clashes in models of IAPP amyloid fibers, suggesting that the increased rate of amyloidformation by the mutant does not result from the relief of steric incompatibility in the fiber state. Transmission electronic microscopy, circular dichroism, and seeding studies were used to probe the structure of the resulting fibers. The S20G-IAPP peptide is toxic to cultured rat INS-1 (transformed rat insulinoma-1) β-cells. The sensitivity of amyloid formation to the identity of residue 20 was exploited to design a variant that is much slower to aggregate and that inhibits amyloidformation by wild-type IAPP. An S20K mutant forms amyloid with an 18-fold longer lag phase. Thioflavin T binding assays, together with experiments using a p-cyanophenylalanine (p-cyanoPhe) variant of human IAPP, show that the designed S20K mutant inhibits amyloid formation by human IAPP. The experiments illustrate how p-cyanoPhe can be exploited to monitor amyloid formation even in the presence of other amyloidogenic proteins.

Copyright © 2011. Published by Elsevier Ltd.

PMID:
22206987
[PubMed - as supplied by publisher]
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11.
Biochem Biophys Res Commun. 2011 Dec 20. [Epub ahead of print]

The Nogo receptor 2 is a novel substrate of Fbs1.

Source

Neurobiochemistry - Biocenter, Innsbruck Medical University, Fritz-Preglstraße 3, 6020 Innsbruck, Austria.

Abstract

Members of the Nogo66 receptor family (NgR) are closely associated with nerve growth inhibition and plasticity in the CNS. All three members, NgR1, NgR2 and NgR3, are GPI anchored and highly glycosylated proteins. The binding and signaling properties of NgR1 are well described, but largely unknown for NgR2. At present the only known ligands are myelin associated glycoprotein (MAG) and amyloid beta precursor protein (APP). Despite the requirement of co-receptors for signaling no other binding partner has been uncovered. To learn more about the interactome of NgR2 we performed pull down experiments and were able to identify F-box protein that recognizes sugar chain 1 (Fbs1) as binding partner. We confirmed this finding with co-immunoprecipitations and in vitro binding assays and showed that the binding is mediated by the substrate recognition domain of Fbs1. As a substrate recognition protein of the SCF complex, Fbs1 binding leads to polyubiquitination and finally degradation of its substrates. This is the first time a member of the Nogo receptor family has been connected with an intracellular degradation pathway, which has not only implications for its production, but also for amyloid deposition in Alzheimer's disease.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID:
22206664
[PubMed - as supplied by publisher]
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12.
J Alzheimers Dis. 2011 Dec 27. [Epub ahead of print]

Fibrillar Amyloid-β1-42 Modifies Actin Organization Affecting the Cofilin Phosphorylation State: A Role for Rac1/cdc42 Effector Proteins and the Slingshot Phosphatase.

Source

Laboratory of Cellular and Molecular Neurosciences, University of Chile and International Center for Biomedicine (ICC), Santiago, Chile.

Abstract

The neuronal cytoskeleton regulates numerous processes that occur in normal homeostasis. Under pathological conditions such as those of Alzheimer's disease (AD), major alterations in cytoskeleton organization have been observed and changes in both microtubules and actin filaments have been reported. Many neurodegenerative consequences of AD are linked to the production and accumulation of amyloid peptides (Aβ) and their oligomers, produced from the internal cleavage of the amyloid-β protein precursor. We previously reported that fibrillar Aβ1-42 (fAβ) treatment of hippocampal neurons induced an increase in Rac1 and Cdc42 activities linking fAβ effects with changes in actin dynamics. Here we show fAβ-induces increased activity of PAK1 and cyclin-dependent kinase 5, and that p21-activated kinase (PAK1) activation targets the LIMK1-cofilin signaling pathway. Increased cofilin dephosphorylation under conditions of enhanced LIM-Kinase 1 (LIMK1) activity suggests that fAβ co-stimulates bifurcating pathways impacting cofilin phosphorylation. Overexpression of slingshot (SSH) prevents the augment of F-actin induced by fAβ after 24 h, suggesting that fAβ-induced changes in actin assembly involve both LIMK1 and SSH. These results suggest that fAb may alter the PAK1/LIMK1/cofilin axis and therefore actin organization in AD.

PMID:
22204905
[PubMed - as supplied by publisher]
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13.
Mol Neurodegener. 2011 Dec 28;6(1):87. [Epub ahead of print]

Transgenic neuronal overexpression reveals that stringently regulated p23 expression is critical for coordinated movement in mice.

Abstract

ABSTRACT:

BACKGROUND:

p23 belongs to the highly conserved p24 family of type I transmembrane proteins, which participate in bidirectional protein transport between the endoplasmic reticulum and Golgi apparatus. Mammalian p23 has been shown to interact with gamma-secretase complex, and modulate secretory trafficking as well as intramembranous processing of amyloid precursor protein in cultured cells. Negative modulation of beta-amyloid production by p23 in cultured cell lines suggested that elevation of p23 expression in neurons might mitigate cerebral amyloid burden.

RESULTS:

We generated several lines of transgenic mice expressing human p23 in neurons under the control of Thy-1.2 promoter. We found that even a 50% increase in p23 levels in the central nervous system of mice causes post-natal growth retardation, severe neurological problems characterized by tremors and seizure, ataxia, and uncoordinated movements, and premature death. The severity of the phenotype closely correlated with the level of p23 overexpression in multiple transgenic lines. While the number and general morphology of neurons in Hup23 mice appeared to be normal throughout the brain, abnormal non-Golgi p23 localization was observed in a subset of neurons with high transgene expression in brainstem. Moreover, detailed immunofluorescence analysis revealed marked proliferation of astrocytes, activation of microglia, and thinning of myelinated bundles in brainstem of Hup23 mice.

CONCLUSIONS:

These results demonstrate that proper level of p23 expression is critical for neuronal function, and perturbing p23 function by overexpression initiates a cascade of cellular reactions in brainstem that leads to severe motor deficits and other neurological problems, which culminate in premature death. The neurological phenotype observed in Hup23 mice highlights significant adverse effects associated with manipulating neuronal expression of p23, a previously described negative modulator of gamma-secretase activity and beta-amyloid production. Moreover, our report has broader relevance to molecular mechanisms in several neurodegenerative diseases as it highlights the inherent vulnerability of the early secretory pathway mechanisms that ensure proteostasis in neurons.

PMID:
22204304
[PubMed - as supplied by publisher]
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14.
Front Biosci (Elite Ed). 2012 Jan 1;4:1582-605.

Therapeutic targets of brain insulin resistance in sporadic Alzheimer's disease.

Source

Departments of Neurology, Neurosurgery, and Neuropathology, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI.

Abstract

Growing evidence supports roles for brain insulin and insulin-like growth factor (IGF) resistance and metabolic dysfunction in the pathogenesis of Alzheimer's disease (AD). Whether the underlying problem stems from a primary disorder of central nervous system (CNS) neurons and glia, or secondary effects of systemic diseases such as obesity, Type 2 diabetes, or metabolic syndrome, the end-results include impaired glucose utilization, mitochondrial dysfunction, increased oxidative stress, neuroinflammation, and the propagation of cascades that result in the accumulation of neurotoxic misfolded, aggregated, and ubiquitinated fibrillar proteins. This article reviews the roles of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-betaaccumulation, and impaired energy metabolism, and discusses therapeutic strategies and lifestyle approaches that could be used to prevent, delay the onset, or reduce the severity of AD. Finally, it is critical to recognize that AD is heterogeneous and has a clinical course that fully develops over a period of several decades. Therefore, early and multi-modal preventive and treatment approaches should be regarded as essential.

PMID:
22201977
[PubMed - in process]
15.
Front Biosci (Elite Ed). 2012 Jan 1;4:1420-33.

Estrogen receptors in lipid raft signalling complexes for neuroprotection.

Source

Laboratory of Cellular Neurobiology, Department of Physiology, School of Medicine; Institute of Biomedical Technologies, La Laguna University; and Canarian Institute of Cancer Research, Tenerife, Spain.

Abstract

Estrogens exert a plethora of actions conducted to brain preservation and functioning. Some of these actions are initiated in lipid rafts, which are particular microstructures of the plasma membrane. Preservation of lipid raft structure in neurons is essential for signal transduction against different injuries, such as Alzheimer's disease (AD). These membrane structures appear to be disrupted as this neuropathology evolves, and that may largely contribute to dysfunction of raft resident proteins involved in intracellular signalling. This review includes a survey of some protein interactions that are involved in the structural maintenance and signal transduction mechanisms for neuronal survival against AD. Particularly relevant are the rapid mechanisms developed by estrogen to prevent neuronal death, through membrane estrogen receptors (mER) interactions with a voltage-dependent anion channel (VDAC) and other protein markers within neuronal lipid rafts. These interactions may have important consequences in estrogen mechanisms to achieve neuroprotection against amyloid beta (Abeta-induced toxicity).

PMID:
22201966
[PubMed - in process]
16.
Front Biosci. 2012 Jan 1;17:451-72.

Metals in alzheimer's disease: a systemic perspective.

Source

Department of Neuroscience, AFaR, Fatebenefratelli Hospital, Rome, Italy, Department of Neurology, Campus Biomedico, University, Rome, Italy.

Abstract

Many results from in vitro and animal studies have highlighted the important role played by specific metals, such as copper, iron and zinc, in the diverse toxic pathways on which Alzheimer's disease (AD) develops. Metals seem to mediate the aggregation and neurotoxicity of amyloid-beta (ABeta), the main constituent of the amyloid plaques, commonly seen in AD (1). The link between metals and AD has been mostly investigated with a focus on their local accumulation in defined areas of the brain critical for AD. In the present review, I have instead approached the issue from the different perspective of a systemic, rather than local, alteration of copper and iron status. This view is supported by the results of a series of in vivo studies demonstrating that abnormalities of metals homeostasis correlate with the main deficits and specific markers of AD, such as ABeta and Tau proteins in the cerebrospinal fluid. These findings clearly suggest that local metals accumulation in brain areas critical for AD should be viewed within a wider framework of metals systemic alteration.

PMID:
22201755
[PubMed - in process]
17.
FEBS Lett. 2011 Dec 23. [Epub ahead of print]

Effect of N-homocysteinylation on physicochemical and cytotoxic properties ofamyloid β-peptide.

Source

Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.

Abstract

Abstract Hyperhomocysteinemia has recently been identified as an important risk factor for Alzheimer's disease (AD). One of the potential mechanisms underlying harmful effects of homocysteine (Hcy) is site-specific acylation of proteinsat lysine residues by homocysteine thiolactone (HCTL). The accumulation of amyloid β-peptide (Aβ) in the brain is a neuropathological hallmark of AD. In the present study we were interested to investigate the effects of N-homocysteinylation on the aggregation propensity and neurotoxicity of Aβ(1-42). By coupling several techniques, we demonstrated that the homocysteinylation of lysine residues increase the neurotoxicity of the Aβ peptide by stabilizing soluble oligomeric intermediates. STRUCTURED SUMMARY OF PROTEIN INTERACTIONS: A Beta 1-42 and A Beta 1-42bind by fluorescence technology (View interaction) A Beta 1-42 and A Beta 1-42bind by electron microscopy (View interaction).

Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

PMID:
22200570
[PubMed - as supplied by publisher]
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18.
J Mol Biol. 2011 Dec 19. [Epub ahead of print]

The Effect of Amyloidogenic Peptides on Bacterial Aging Correlates with Their Intrinsic Aggregation Propensity.

Source

Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.

Abstract

The formation of aggregates by misfolded proteins is thought to be inherently toxic, affecting cell fitness. This observation has led to the suggestion that selection against protein aggregation might be a major constraint on protein evolution. The precise fitness cost associated with protein aggregation has been traditionally difficult to evaluate. Moreover, it is not known if the detrimental effect of aggregates on cell physiology is generic or depends on the specific structural features of the protein deposit. In bacteria, the accumulation of intracellular protein aggregates reduces cell reproductive ability, promoting cellular aging. Here, we exploit the cell division defects promoted by the intracellular aggregation of Alzheimer's-disease-related amyloid β peptide in bacteria to demonstrate that the fitness cost associated with protein misfolding and aggregation is connected to the protein sequence, which controls both the in vivo aggregation rates and the conformational properties of the aggregates. We also show that the deleterious impact of protein aggregation on bacterial division can be buffered by molecular chaperones, likely broadening the sequential space on which natural selection can act. Overall, the results in the present work have potential implications for the evolution ofproteins and provide a robust system to experimentally model and quantify the impact of protein aggregation on cell fitness.

Copyright © 2011 Elsevier Ltd. All rights reserved.

PMID:
22200483
[PubMed - as supplied by publisher]
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19.
Med Clin (Barc). 2011 Dec 22. [Epub ahead of print]

[New trends in the treatment of amyloidosis.]

[Article in Spanish]

Source

Unidad de Enfermedades Autoinmunes y Sistémicas, Servicio de Medicina Interna, Hospital General Universitario Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, España.

Abstract

Amyloidosis is a clinical disorder caused by extracellular deposition of proteins that are normally soluble as insoluble fibrils that damage different organs. More than 20 proteins can form amyloid deposits. All types of amyloid fibrils have a secondary structure with a β folded shape that is characteristic and makes them to adopt a green birefringence after stained with Congo red and viewed under cross-polarized light. Amyloidosis can be acquired or hereditary, systemic or localized, and are classified by the fibril precursor protein. Advances in the knowledge of the pathogenesis of amyloidosis allows the development of new diagnostic and therapeutical schemes that are currently under investigation.

Copyright © 2011 Elsevier España, S.L. All rights reserved.

PMID:
22197598
[PubMed - as supplied by publisher]
20.
Trends Microbiol. 2011 Dec 22. [Epub ahead of print]

Diversity, biogenesis and function of microbial amyloids.

Source

Department of Molecular Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.

Abstract

Amyloid is a distinct β-sheet-rich fold that many proteins can acquire. Frequently associated with neurodegenerative diseases in humans, including Alzheimer's, Parkinson's and Huntington's diseases, amyloids are traditionally considered the product of protein misfolding. However, the amyloid fold is now recognized as a ubiquitous part of normal cellular biology. Functional amyloids have been identified in nearly all facets of cellular life, with microbial functional amyloids leading the way. Unlike disease-associated amyloids, functional amyloids are assembled by dedicated, directed pathways and ultimately perform a physiological function that benefits the organism. The evolved amyloidassembly and disassembly pathways of microbes have provided novel insights into how cells have harnessed theamyloid assembly process for productive means. An understanding of functional amyloid biogenesis promises to provide a fresh perspective on the molecular events that underlie disease-associated amyloidogenesis. Here, we review functional microbial amyloids with an emphasis on curli fibers and their role in promoting biofilm formation and other community behaviors.

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