Tuesday, January 3, 2012

amyloid protein | What is amyloid protein|Papers on amyloid protein |Research on amyloid protein| Publications on amyloid protein


1.
Environ Toxicol Pharmacol. 2011 Dec 10;33(2):135-140. [Epub ahead of print]

The profile of β-amyloid precursor protein expression of rats induced by aluminum.

Source

Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China.

Abstract

The environmental agent aluminum has been extensively investigated for a potential relationship with amyloid precursorprotein (APP) expression. Despite many investigations, there is at present no definite proof from which to draw a conclusion. Since APP is an integral membrane protein expressed in different tissues and capable of fluxes across the blood-brain barrier (BBB), which may ultimately affect APP level in brain, it is necessary to assess the expression profile among vital body organs. The present study compared aluminum oxide and aluminum chloride injected rats with control rats (saline treated) to observe if aluminum affected APP expression patterns in different organs by immunohistochemistry (IHC). The expression of APP was observed in the brain of aluminum chloride treated rats and in the liver of aluminum oxide injected group. Results of double IHC staining showed that it is Kupffer cells, which are located in liver sinus and expressed APP after aluminum oxide treatment. Oxidative stress is suggested as the potential pathway that aluminum chloride exert effects in brain. These results suggest that different aluminum compounds may impact the expression of APP in brain and liver tissues. The mechanism that aluminum induced liver APP expression still needs further investigation.

Copyright © 2011 Elsevier B.V. All rights reserved.

PMID:
22209725
[PubMed - as supplied by publisher]
2.
Res Vet Sci. 2011 Dec 28. [Epub ahead of print]

Acute phase proteins in healthy and sick cats.

Source

School of Veterinary Science, The University of Queensland, Gatton, QLD 4343, Australia.

Abstract

Serum acute phase protein concentrations are used as diagnostic, therapeutic and prognostic markers in human and, less frequently, in animal medicine. The aim of this study was to determine how the health status and signalment of the cat are associated with concentrations of acute phase proteins. Generally, medians of the positive acute phase proteinsappeared to be higher in sick cats compared to healthy cats. In multivariable regression models, log-transformed serumamyloid A concentration was higher in older cats, in sick and in female cats, while log-transformed α1-acid glycoprotein and haptoglobin concentrations were higher in older cats and were associated with interactions of health status (sick/healthy) and gender (male/female). The data from healthy cats in this study contribute to the limited knowledge of normal reference ranges for this species. This study highlights the potential of acute phase proteins as diagnostic markers in sick cats, but also emphasises that the signalment of the cat needs to be taken into consideration.

Copyright © 2011 Elsevier Ltd. All rights reserved.

PMID:
22209081
[PubMed - as supplied by publisher]
3.
J Nutr Biochem. 2011 Dec 29. [Epub ahead of print]

Trans fatty acids enhance amyloidogenic processing of the Alzheimer amyloidprecursor protein (APP).

Source

Deutsches Institut für DemenzPrävention (DIDP), Neurodegeneration and Neurobiology, 66421 Homburg, Germany.

Abstract

Hydrogenation of oils and diary products of ruminant animals leads to an increasing amount of trans fatty acids in the human diet. Trans fatty acids are incorporated in several lipids and accumulate in the membrane of cells. Here we systematically investigate whether the regulated intramembrane proteolysis of the amyloid precursor protein (APP) is affected by trans fatty acids compared to the cis conformation. Our experiments clearly show that trans fatty acids compared to cis fatty acids increase amyloidogenic and decrease nonamyloidogenic processing of APP, resulting in an increased production of amyloid beta (Aβ) peptides, main components of senile plaques, which are a characteristic neuropathological hallmark for Alzheimer's disease (AD). Moreover, our results show that oligomerization and aggregation of Aβ are increased by trans fatty acids. The mechanisms identified by this in vitro study suggest that the intake of trans fatty acids potentially increases the AD risk or causes an earlier onset of the disease.

Copyright © 2012 Elsevier Inc. All rights reserved.

PMID:
22209004
[PubMed - as supplied by publisher]
4.
Turk Patoloji Derg. 2012;28(1):44-48. doi: 10.5146/tjpath.2012.01096.

Amyloidosis of Seminal Vesicles; Incidence and Pathologic Characteristics.

Source

Department of Pathology, Ege University, Faculty of Medicine, İZMİR, TURKEY.

Abstract

Objective: Amyloidosis is a rare disease with various etiologies with extracellular amyloid protein depositions. At present, at least 26 distinctive amyloid forms have been detected with different clinical importance and treatment. They have characteristic staning fetaures with Congo red. Amyloid may be detected in 2-10% of prostates that have been removed because of hyperplasia or carcinoma. Amyloidosis of seminal vesicles is accepted as senil amyloidosis and it is not accompanied by systemic amyloidosis or clinical symptoms. This condition is the most common form of localized amyloidosis. In this study we aimed to investigate incidence and histologic characteristics of amyloidosis of seminal vesicles in radical prostatectomy materials of the patients whose prostate carcinomas were treated surgically. Material and Method: Amyloid depositions in seminal vesicles of 207 radical prostatectomy materials that prostates had been removed due to localized prostate carcinoma. Amyloid depositions were confirmed with Congo red staining and polarization microscope. Results: Amyloidosis of seminal vesicles was detected in 10 (4.8%) of cases. Mean age of the patients is 66.2 years. Amyloid depositions tend to be nodular and bilateral in subepithelial region of affected seminal vesicles. Amyloid depositions were not detected in blood vessels in seminal vesicles or prostate parenchyma. Conclusion: Localized amyloidosis of seminal vesicles is not an unusual finding. amyloidosis of seminal vesicles incidence in Turkish patients included in this study and histopathologic characteristics of these patients are not different from the other studies. Systemic AA amyloidosis is the most common form of amyloidosis in our country. To be aware of amyloidosis of seminal vesicles is of importance in discrimination from the other forms of amyloidosis.

PMID:
22207431
[PubMed - as supplied by publisher]
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5.
Insect Biochem Mol Biol. 2011 Dec 22. [Epub ahead of print]

Functional amyloids in insect immune response.

Source

Università della Basilicata, Dipartimento di Biologia, Difesa e Biotecnologie Agro-Forestali, via dell'Ateneo Lucano 10, 85100 Potenza, Italy.

Abstract

The innate immune system of insects consists of humoural and cellular responses that provide protection against invading pathogens and parasites. Defence reactions against these latter include encapsulation by immune cells and targeted melanin deposition, which is usually restricted to the surface of the foreign invader, to prevent systemic damage. Here we show that a protein produced by haemocytes of Heliothis virescens (Lepidoptera, Noctuidae) larvae, belonging to XendoU family, generates amyloid fibrils, which accumulate in large cisternae of the rough endoplasmic reticulum and are released upon immune challenge, to form a layer coating non-self objects entering the haemocoel. This amyloid layer acts as a molecular scaffold that promotes localised melanin synthesis and the adhesion of immune cells around the non-self intruder during encapsulation response. Our results demonstrate a new functional role for theseprotein aggregates that are commonly associated with severe human diseases. We predict that insects will offer new powerful experimental systems for studying inducible amyloidogenesis, which will likely provide fresh perspectives for its prevention.

Copyright © 2011 Elsevier Ltd. All rights reserved.

PMID:
22207151
[PubMed - as supplied by publisher]
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6.
J Alzheimers Dis. 2011 Dec 29. [Epub ahead of print]

Altered CSF Orexin and α-Synuclein Levels in Dementia Patients.

Source

Molecular Memory Research Unit, The Wallenberg Lab, Lund University, Department of Clinical Sciences Malmö, Sweden.

Abstract

Neurodegenerative dementia, most frequently represented by Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), is often accompanied by altered sleeping patterns and excessive daytime sleepiness. Studies showing an association between the neuropeptide orexin and AD/DLB-related processes such as amyloid-β (Aβ)1-42 plaque formation, α-synuclein accumulation, and inflammation indicate that orexin might play a pathogenic role similar to the situation in narcolepsy. Our study of patients with AD (n = 26), DLB (n = 18), and non-demented controls (n = 24) shows a decrease in cerebrospinal fluid (CSF) orexin concentrations in DLB versus AD patients and controls. The observed differences in orexin levels were found to be specific to female DLB patients. We also show that the female DLB patients exclusively displayed lower levels of α-synuclein compared to AD patients and controls. Orexin was linked to α-synuclein and total-tau in female non-demented controls whereas associations between orexin and Aβ1-42 concentrations were absent in all groups regardless of gender. Thus, the proposed links between orexin, Aβ, and α-synuclein pathology could not be monitored in CSF protein concentrations. Interestingly, α-synuclein was strongly correlated to the CSF levels of total-tau in all groups, suggesting α-synuclein to be an unspecific marker of neurodegeneration. We conclude that lower levels of CSF orexin are specific to DLB versus AD and appear unrelated to Aβ1-42 and α-synuclein levels in AD and DLB. Alterations in CSF orexin and α-synuclein levels may be related to gender which warrants further investigation.

PMID:
22207004
[PubMed - as supplied by publisher]
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7.
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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8.
Neurobiol Aging. 2011 Dec 27. [Epub ahead of print]

Calpastatin modulates APP processing in the brains of β-amyloid depositing but not wild-type mice.

Source

Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA; New York University School of Medicine, New York, NY, USA.

Abstract

We report that neuronal overexpression of the endogenous inhibitor of calpains, calpastatin (CAST), in a mouse model of human Alzheimer's disease (AD) β-amyloidosis, the APP23 mouse, reduces β-amyloid (Aβ) pathology and Aβ levels when comparing aged, double transgenic (tg) APP23/CAST with APP23 mice. Concurrent with Aβ plaque deposition, aged APP23/CAST mice show a decrease in the steady-state brain levels of the amyloid precursor protein (APP) and APP C-terminal fragments (CTFs) when compared with APP23 mice. This CAST-dependent decrease in APP metabolite levels was not observed in single tg CAST mice expressing endogenous APP or in younger, Aβ plaque predepositing APP23/CAST mice. We also determined that the CAST-mediated inhibition of calpain activity in the brain is greater in the CAST mice with Aβ pathology than in non-APP tg mice, as demonstrated by a decrease in calpain-mediated cytoskeleton protein cleavage. Moreover, aged APP23/CAST mice have reduced extracellular signal-regulated kinase 1/2 (ERK1/2) activity and tau phosphorylation when compared with APP23 mice. In summary, in vivo calpain inhibition mediated by CAST transgene expression reduces Aβ pathology in APP23 mice, with our findings further suggesting that APP metabolism is modified by CAST overexpression as the mice develop Aβ pathology. Our results indicate that the calpain system in neurons is more responsive to CAST inhibition under conditions of Aβ pathology, suggesting that in the disease state neurons may be more sensitive to the therapeutic use of calpain inhibitors.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID:
22206846
[PubMed - as supplied by publisher]
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9.
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. Published by Elsevier Inc.

PMID:
22206664
[PubMed - as supplied by publisher]
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10.
Mol Pharm. 2011 Dec 29. [Epub ahead of print]

Phosphorus Dendrimers Affect Alzheimer's (Aβ1-28) Peptide and MAP-TauProtein Aggregation.

Abstract

Alzheimer's disease (AD) is characterized by pathological aggregation of β-amyloid peptides and MAP-Tau protein. β-amyloid (Aβ) is a peptide responsible for extracellular Alzheimer's plaque formation. Intracellular MAP-Tau aggregates appear as a result of hyperphosphorylation of this cytoskeletal protein. Small, oligomeric forms of Aβ are intermediate products that appear before the amyloid plaques are formed. These forms are believed to be most neurotoxic. Dendrimers are highly branched polymers, which may find an application in regulation of amyloid fibril formation. Several biophysical and biochemical methods, like circular dichroism (CD), fluorescence intensity of thioflavin T and thioflavin S, transmission electron microscopy, spectrofluorimetry (measuring quenching of intrinsic peptide fluorescence) and MTT-cytotoxicity assay, were applied to characterize interactions of cationic phosphorus-containing dendrimers of generation 3 and generation 4 (CPDG3, CPDG4) with the fragment of amyloid peptide (Aβ1-28) and MAP-Tau protein. We have demonstrated that CPDs are able to affect β-amyloid and MAP-Tau aggregation processes. A neuro-2a cell line (N2a) was used to test cytotoxicity of formed fibrils and intermediate products during the Aβ1-28 aggregation. It has been shown that CPDs might have a beneficial effect by reducing the system toxicity. Presented results suggest that phosphorus dendrimers may be used in the future as agents regulating the fibrilization processes in Alzheimer's disease.

PMID:
22206488
[PubMed - as supplied by publisher]
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11.
Neurochem Res. 2011 Dec 29. [Epub ahead of print]

Brain Serum Amyloid P Levels are Reduced in Individuals that Lack Dementia While Having Alzheimer's Disease Neuropathology.

Source

Department of Biochemistry and Cell Biology, Rice University, Houston, TX, 77005-1894, USA.

Abstract

The neuropathological signs of Alzheimer's disease (AD) include beta amyloid plaques and neurofibrillary tangles. There is a significant population of individuals that have these key hallmarks but show no signs of cognitive impairment, termed non-demented with AD neuropathology (NDAN). The protective mechanism allowing these individuals to escape dementia is unknown. Serum amyloid P (SAP) is a serum protein associated with wound repair that is elevated in the brains of Alzheimer's patients and binds to amyloid plaques. Using immunoblotting and immunohistochemistry, we evaluated SAP levels in postmortem samples of hippocampus and frontal cortex in age-matched controls, AD, and NDAN individuals. AD individuals had significantly increased SAP levels compared to normal controls, while NDAN samples had no significant difference in SAP levels compared to normal controls. Our results suggest that low levels of SAP in plaques marks the brains of individuals that escape dementia despite the presence of beta amyloid plaques and tangles.

PMID:
22205573
[PubMed - as supplied by publisher]
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12.
Neurodegener Dis. 2011 Dec 23. [Epub ahead of print]

Statins in Unconventional Secretion of Insulin-Degrading Enzyme and Degradation of the Amyloid-β Peptide.

Source

Department of Neurology, University of Bonn, Bonn, Germany.

Abstract

Population-based studies demonstrated that statins might decrease the risk of developing Alzheimer's disease (AD). Statins inhibit the 3-hydroxy-3-methyl-glutaryl-coenzyme-A reductase and thereby de novo synthesis of cholesterol. Cell culture and animal studies indicated that cholesterol affects the proteolytic processing of the amyloid precursor proteinand the generation of amyloid-β (Aβ). Recently, we have demonstrated that statins can also stimulate the degradation of Aβ. The statin-induced clearance of Aβ could be attributed to increased release of the insulin-degrading enzyme (IDE) via an exosome-related unconventional secretory pathway. Interestingly, this statin-induced secretion of exosome-associated IDE was independent of cellular cholesterol concentrations, but rather caused by impairment of isoprenoid biosynthesis and protein prenylation. We further identified a new hexapeptide sequence in the C-terminal region of IDE, named the SlyX motif that is critically involved in IDE secretion. Taken these findings together, the increased clearance of Aβ by stimulated secretion of IDE might contribute to the protective effects of statins against AD.

Copyright © 2011 S. Karger AG, Basel.

PMID:
22205103
[PubMed - as supplied by publisher]
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13.
Neurodegener Dis. 2011 Dec 23. [Epub ahead of print]

p53, a Pivotal Effector of a Functional Cross-Talk Linking Presenilins and Pen-2.

Source

Institut de Pharmacologie Moléculaire et Cellulaire et Institut de NeuroMédecine Moléculaire, Equipe Labellisée Fondation pour la Recherche Médicale, Valbonne, France.

Abstract

The γ-secretase is a multiprotein complex responsible for the ultimate cut yielding amyloid-β peptides and their N-terminal truncated species. This complex is composed of at least four distinct entities, namely presenilin-1 (PS1) or PS2, anterior pharynx defective-1, presenilin enhancer-2 (Pen-2) and nicastrin. Very few studies examined the transcriptional regulation of this complex, and more precisely, whether some of the members functionally interact. Here, we summarize our previous data documenting the fact that Pen-2 controls cell death in a p53-dependent manner and our recent demonstration of a pivotal role of p53 as a regulator of Pen-2 transcription. As PS trigger amyloid precursorprotein intracellular domain-dependent regulation of p53, our studies delineate a feedback control mechanism by which PS and Pen-2 functionally interact in a p53-dependent manner.

Copyright © 2011 S. Karger AG, Basel.

PMID:
22205087
[PubMed - as supplied by publisher]
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14.
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 amyloidprotein 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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15.
Mol Neurodegener. 2011 Dec 28;6(1):88. [Epub ahead of print]

The Alzheimer's beta-secretase enzyme BACE1 is required for accurate axon guidance of olfactory sensory neurons and normal glomerulus formation in the olfactory bulb.

Abstract

ABSTRACT:

BACKGROUND:

The beta-secretase, beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), is a prime therapeutic target for lowering cerebral beta-amyloid (Abeta) levels in Alzheimer's disease (AD). Clinical development of BACE1 inhibitors is being intensely pursued. However, little is known about the physiological functions of BACE1, and the possibility exists that BACE1 inhibition may cause mechanism-based side effects. Indeed, BACE1-/- mice exhibit a complex neurological phenotype. Interestingly, BACE1 co-localizes with presynaptic neuronal markers, indicating a role in axons and/or terminals. Moreover, recent studies suggest axon guidance molecules are potential BACE1 substrates. Here, we used a genetic approach to investigate the function of BACE1 in axon guidance of olfactory sensory neurons (OSNs), a well-studied model of axon targeting in vivo.

RESULTS:

We bred BACE1-/- mice with gene-targeted mice in which GFP is expressed from the loci of two odorant-receptors (ORs), MOR23 and M72, and olfactory marker protein (OMP) to produce offspring that were heterozygous for MOR23-GFP, M72-GFP, or OMP-GFP and were either BACE1+/+ or BACE1-/-. BACE1-/- mice had olfactory bulbs (OBs) that were smaller and weighed less than OBs of BACE1+/+ mice. In wild-type mice, BACE1 was present in OSN axon terminals in OB glomeruli. In whole-mount preparations and tissue sections, many OB glomeruli from OMP-GFP; BACE1-/- mice were malformed compared to wild-type glomeruli. MOR23-GFP; BACE1-/- mice had an irregular MOR23 glomerulus that was innervated by randomly oriented, poorly fasciculated OSN axons compared to BACE1+/+ mice. Most importantly, M72-GFP; BACE1-/- mice exhibited M72 OSN axons that were mis-targeted to ectopic glomeruli, indicating impaired axon guidance in BACE1-/- mice.

CONCLUSIONS:

Our results demonstrate that BACE1 is required for the accurate targeting of OSN axons and the proper formation of glomeruli in the OB, suggesting a role for BACE1 in axon guidance. OSNs continually undergo regeneration and hence require ongoing axon guidance. Neurogenesis and the regeneration of neurons and axons occur in other adult populations of peripheral and central neurons that also require axon guidance throughout life. Therefore, BACE1 inhibitors under development for the treatment of AD may potentially cause axon targeting defects in these neuronal populations as well.

PMID:
22204380
[PubMed - as supplied by publisher]
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16.
Curr Pharm Des. 2011 Dec;17(37):4132-46.

Inflammatory markers in hyperlipidemia: from experimental models to clinical practice.

Source

75 Mikras Asias Str, 115 27 Athens, Greece. gsiasos@med.uoa.gr.

Abstract

The role of inflammation in the development and progression of cardiovascular diseases is well established. Systemic inflammation and immune system play a central role in atherogenesis. The strong dependence of the atherosclerotic process on both a state of continuous low grade inflammation and the presence of lipid abnormalities gave impetus to research the association between hyperlipidemia and inflammatory status. In experimental and clinical studies, several inflammatory markers such as C-reactive protein, tumor necrosis factor-alpha, interleukin 6, nuclear factor kappa-β, adhesion molecules, serum amyloid-α, lipoprotein-associated phospholipase A2, fibrinogen and sCD40 ligand are associated with lipids level. Although, cholesterol lowering treatment has several important beneficial effects, there is still little clinical experience or data from clinical trials, in order to treat patients with hyperlipidemia and impaired inflammatory status.

PMID:
22204374
[PubMed - in process]
17.
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
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18.
Neurochem Int. 2011 Dec 19. [Epub ahead of print]

Promotion of β-amyloid production by C-reactive protein and its implications in the early pathogenesis of Alzheimer's disease.

Source

Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.

Abstract

C-reactive protein (CRP) and β-amyloid protein (Aβ) are involved in the development of Alzheimer's disease (AD). However, the relationship between CRP and Aβ production is unclear. In vitro and in vivo experiments were performed to investigate the association of CRP with Aβ production. Using the rat adrenal pheochromocytoma cell line (PC12 cells) to mimic neurons, cytotoxicity was evaluated by cell viability and supernatant lactate dehydrogenase (LDH) activity. The levels of amyloid precursor protein (APP), beta-site APP cleaving enzyme (BACE-1), and presenilins (PS-1 and PS-2) were investigated using real-time polymerase chain reaction and Western blotting analysis. Aβ1-42 was measured by enzyme-linked immunosorbent assay. The relevance of CRP and Aβ as well as potential mechanisms were studied using APP/PS1 transgenic (Tg) mice. Treatment with 0.5-4.0μM CRP for 48h decreased cell viability and increased LDH leakage in PC12 cells. Incubation with CRP at a sub-toxic concentration of 0.2μM increased the mRNA levels of APP, BACE-1, PS-1, and PS-2, as well as Aβ1-42 production. CRP inhibitor reversed the CRP-induced upregulations of the mRNA levels of APP, BACE-1, PS-1, and PS-2, and the protein levels of APP, BACE-1, PS-1, and Aβ1-42, but did not reversed Aβ1-42 cytotoxicity. The cerebral levels of CRP and Aβ1-42 in APP/PS1 Tg mice were positively correlated, accompanied with the elevated mRNA expressions of serum amyloid P component (SAP), complement component 1q (C1q), and tumor necrosis factor-α (TNF-α). These results suggest that CRP cytotoxicity is associated with Aβ formation and Aβ-related markers expressions; CRP and Aβ were relevant in early-stage AD; CRP may be an important trigger in AD pathogenesis.

Copyright © 2011. Published by Elsevier Ltd.

PMID:
22202667
[PubMed - as supplied by publisher]
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19.
Front Biosci (Schol Ed). 2012 Jan 1;4:1126-50.

Alpha, beta-and gamma-secretases in alzheimer's disease.

Source

Universita degli Studi di Milano, Department of Pharmacological Sciences, Via Balzaretti, 9, Milano, Italy.

Abstract

Generation of Amyloid peptide (Abeta) is at the beginning of a cascade that leads to Alzheimer's disease. Currenty, the mechanisms of Abeta generation and Abeta prevention are subject of intensive research. Amyloid precursor protein(APP), as well as beta- and gamma-secretases are the principal players involved in Abeta production, while alpha-secretase cleavage on APP prevents Abeta deposition. Inhibitors or modulators that target beta- and gamma-secretases as well as alpha-secretase activators are promising candidates for treatment of Alzheimer's disease. A deep knowledge of the secretases is required to develop disease modifying drugs that target them. The most challenging quest is to translate the growing knowledge about the cell biology of secretases and their mechanisms of action into effective therapeutics. Here, we review the main features of the secretases.

PMID:
22202113
[PubMed - in process]
20.
Front Biosci (Elite Ed). 2012 Jan 1;4:1951-65.

Role of WWOX/WOX1 in Alzheimer's disease pathology and in cell death signaling.

Source

Institute of Basic Medicine Science, National Cheng Kung University, Tainan, Taiwan, 70101.

Abstract

Alzheimer's disease (AD) is the most common form of dementia with a progressive course. AD pathology is a manifestation of the underlying severity and neuroanatomic involvement of specific vulnerable brain regions and circuits that are responsible for neuronal dysfunction and death. The etiology of AD is largely unknown. It has been hypothesized that multiple factors, including genetic components, oxidative stress, intracellular or extracellular accumulation of amyloid, dysfunction of cystoskeletal and synapse components, neuronal loss by apoptosis, neuronal excitotoxicity, inflammation, mitochondria dysfunction, etc., may play important roles in the onset of the disease. WWOX/WOX1 is a candidate tumor suppressor. Human WWOX gene, encoding the WW domain-containing oxidoreductase (designated WWOX, FOR, or WOX1) protein, has been mapped to a fragile site on the chromosome ch16q23.3-24.1. Functionally, the WW domain is not only a tumor suppressor, but also a participant in molecular interactions, signaling, and apoptosis in many diseases. In this article, we review the potential mechanism by which WWOX/WOX1 may participate in the pathogenesis of AD with a focus on cell death signaling pathways in neurons.

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