Tuesday, January 3, 2012

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


1.
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]
2.
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 precursor protein (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]
3.
Neurobiol Aging. 2011 Dec 29. [Epub ahead of print]

Impaired TrkB receptor signaling contributes to memory impairment in APP/PS1 mice.

Source

A. I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland.

Abstract

Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, learning, and memory. Levels of BDNF and its main receptor TrkB (TrkB.TK) have been reported to be decreased while the levels of the truncated TrkB (TrkB.T1) are increased in Alzheimer's disease. We show here that incubation with amyloid-β increased TrkB.T1 receptor levels and decreased TrkB.TK levels in primary neurons. In vivo, APPswe/PS1dE9 transgenic mice (APdE9) showed an age-dependent relative increase in cortical but not hippocampal TrkB.T1 receptor levels compared with TrkB.TK. To investigate the role of TrkB isoforms in Alzheimer's disease, we crossed AP mice with mice overexpressing the truncated TrkB.T1 receptor (T1) or the full-length TrkB.TK isoform. Overexpression of TrkB.T1 in APdE9 mice exacerbated their spatial memory impairment while the overexpression of TrkB.TK alleviated it. These data suggest thatamyloid-β changes the ratio between TrkB isoforms in favor of the dominant-negative TrkB.T1 isoform both in vitro and in vivo and supports the role of BDNF signaling through TrkB in the pathophysiology and cognitive deficits of Alzheimer's disease.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID:
22209410
[PubMed - as supplied by publisher]
4.
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]
5.
IEEE Trans Biomed Eng. 2011 Dec 26. [Epub ahead of print]

Investigating the Neural Correlates of Pathological Cortical Networks in Alzheimer's Disease using Heterogeneous Neuronal Models.

Abstract

This paper describes an investigation into the pathophysiological causes of abnormal cortical oscillations in Alzheimer's disease (AD) using two heterogeneous neuronal network models. The effect of excitatory circuit disruption on the betaband power (13-30 Hz) using a conductance-based network model of 200 neurons is assessed. Then, the neural correlates of abnormal cortical oscillations in different frequency bands based on a larger network model of 1000 neurons consisting of different types of cortical neurons is also analyzed. Electroencephalography (EEG) studies in AD patients have shown that beta band power (13-30 Hz) decreased in the early stages of the disease with a parallel increase in theta band power (4-7 Hz). This abnormal change progresses with the later stages of the disease but with decreased power spectra in other fast frequency bands plus an increase in delta band power (1-3 Hz). Our results show that, despite the heterogeneity of the network models, the beta band power is significantly affected by excitatory neural and synaptic loss. Secondly, the results of modeling a functional impairment in the excitatory circuit shows that beta band power exhibits the most decrease compared with other bands. Previous biological experiments on different types of cultural excitatory neurons show that cortical neuronal death is mediated by dysfunctional ionic behavior that might specifically contribute to the pathogenesis of β-amyloid peptide (Aβ)-induced neuronal death in AD. Our study also shows that beta band power was the first affected component when the modeled excitatory circuit begins to lose neurons and synapses.

PMID:
22207633
[PubMed - as supplied by publisher]
Click here to read
6.
J Alzheimers Dis. 2011 Dec 29. [Epub ahead of print]

Genomic and Nongenomic Signaling Induced by 1α,25(OH)2-Vitamin D3 Promotes the Recovery of Amyloid-β Phagocytosis by Alzheimer's Disease Macrophages.

Source

Department of Biochemistry, University of California, Riverside, California, USA.

Abstract

Brain clearance of amyloid-β (Aβ42) by innate immune cells is necessary for maintenance of normal brain function. Phagocytosis of soluble Aβ42 by Alzheimer's disease (AD) macrophages is defective, recovered in all "Type I and Type II" AD patients by 1α,25(OH)2-vitamin D3 (1,25D3) and blocked by the nuclear vitamin D receptor (VDR) antagonist (23S)-25-dehydro-1α(OH)-vitamin D3-26,23-lactone (MK). Bisdemethoxycurcumin (BDC) is a VDR ligand and additive with 1,25D3 in promoting Aβ42 phagocytosis by Type I, but not by Type II macrophages. Here, we define the following intracellular mechanisms regulated by 1,25D3 that are associated with recovery of phagocytosis and consistent with the selectivity of BDC: 1) 1,25D3 potentiates a 4,4-diisothiocyanostilbene-2,2-disulfonic acid-sensitive chloride channel (i.e., ClC-3) currents in both Type I and II AD macrophages, but curcumin only potentiates the currents in Type I cells; 2) 1,25D3 is particularly effective in upregulating ClC-3 mRNA expression in Type II peripheral blood mononuclear cells (PBMCs) while both 1,25D3 and the BDC analog, C180, upregulate VDR mRNA, repressed by Aβ42 in Type II PBMCs; and 3) 1,25D3-induced Aβ42 phagocytosis is attenuated by the calcium-dependent ClC-3 blocker, inositol 3,4,5,6-tetraphosphate (IP4), in both AD Types and by the MEK1/2 inhibitor U0126 only in Type II macrophages. VDR hydrogen/deuterium exchange coupled mass spectrometry and computational results show differences between the abilities of 1,25D3 and curcuminoids to stabilize VDR helices associated with the regulation of gene transcription. The structure-function results provide evidence that 1,25D3 activation of VDR-dependent genomic and nongenomic signaling, work in concert to recover dysregulated innate immune function in AD.

PMID:
22207005
[PubMed - as supplied by publisher]
Click here to read
7.
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]
Click here to read
8.
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]
Click here to read
9.
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]
Click here to read
10.
Neurobiol Aging. 2011 Dec 27. [Epub ahead of print]

A new neuronal target for beta-amyloid peptide in the rat hippocampus.

Source

Centre de Psychiatrie et Neurosciences, UMR 894, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.

Abstract

In Alzheimer's disease, amyloid beta peptide (Aβ) accumulation is associated with hippocampal network dysfunction. Intrahippocampal injections of Aβ induce aberrant inhibitory septohippocampal (SH) network activity in vivo and impairment of memory processing. In the present study, we observed, after hippocampal Aβ treatment, a selective loss of neurons projecting to the medial septum (MS) and containing calbindin (CB) and/or somatostatin (SOM). Other GABAergic neuronal subpopulations were not altered. Thus, the present study identifies hippocamposeptal neuron populations as specific targets for Aβ deposits. We observed that in Aβ-treated rats but not in controls, glutamate agonist application induced rhythmic bursting in 55% of the slow-firing neurons in the medial septum. This suggests that hippocampal Aβ can trigger modifications of the septohippocampal pathway via the alteration of a specific neuronal population. Long-range hippocamposeptal GABA/calbindin neurons, targets of hippocampal amyloid deposits, are implicated in supporting network synchronization. By identifying this target, we contribute to the understanding of the mechanisms underlying deleterious effects of Aβ, one of the main agents of dementia in Alzheimer's disease.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID:
22206845
[PubMed - as supplied by publisher]
Click here to read
11.
Crit Care. 2011 Dec 29;15(6):R297. [Epub ahead of print]

Biomarkers associated with delirium in critically ill patients and their relation with long-term subjective cognitive dysfunction; indications for different pathways governing delirium in inflamed and non-inflamed patients.

Abstract

ABSTRACT:

INTRODUCTION:

Delirium occurs frequently in critically ill patients and is associated with disease severity and infection. Although several pathways for delirium have been described, biomarkers associated with delirium in ICU patients is not well studied. We examined plasma biomarkers in delirious and non-delirious patients and the role of these biomarkers on long-term cognitive function.

METHODS:

In an exploratory observational study we included 100 ICU patients with or without delirium and with ("inflamed") and without ("non-inflamed") infection/SIRS. Delirium was diagnosed using the confusion assessment method-ICU (CAM-ICU). Within 24 hours following the onset of delirium, blood was obtained for biomarker analysis. There were no differences in patient characteristics between delirious and non-delirious patients. To determine associations between biomarkers and delirium univariate and multivariate logistic regression analyses was performed. Eighteen months after ICU discharge, a cognitive failure questionnaire was distributed to the ICU survivors.

RESULTS:

In total 50 delirious and 50 non-delirious patients were included. We found that IL-8, MCP-1, PCT, cortisol and S100-beta were significantly associated with delirium in inflamed patients (N=46). In the non-inflamed group of patients (N=54) IL-8, IL-1ra, IL-10 ratio A-beta1-42/40 and ratio A-betaN-42/40 were significantly associated with delirium. In multivariate regression analysis IL-8 was independently associated (odds ratio 9.0; 95%CI 1.8-44.0) with delirium in inflamed patients and IL-10 (OR 2.6; 95%CI 1.1 - 5.9) and A-beta1-42/40 (OR 0.03; 95%CI 0.002 - 0.50) with delirium in non-inflamed patients. Furthermore, levels of several amyloid-beta forms, but not human Tau or S100-beta, were significantly correlated with self reported cognitive impairment 18 months after ICU discharge, while inflammatory markers were not correlated to impaired long-term cognitive function.

CONCLUSIONS:

In inflamed patients the proinflammatory cytokine IL-8 was associated with delirium. While in non-inflamed patients anti-inflammatory cytokine IL-10 and A-beta1-42/40 were associated with delirium. This suggests that the underlying mechanism governing the development of delirium in inflamed patients differs from that in non-inflamed patients. Finally, elevated levels of amyloid-beta correlate with long-term subjective cognitive impairment delirium may represent the first sign of a (subclinical) dementia process. Future studies need to confirm these results.

PMID:
22206727
[PubMed - as supplied by publisher]
Click here to read
12.
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]
Click here to read
13.
Mol Pharm. 2011 Dec 29. [Epub ahead of print]

Phosphorus Dendrimers Affect Alzheimer's (Aβ1-28) Peptide and MAP-Tau Protein 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]
Click here to read
14.
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]
Click here to read
15.
Mol Neurobiol. 2011 Dec 29. [Epub ahead of print]

Brain Insulin Signaling and Alzheimer's Disease: Current Evidence and Future Directions.

Source

Department of Neuroscience, Uppsala University, Box 593, Husargatan 3, Uppsala, Sweden.

Abstract

Insulin receptors in the brain are found in high densities in the hippocampus, a region that is fundamentally involved in the acquisition, consolidation, and recollection of new information. Using the intranasal method, which effectively bypasses the blood-brain barrier to deliver and target insulin directly from the nose to the brain, a series of experiments involving healthy humans has shown that increased central nervous system (CNS) insulin action enhances learning and memory processes associated with the hippocampus. Since Alzheimer's disease (AD) is linked to CNS insulin resistance, decreased expression of insulin and insulin receptor genes and attenuated permeation of blood-borne insulin across the blood-brain barrier, impaired brain insulin signaling could partially account for the cognitive deficits associated with this disease. Considering that insulin mitigates hippocampal synapse vulnerability to amyloid beta and inhibits the phosphorylation of tau, pharmacological strategies bolstering brain insulin signaling, such as intranasal insulin, could have significant therapeutic potential to deter AD pathogenesis.

PMID:
22205300
[PubMed - as supplied by publisher]
Click here to read
16.
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 protein and 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]
Click here to read
17.
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 precursor protein 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]
Click here to read
18.
Pathobiology. 2011 Dec 28;79(2):55-71. [Epub ahead of print]

Road to Alzheimer's Disease: The Pathomechanism Underlying.

Source

Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

Abstract

Alzheimer's disease (AD), the most common cause of dementia, results from the interplay of various deregulated mechanisms triggering a complex pathophysiology. The neurons suffer from and slowly succumb to multiple irreversible damages, resulting in cell death and thus memory deficits that characterize AD. In spite of our vast knowledge, it is still unclear as to when the disease process starts and how long the perturbations continue before the disease manifests. Recent studies provide sufficient evidence to prove amyloid β (Aβ) as the primary cause initiating secondary events, but Aβ is also known to be produced under normal conditions and to possess physiological roles, hence, the questions that remain are: What are the factors that lead to abnormal Aβ production? When does Aβ turn into a pathological molecule? What is the chain of events that follows Aβ? The answers are still under debate, and further insight may help us in creating better diagnostic and therapeutic options in AD. The present article attempts to review the current literature regarding AD pathophysiology and proposes a pathophysiologic cascade in AD.

Copyright © 2011 S. Karger AG, Basel.

PMID:
22205086
[PubMed - as supplied by publisher]
Click here to read
19.
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]
Click here to read
20.
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.

No comments:

Post a Comment