bluuebunny/crossref_metadata_2025 huggingface dataset:
Activation of the c‐Jun N Terminal Kinase Pathway in an Animal Model of Parkinson's Disease
Authors: WILLESEN METTE GEORGI , GAMMELTOFT STEEN , VAUDANO ELISABETTA
Published: July 2009

Abstract: In neuronal stress and degeneration, mitogen‐activated protein (MAP) kinase signaling pathways play an important role. We studied the pattern of activation of the c‐Jun N terminal kinase (JNK) signal transduction pathway during the course of a subacute MPTP mouse model of Parkinson's disease. In this model, there was no significant neuronal loss, but the function of the dopaminergic neurons was significantly decreased. During MPTP administration, phosphorylation of p‐Jun was increased in the substantia nigra, and MKK4 was increased both in the striatum and substantia nigra. We conclude that after MPTP intoxication in the mouse, activation of the JNK pathway occurs both in the striatum and in the substantia nigra. This activation does not seem to corrrelate with loss of neuronal cell bodies but might represent a response to damage/loss of axonal terminals.
Association of Bcl‐2 with Cyclin A/Cdk‐2 Complex and Its Effects on Cdk‐2 Activity
Authors: CRESCENZI ELVIRA , SANNINO MARIA , TONZIELLO GILDA , PALUMBO GIUSEPPE
Published: July 2009

Abstract: In the human endometrial carcinoma cell line HEC1B, the overexpression of Bcl‐2 leads to a G2/M cell cycle arrest. The experiments presented in this work suggest a direct interaction between the antiapoptotic protein Bcl‐2 and the cyclin‐dependent kinase Cdk‐2 and suggest that such interaction is cell cycle dependent. While further experiments are currently under way in our laboratory to elucidate the significance of Cdk‐2/Bcl‐2 complexes in PCD and cell cycle regulation, we demonstrate also a specific inhibitory function of Bcl‐2 on the activity of the coprecipitated kinase.
Proteasome Inhibition Enhances Lipofuscin Formation
Authors: TERMAN ALEXEI , SANDBERG SARA
Published: July 2009

Abstract: Lipofuscin, a hallmark of aged nondividing cells, is an undegradable autofluorescent intralysosomal substance composed essentially of oxidized, cross‐linked proteins. To test whether impaired activity of proteasomes—which, along with lysosomes, belong to major cellular proteolytic systems—may contribute to lipofuscinogenesis, we exposed growth‐arrested human fibroblasts to subapoptotic doses (2 and 5 nM) of a highly specific proteasome inhibitor, MG‐262. This resulted in accelerated lipofuscin accumulation (especially when MG‐262 exposure was combined with mild hyperoxia—i.e., cultivation at 40% ambient oxygen versus 8% for controls); and enhanced immunostaining for ubiquitin, reflecting accumulation of modified cytosolic proteins subjected for degradation, and cathepsin L, reflecting enlargement of the lysosomal compartment. These data suggest that insufficient proteasomal function may contribute to lipofuscinogenesis by a compensatory increase in the amount of proteins that are difrected for lysosomal degradation. The findings may be helpful for the understanding of cellular aging as well as diseases associated with intralysosomal accumulation of undegradable material.
Signal Transduction through Tyrosine‐Phosphorylated Carboxy‐Terminal Fragments of APP via an Enhanced Interaction with Shc/Grb2 Adaptor Proteins in Reactive Astrocytes of Alzheimer's Disease Brain
Authors: RUSSO CLAUDIO , DOLCINI VIRGINIA , SALIS SERENA , VENEZIA VALENTINA , VIOLANI ELISABETTA , CARLO PIA , ZAMBRANO NICOLA , RUSSO TOMMASO , SCHETTINI GENNARO
Published: July 2009

Abstract: The processing of the amyloid precursor protein (APP) through the formation of C‐terminal fragments (CTFs) and the production of β‐amyloid, are events likely to influence the development and the progression of Alzheimer's disease (AD). APP is a transmembrane protein similar to a cell‐surface receptor with the intraluminal NPTY motif in the cytosolic C terminus. Although APP holoprotein can be bound to intracellular proteins like Fe65, X11, and mDab, the ultimate function and the mechanisms through which this putative receptor transfers its message are unclear. Here it is shown that in human brain, a subset of tyrosine‐phosphorylated CTFs represent docking sites for the adaptor protein ShcA. ShcA immunoreactivity is greatly enhanced in Alzheimer's patients; it is mainly localized to glial cells and occurs at reactive astrocytes surrounding cerebral vessels and amyloid plaques. Grb2 also is involved in complexes with ShcA and tyrosine‐phosphorylated CTFs, and in AD brain the interaction between Grb2‐ShcA and CTFs is enhanced. Also, a higher amount of phospho‐ERK1,2 is present in AD brain in comparison with control cases, likely as a result of the ShcA activation. In vitro experiments show that the ShcA‐CTFs interaction is strictly confined to glial cells when treated with thrombin, which is a well‐known ShcA and ERK1,2 activator, mitogen, and regulator of APP cleavage. In untreated cells ShcA does not interact with either APP or CTFs, although they are normally produced. Altogether these data suggest that CTFs are implicated in cell signaling via Shc transduction machinery, likely influencing MAPK activity and glial reaction in AD patients.
The Role of the Carboxyl‐Terminal Fragments of Amyloid Precursor Protein in Alzheimer's Disease
Authors: LAHIRI D. K. , KOTWAL G. J. , FARLOW M. R. , SIMA A. , KUPSKY W. , SARKAR F. H. , SAMBAMURTI K.
Published: July 2009

Abstract: Two major pathological hallmarks of Alzheimer's disease (AD) are the senile plaques that are primarily composed of amyloid β‐peptide (Aβ) and neurofibrillary tangles consisting of tau aggregates. Aβ is generated proteolytically from a family of Aβ‐containing precursor proteins (APP; 695–770 amino acid) by secretase enzymes to different specific carboxyl‐terminal fragments (CTFs). Herein we examined APP and its products in autopsied brain sections from 10 AD and 10 non‐AD control subjects immunochemically using an antibody that was raised against APP751‐770 residue (O443). The O443 antibody was initially characterized by Western blot analysis and immunoprecipitation. In this study, we used this antibody for immunohistochemical analysis to determine the distribution of APP and its CTF species. In 10 brain regions showing different levels of plaques and tangles, antibody O443 stained the perinuclear region of the nucleus, plaques, and neurites. Tangle‐bearing neurons also appeared to stain with the antibody, suggesting that these dysfunctional neurons continue to synthesize APP/CTF. Alternatively, the normally short‐lived APP/CTF can be stabilized and persist in these neurons. Taken together, these results suggest that, in addition to the widely believed role of Aβ, CTFs may play a key role in the pathogenesis of AD. Studying their localization and biogenesis may reveal the biological activities of CTFs of APP. The present study may pave the way for possible antiamyloidogenic therapy in the treatment of AD.
Functional Characterization of the 5′‐Regulatory Region of the Murine Apolipoprotein Gene
Authors: LAHIRI D. K. , ALLEY G. M. , GE Y.‐W. , DU Y.
Published: July 2009

Abstract: The apolipoprotein E (APOE) gene causes a major risk factor for the development of Alzheimer's disease (AD). To study the transcription control of the mouse (m) APOE gene, we first tested the promoter activity of a 721‐base‐pair (bp) 5′‐flanking region, which is located 771 bp upstream from the translation initiation codon. We cloned the 721‐bp region upstream of the reporter chloramphenicol acetyl transferase (CAT) gene into a promoterless vector (pBLCAT3). The mAPOE promoter and vector DNA were separately transfected in rat glial C6 and neuronal PC12 cell lines. The 721‐bp APOE region (from position 329 to 1050) is functionally active in different cell lines tested. The serial deletion analysis indicates that the 266‐bp promoter region (from 784 to 1050) has the highest and the 67‐bp region (from 983 to 1050) the lowest activity on the reporter gene in neuronal and astrocytic cell lines. These studies suggest that the 147‐bp region (from 637 to 784) has a negative regulatory effect on the reporter gene. In the gel shift assay, the 67‐bp region binds to a specific transcription factor(s) in PC12 nuclear extracts. Our results suggest that mAPOE can also be expressed in neuronal cells in addition to the astrocytic cells. Characterization of mAPOE promoter is important for the AD drug development discovery and APOE transgenic mice studies.
The Roles of p53, DNA Repair, and Oxidative Stress in Ultraviolet C Induction of Proliferating Cell Nuclear Antigen Expression
Authors: CHANG YU‐CHING , CHANG HSUEH‐WEI , LIAO CHU‐BIN , LIU YIN‐CHANG
Published: July 2009

Abstract: The expression of proliferating cell nuclear antigen (PCNA) promoter was moderately induced in UV‐irradiated, quiescent human and rodent cells. The induction was independent of tumor suppressor gene p53, because the PCNA expression was UV‐inducible in the subclones of human fibroblasts in which the activity of p53 was abrogated by human papilloma virus E6. Furthermore, the induction did not depend on DNA repair, since PCNA was UV inducible in UVL‐10 and xrs‐6 cells, in which nucleotide excision repair and double‐stranded repair, respectively, are largely compromised. However, the induction was inhibited by antioxidant N‐acetylcysteine. The role of oxidative stress observed here is consistent with the previous finding that the proximal AP‐1 site is critical to the UV inducibility of PCNA promoter.
Thalidomide Suppresses the Interleukin 1β‐Induced NFκB Signaling Pathway in Colon Cancer Cells
Authors: JIN SOO HYUN , KIM TAE IL , HAN DONG SOO , SHIN SUNG KWAN , KIM WON HO
Published: July 2009

Abstract: Thalidomide has been shown to have both antiinflammatory and antiangiogenic effects in several diseases. However, its cellular target and mechanism of action are poorly understood. We investigated the action mechanism of thalidomide through the NFκB pathway. Thalidomide inhibited interleukin (IL) 1β‐induced NFκB transcriptional activation and IL‐8 production in Caco‐2 colon cancer cells. In addition, thalidomide suppressed NFκB nuclear translocation, IκB degradation, and NFκB‐inducing kinase (NIK)‐induced NFκB transcriptional activation. These results suggest that the molecular target of the effects of thalidomide may be IκB phosphorylation by IκB kinase (IKK), whose activation follows NIK activation and precedes IκB degradation in the NFκB pathway.
Transcriptional Inhibition of CYP24 by Genistein
Authors: FARHAN HESSO , CROSS HEIDE S.
Published: July 2009

Abstract: 1,25 Dihydroxyvitamin D3 (1,25‐D3) can be considered an antitumorigenic agent, which can be used in the therapy of malignant diseases such as prostate cancer. In this respect, it is important to note that some prostatic cancer cells express high levels of CYP24, a cytochrome enzyme involved in degradation of 1,25‐D3. Genistein, a widely occurring isoflavonoid, inhibits cytochrome enzymes and also exerts antitumorigenic effects. Here, we therefore investigated the effect of genistein on cytochrome enzymes involved in vitamin D metabolism. Treatment of DU‐145 prostatic cancer cells with genistein led to a time‐ and dose‐dependent inhibition of CYP24. Additionally CYP27B1 was also inhibited. CYP27B1 is the cytochrome enzyme that synthesizes 1,25‐D3. RT‐PCR showed that the effect of genistein was mainly due to inhibition of transcription. This often involves the activity of histone deacetylases (HDAC). Thus we tested if the HDAC inhibitor trichostatin A (TSA) reversed the effect of genistein on vitamin D hydroxylases. TSA per se reduced expression of CYP24 mRNA and synergized with genistein to abolish expression after an incubation of 24 h. Importantly, TSA, which itself did not affect CYP27B1 expression, rescued CYP27B1 from transcriptional inhibition by genistein. In conclusion, our data argue for the use of genistein to resensitize prostate cancer cells to 1,25‐D3; the addition of TSA may preserve the ability of these cells to synthesize 1,25‐D3.
Redox Control by Dithiol‐Disulfide Exchange in Plants
Authors: ROUHIER NICOLAS , GELHAYE ERIC , JACQUOT JEAN‐PIERRE
Published: July 2009

Abstract: This paper describes the existence of two pathways efficient in the reduction of disulfide bridges on selected proteins and mitochondria of photosynthetic organisms. The first is constituted by NADPH, the flavoenzyme NADPH thioredoxin reductase, and thioredoxin; and the second by NADPH, glutathione reductase, glutathione, and glutaredoxin. Molecular details concerning the proteins participating in these redox regulatory cascades are provided, and their molecular targets and functions are described.
Purification of Proteins Susceptible to Oxidation at Cysteine Residues: Identification of Malate Dehydrogenase as a Target for S‐Glutathiolation
Authors: EATON PHILIP , SHATTOCK MICHAEL J.
Published: July 2009

Abstract: The cysteine residues of proteins are susceptible to a range of oxidative modifications, including S‐glutathiolation. Here we present a study in which we used glutathione‐agarose to purify cardiac proteins that undergo S‐glutathiolation during oxidative stress. We then identified one of the oxidized proteins as malate dehydrogenase.
Intercellular Adhesion Molecule‐1 in the Heart
Authors: NIESSEN HANS W. M. , KRIJNEN PAUL A. J. , VISSER CEES A. , MEIJER CHRIS J. L. M. , HACK C. ERIK
Published: July 2009

Abstract:Intercellular adhesion molecule‐1 (ICAM‐1) belongs to the superfamily of immunoglobulin‐like adhesion molecules. Up‐regulation of ICAM‐1 occurs in many different pathophysiological processes. Also, cardiomyocytes can express ICAM‐1—for example, in acute myocardial infarction. Moreover, inhibition of ICAM‐1 expression in the heart dramatically reduces infarct size. Hence, inhibitors of ICAM‐1 may provide a novel therapeutic option for acute myocardial infarction.
Mixed Dementia—the Most Common Cause of Dementia
Authors: KORCZYN AMOS D.
Published: July 2009

Abstract: The existence of vascular dementia (VaD) was first identified by Marie, who described the etat lacunaire, and by Binswanger, who identified white matter lesions. The role of cortical lesions, while clear to clinicians, was highlighted only later by the pathological studies of Tomlinson and the clinical demonstrations of Hachinski et al., who have defined multi‐infarct dementia. Lately, the emphasis shifted to pathogenic mechanisms with the identification of a multitude of processes, including lipohyalinosis, cardiac dysfunction, and genetic causes, to name only a few. Epidemiologic studies have demonstrated the high frequency of VaD, as well as the fact that vascular factors can contribute to Alzheimer's disease (AD). All these considerations converge to the realization that VaD is an extremely important clinical entity and that its prevention and treatment are within reach. In fact, there are more data on how to prevent strokes (and presumably VaD) than AD. Moreover, many factors that were identified as contributing to cerebrovascular disease in general and VaD in particular are frequently suspected as predisposing to AD as well. This surprising finding highlights the importance of mixed vascular‐degenerative dementia as a disorder that has to be properly defined and has important implications on prevention and treatment.
Similarities and Differences between Alzheimer's Disease and Vascular Dementia from the Viewpoint of Nutrition
Authors: OTSUKA M. , YAMAGUCHI K. , UEKI A.
Published: July 2009

Abstract: Dietary habits were compared in patients with Alzheimer's disease (AD) and those with vascular dementia (VaD). Twenty‐seven patients with AD, 15 patients with VaD, and 49 age‐matched controls were enrolled. Nutritional status was assessed using a semiquantified food‐frequency questionnaire. Dietary habits were very similar in male patients with AD and VaD. Both groups had significantly higher energy intake than their energy demands: +25% for AD and +35% for VaD, respectively. However, major sources of energy were different: grains and animal fats for AD versus only grains for VaD. Calculation of nutrients revealed excess intake of n‐6 polyunsaturated fatty acids (PUFA) and relative deficiencies of multiple vitamins including antioxidants, vitamin C and carotene, and the vitamin B group. In contrast, dietary habits in female patients with AD differed significantly from those of male patients. Female patients consumed significantly lower amounts of fish and green vegetables. Calculation of nutrients showed absolute deficiencies of n‐3 PUFA, multiple vitamins, and minerals. Our results show that AD and VaD are similar from the viewpoint of nutrition, except for the higher consumption of animal fats for AD patients, probably reflecting Westernization of dietary habits in recent years. Nutrition may be relevant to the pathogenesis of dementia through many processes. Higher intake of energy and lower intake of antioxidants may exaggerate the process of dementia through oxidative stress. Excessive amounts of n‐6 PUFA or deficiency of n‐3 PUFA may cause chronic inflammation, platelet aggregation, or endothelial dysfunction of microvasculature. Nutrition may be useful for preventing dementia, although gender‐specific differences must be taken into account.
Lessons from CADASIL
Authors: RUCHOUX MARIE‐MAGDELEINE , BRULIN PEGGY , BRILLAULT JULIEN , DEHOUCK MARIE‐PIERRE , CECCHELLI ROMEO , BATAILLARD MARC
Published: July 2009

Abstract: Vascular dementia (VaD) includes several different vascular mechanisms and changes in the brain. Among VaD, CADASIL is an inherited angiopathy caused by mutations in the Notch3 gene. The pathological hallmark of CADASIL is a granular osmiophilic material deposit (GOM) that is not only found in the brain, but also in the peripheral vascular tree. Consequently, a window into the brain was opened from a strictly neurological disease with tremendous consequences thanks to a skin biopsy. The latter was and continues to be used as a diagnostic tool for CADASIL, despite an immunohistochemical test that is now available. The skin biopsy first used as a diagnostic tool revealed the existence of numerous other VaDs presenting systemic vascular changes. Later, skin biopsy became a research tool, and a morphological skin vessel change classification was proposed on 300 patients. Interestingly, similar skin vessel lesions appear to be related to the same biological modifications. In addition, an early destruction of the medial muscle cells was noticed in 74% of cases. Because vascular smooth muscle cells secrete a powerful endothelial permeability factor (VEGF), their destruction could lead to a decrease in vascular permeability. Cocultures of endothelial cells with vascular muscle cells showed that their presence doubled vascular permeability. Thus, alteration or the loss of vascular muscle cells likely results in hypopermeability, in addition to vessel wall hypotonia and a watershed hypoperfusion. The wealth of information brought forth by knowledge of CADASIL provided new tools for research and clues for understanding the consequences of vascular impairments in dementia.
Genetic Analysis of Vascular Factors in Alzheimer's Disease
Authors: WAKUTANI YOSUKE , KOWA HISANORI , KUSUMI MASAYOSHI , YAMAGATA KAORU , WADA‐ISOE KENJI , ADACHI YOSHIKI , TAKESHIMA TAKAO , URAKAMI KATSUYA , NAKASHIMA KENJI
Published: July 2009

Abstract: Genetic risk factors for Alzheimer's disease (AD) have been extensively examined. Several risk factors for AD are shared with vascular dementia (VaD). We performed genetic case‐control studies on polymorphisms of the apolipoprotein E (ApoE) gene, the methylene tetrahydrofolate reductase (MTHFR) gene, and the angiotensin‐converting enzyme (ACE) gene. The most acceptable genetic risk factor for the development of AD is the ApoE epsilon‐4 (ApoE ε4) allele. ApoE promoter polymorphisms have also been reported to be associated with AD. As expected, the ApoE ε4 allele had strong association with AD in our samples. The ApoE ε4 allele was also estimated as a risk factor for VaD. An ApoE promoter polymorphism (−291T/G) did not show positive association with AD or any other diseases. Common MTHFR phenotypes are thought to genetically regulate blood homocysteine level, which has been associated with AD. We failed to show independent associations between AD and the common MTHFR polymorphisms (C677T and A1298C). A deletion polymorphism at intron 16 of the ACE gene has also been associated with AD. In our study, we found a significant ethnic difference of the genotype distribution, but failed to replicate the positive association between the I allele and AD.
Pathological Lesions in Vascular Dementia
Authors: PANTONI LEONARDO , PALUMBO VANESSA , SARTI CRISTINA
Published: July 2009

Abstract:According to current diagnostic criteria, a definite diagnosis of vascular dementia (VaD) can be reached on pathological grounds by showing the presence of vascular lesions and the absence of degenerative changes exceeding those expected for age. However, while it is commonly accepted that VaD is a group of heterogeneous entities rather than a process with a unique pathological substrate, the spectrum of vessel and parenchyma changes etiologically associated with the clinical syndrome remains basically unidentified. The review of some recent clinical‐pathological series shows that different studies have assessed the presence of dissimilar vascular lesions and that, in many cases, no pathological definition was given. This has hindered the clarification of clinical‐pathological correlations in the field of VaD. In this scenario, the use of animal models of cerebrovascular diseases may help to elucidate the type of lesions possibly linked with cognitive impairment in humans and might provide insight into some of the pathophysiological mechanisms of vascular cognitive impairment. A consensus is today needed in order to harmonize the pathological examination of vascular lesions in cases of dementia. An ongoing survey aimed at collecting information about the procedures used in different pathological laboratories in the assessment of lesions possibly associated with dementia is finally presented.
Cholesterol and Cognition
Authors: SPARKS D. LARRY , MARTINS RALPH , MARTIN TIM
Published: July 2009

Abstract: This report presents the scientific rationale and hypothesis for the investigator‐initiated, double‐blind, placebo‐controlled Alzheimer's Disease Cholesterol‐Lowering Treatment Trial. As part of the supporting preclinical data, accumulation of neuronal β‐amyloid immunoreactivity was investigated in 12‐month‐old male spontaneously hypercholesterolemic Watanabe rabbits, female Watanabe rabbits between 3 and >36 months of age, and untreated female New Zealand white rabbits between 6 and 12 months of age. Prior evidence suggests that there are significant accumulations of neuronal β‐amyloid immunoreactivity in the cholesterol‐fed New Zealand white rabbit. At 3 months of age, abundant β‐amyloid immunoreactive neurons are also found in female hypercholesterolemic Watanabe rabbits. By 6 months of age, as female Watanabe rabbits are approaching sexual maturity, the number of β‐amyloid immunoreactive neurons was somewhat reduced, but the intensity of the immunoreactivity was clearly and consistently diminished. Very few neurons expressing β‐amyloid immunoreactivity were identifiable among the 12‐month‐old Watanabe female rabbits. Variably increased numbers of intensely stained β‐amyloid immunoreactive neurons were observed in retired breeder female animals over 3 years of age. Twelve‐month‐old male Watanabe rabbits exhibited levels of neuronal β‐amyloid immunoreactivity consistent with younger and older female animals, but greater than the adult 12‐month‐old females. Cholesterol levels in the blood were not noticeably different among females over the age range investigated or compared to 12‐month‐old males. Estrogen levels varied with age in female Watanabe rabbits in an apparent inverse relationship with neuronal β‐amyloid immunoreactivity. However, there was no evidence of increased neuronal β‐amyloid immunoreactivity in untreated female New Zealand white rabbits with “normal” circulating cholesterol levels at any age investigated. Therefore, under conditions of stable, but elevated, circulating cholesterol levels, pathologic accumulation of neuronal β‐amyloid immunoreactivity was similar in male Watanabe rabbits and female animals prior and subsequent to estrus. The intensity of observable neuronal β‐amyloid immunoreactivity accumulation decreases in female animals as circulating estrogen levels increased with sexual maturity. These data suggest that a loss of circulating estrogen could mark the collapse of a system previously protecting a female from conditions conducive to production of β‐amyloid as a putative neurotoxin in AD. This may, in part, explain the epidemiological evidence for “protective” effects of estrogen in AD.
Cholesterol, a Modulator of Membrane‐Associated Aβ‐Fibrillogenesis
Authors: McLAURIN J. , DARABIE A. A. , MORRISON M. R.
Published: July 2009

Abstract: One of the major pathological features of Alzheimer's disease (AD) is the presence of extracellular amyloid plaques that are predominantly composed of the amyloid‐β peptide (Aβ). Characterization of plaques demonstrated the predominance of two peptides differing at the carboxyl terminus by two hydrophobic amino acids, Aβ40 and Aβ42. Diffuse plaques associated with AD are composed predominantly of Aβ42, whereas senile plaques contain both Aβ40 and Aβ42. Recently, it has been suggested that diffuse plaque formation is initiated as a plasma membrane‐bound Aβ species and that Aβ42 is the critical component. In order to investigate this hypothesis, we have examined Aβ40/42‐lipid interactions using in situ atomic force microscopy, electron microscopy, and fluorescence anisotropy. While the association of Aβ42 with planar bilayers resulted in peptide aggregation, but no fiber formation, this was not the case for Aβ40, where we observed preferential fiber formation. Cholesterol, a key membrane component and modulating factor in AD, is inversely correlated with the extent of Aβ40/42‐bilayer interaction. These results were confirmed using fluorescence anisotropy to evaluate the effect of Aβ on membrane fluidity and fluorimetry to confirm membrane integrity. Our results suggest that the enhanced amyloidogenic properties of Aβ42 are not correlated with fibril formation, but with aggregation on bilayer surfaces.
Cholesterol‐Dependent Aggregation of Amyloid β‐Protein
Authors: YANAGISAWA KATSUHIKO , MATSUZAKI KATSUMI
Published: July 2009

Abstract: One of the fundamental pathological processes of Alzheimer's disease (AD) is the aggregation of the amyloid β‐protein (Aβ). In the case of familial AD, the expression of genes responsible for this disease is likely to enhance aggregation of Aβ through its enhanced generation. However, there is no evidence to indicate thus far that in the case of sporadic AD, a major form of the disease, the generation of Aβ is altered. Thus, one could assume that the aggregation of Aβ in AD is induced by unknown posttranslational modification or by an altered clearance mechanism, or both. We previously identified a novel Aβ species in the human brain that exhibited early pathological changes of AD. This Aα is characterized by its tight binding to GM1 ganglioside (GM1). Based on its unique molecular characteristics, including its extremely high aggregation potential and altered immunoreactivity, we hypothesized that Aβ undergoes conformational alteration and acts as a seed for Aβ fibrillogenesis. In regard to the molecular mechanism underlying the formation of GM1‐Aβ, we recently found that binding of Aβ to GM1 was facilitated in cholesterol‐rich environments and, furthermore, it was dependent on the cholesterol‐induced clustering of GM1 in the host membranes. Recently, increasing evidence indicates that cholesterol is a risk factor for AD development. The results of our current studies may provide a new insight into the molecular mechanism underlying the cholesterol‐dependent development of AD.
Hemodynamic Aspects of Alzheimer's Disease
Authors: NAGATA KEN , SATO MIKA , SATOH YUICHI , WATAHIKI YASUHITO , KONDOH YASUSHI , SUGAWARA MAKI , BOX GEORGIA , WRIGHT DAVID , LEUNG SUMIE , YUYA HIROMICHI , SHIMOSEGAWA EKU
Published: July 2009

Abstract: Neuroradiological functional imaging techniques demonstrate the patterns of hypoperfusion and hypometabolism that are thought to be useful in the differential diagnosis of Alzheimer's disease (AD) from other dementing disorders. Besides the distribution patterns of perfusion or energy metabolism, vascular transit time (VTT), vascular reactivity (VR), and oxygen extraction fraction (OEF), which can be measured with positron emission tomography (PET), provide hemodynamic aspects of brain pathophysiology. In order to evaluate the hemodynamic features of AD, PET studies were carried out in 20 patients with probable AD and 20 patients with vascular dementia (VaD). The PET findings were not included in their diagnostic process of AD. Using oxygen‐15‐labeled compounds, cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), OEF, cerebral blood volume, and VTT were measured quantitatively during resting state. To evaluate VR, CBF was also measured during CO2 inhalation. There was a significant increase in OEF in and around the parietotemporal cortices, but both VTT and VR were well preserved in patients with AD. By contrast, VR was markedly depressed and VTT was mildly prolonged in patients with VaD. Thus, from the hemodynamic point of view, the preservation of vascular reserve may be a distinct difference between AD and VaD. Furthermore, this indicates a hemodynamic integrity of the vasculature in the level of arterioles in AD.
Imaging Interactions between Alzheimer's Disease and Cerebrovascular Disease
Authors: WU CHRISTINE C. , MUNGAS DAN , EBERLING JAMIE L. , REED BRUCE R. , JAGUST WILLIAM J.
Published: July 2009

Abstract: There is a growing body of evidence suggesting that Alzheimer's disease (AD) and cerebrovascular disease (CVD), two common disorders of aging, are related in ways that extend beyond their coincident co‐occurrence. Thus, there is a need to understand how the two pathological processes interact to contribute to dementia. In this article, we review two recent studies from our laboratory that use MRI and PET to begin to reveal the nature and mechanisms of the relationship between AD, CVD, and dementia.
Donepezil Treatment of Vascular Dementia
Authors: MEYER JOHN STIRLING , CHOWDHURY MUNIR H. , XU GELIN , LI YAN‐SHENG , QUACH MINH
Published: July 2009

Abstract: Cholinergic deficits are clinicopathological hallmarks of Alzheimer's disease (DAT) and during the past decade have been the sole target for clinically effective treatments. By contrast, vascular dementia subtypes (VaD) are heterogeneous clinical syndromes, and therapeutic approaches have been directed toward control of vascular risk factors. Little attention has been paid to cholinergic deficits as a mechanism contributing to cognitive impairments in VaD as a potential target for treatment. The purpose of the study was to determine whether there are therapeutic benefits from long‐term treatment with cholinesterase inhibitors among VaD patients. Ten VaD patients were diagnosed according to DSM‐III‐R and NINDS‐AIREN criteria and classified into subtypes by neuroimaging. All were treated with titrated doses of donepezil for a mean interval of 15 months. At baseline and follow‐up clinic visits, patients underwent medical and neurological examinations, as well as neuropsychological testing including Mini‐Mental Status Examinations (MMSE) and Cognitive Capacity Screening Examinations (CCSE). Cognitive statuses of 10 treated patients were then compared before and after treatment. Net changes were expressed as annual MMSE score changes (ΔMMSE/year) and annual CCSE score changes (ΔCCSE/year). Of the 10 treated VaD patients, cognitive improvements were found when comparisons were made before and after treatment. Ten treated patients also showed greater cognitive improvements, while untreated patients showed continued cognitive decline. This study suggests that cholinergic deficits in VaD are due to neuronal ischemic damage with loss of acetylcholine and that treatment of VaD with cholinesterase inhibitors is a rational therapy.
An Overview of the Pathology and Approaches to Tissue Engineering
Authors: OCHOA ERIN R. , VACANTI JOSEPH P.
Published: July 2009

In tissue engineering, there is an attempt to culture living tissues for surgical transplantation. In vitro and in vivo approaches have produced vascular and cardiovascular components, cartilage, bone, intestine, and liver. Attempts to microdesign cell‐culture support scaffolds have used a new generation of biocompatible and bioabsorbable polymers. Suspensions of donor cells are seeded onto protein‐coated polymer scaffolds and grown to confluence in dynamic bioreactors. In vitro techniques produce monolayers of tissues. Denser masses are achieved by implanting monolayers onto a host, or by culturing cell/polymer constructs in vivo. Existing techniques have produced functioning heart valves from sheep endothelial cells and myofibroblasts. Cultured ovine arterial cells have replaced 2‐cm segments of pulmonary artery in lambs. Chondrocyte cultures have produced a human‐ear‐shaped construct, temporo‐mandibular joint discs, meniscal replacement devices, and human‐phalange‐shaped constructs, complete with a joint. The culture of composite tissue types has recently been reported. Intestinal organoid units containing a mesenchymal core with surrounding polarized epithelia have been used in lieu of an ileal pouch in Lewis rats, and the long‐term culture of rat hepatocytes has revealed cellular differentiation and neomorphology resembling elements of a biliary drainage system. To sustain the in vitro culture of dense tissues prior to implantation, micro‐electro‐mechanical systems (MEMS) fabrication technologies have been adapted to create wafers of polymer containing sealed, branching, vascular‐type spaces. After seeding with rat lung endothelial cells, followed by 5 days of bioreactor culture, the result is an endothelial network with controlled blood flow rates, pressure, and hematocrit. When these customized vascular systems can be used to support in vitro culture, a new generation of dense, composite, morphologically complex tissues will be available for clinical development.
Research Perspectives in Inherited Lymphatic Disease
Authors: FERRELL ROBERT E.
Published: July 2009

Abstract: The hereditary lymphedemas provide an opportunity to identify genes involved in normal and deranged lymphatic development. Genetic analysis of families with Milroy's disease identified mutations in VEGFR3 as a cause of congenital lymphedema, confirming the importance of VEGFC/VEGFR3 signaling in lymphatic development. These observations led to the identification of a mouse model for primary lymphedema, and subsequent analysis of this mouse model, using transgenic and gene transfer techniques, has provided initial clues to the development of a biologically based therapy for primary lymphedema. Of more importance from a public health perspective is the fact that manipulation of this pathway may lead to effective therapies for the more prevalent forms of secondary lymphedema. Identification of FOXC2 as the gene mutated in the lymphedema‐distichiasis syndrome has revealed new molecular insight into lymphatic development. Molecular analysis of the FOXC2 pathway may provide clues to developmental pathways shared by the lymphatic system and the other developmental abnormalities associated with this complex syndrome. With improving knowledge of the human genome, genetic analysis of families with lymphedema continues to offer one of the most promising approaches to identifying genes influencing lymphatic development.
Contractility Patterns of Normal and Pathologically Changed Human Lymphatics
Authors: OLSZEWSKI WALDEMAR L.
Published: July 2009

Abstract: Human leg lymphatics contract spontaneously, rhythmically propelling lymph. This intrinsic property regulates the fluid environment in the intercellular space in skin, connective tissue, and perivascular spaces. The pressures generated by lymphatic contractions constitute the main force for lymph flow. This mechanism is of utmost importance during night rest, anesthesia, and immobilization, as well as in those with damaged peripheral motor neurons. All supporting forces are only secondary to those created by spontaneous lymphatic contractions. The intrinsically regulated lymph flow depends on tissue fluid and lymph production rate. The transport capacity of lymphatics adjusts to the fluid load. Under physiological conditions, limb activity and position only slightly change lymph flow. In obstructive lymphedema, high lymph pressures can be observed. They are usually generated by leg muscle contraction, whereas the spontaneous contractility of lymphatics becomes ineffective in lymph transport because of low generated pressures and lymphatic valve insufficiency. The knowledge of lymph flow in normal and lymphedematou limbs will be useful in the derivation of rational treatments for lymphedema.
Preclinical Models of Lymphatic Disease
Authors: ROCKSON STANLEY G.
Published: July 2009

Abstract: The human disease states that are characterized by functional lymphatic insufficiency currently lack a cure. Molecular approaches may ultimately provide a therapeutic window to reverse the stigmata of both primary and secondary lymphatic insufficiency. To harness the potential therapeutic power of lymphangiogenesis, testing the safety and efficacy of the treatment response will be necessary. This, in turn, necessitates the availability of suitable preclinical animal models of the disease processes in question, along with suitable research tools to permit an assessment of the response to applied therapies. An ideal model would reproducibly and inexpensively replicate the untreated disease of human lymphedema. It would closely simulate the biology, as we understand it, of the human disease, and would replicate both the pathogenesis of the disease, including its natural history and the temporal patterns of its clinical expression. In this way, one might aspire to make valid predictions about the human applicability of therapy by extrapolation from observations in animal models. In addition to the availability of suitable animal models, the required investigative tools must also be available. In the context of lymphangiogenesis, to assess the therapeutic response, one must certainly possess the ability to recognize newly developed lymphatic vasculature. Sophisticated immunohistochemical and imaging techniques make this increasingly feasible. Initial experimental observations indicate that growth factor and gene therapy with VEGF‐C holds promise for the treatment of both primary and secondary forms of lymphedema.
Insights into the Molecular Pathogenesis and Targeted Treatment of Lymphedema
Authors: SAARISTO ANNE , KARKKAINEN MARIKA J. , ALITALO KARI
Published: July 2009

Abstract: Abnormal function of the lymphatic vessels is associated with a variety of diseases, such as tumor metastasis and lymphedema. The development of strategies for local and controlled induction or inhibition of lymphangiogenesis would thus be of major importance for the treatment of such diseases. Two growth factors, vascular endothelial growth factor C (VEGF‐C) and D (VEGF‐D), have been found to be important in the proper formation and maintenance of the lymphatic network, through their receptor VEGFR‐3. In patients with lymphedema, heterozygous inactivation of VEGFR‐3 leads to primary lymphedema due to defective lymphatic drainage in the limbs. We have shown that VEGF‐C gene transfer to the skin of mice with lymphedema induces regeneration of the cutaneous lymphatic vessel network. However, as is the case with VEGF, high levels of VEGF‐C cause blood vessel growth and leakiness, resulting in tissue edema. Strategies to avoid these side‐effects have also been developed. This new field of reseach has important implications for the development of new therapies for human lymphedema.
A Stepwise Model of the Development of Lymphatic Vasculature
Authors: OLIVER GUILLERMO , HARVEY NATASHA
Published: July 2009

Abstract: Although lymphedema was first described more than a century ago, little progress has been made in understanding the mechanisms that cause it. Investigation of the normal development of the lymphatic system has been hindered by the lack of known lymphatic‐specific markers. In 1902, F. Sabin proposed the most widely accepted theory about the origin of the lymphatic vasculature. This model proposed that isolated primitive lymph sacs bud from the endothelium of veins during early development; from these primary lymph sacs, the peripheral lymphatic system spreads by endothelial sprouting into tissues where local capillaries form. In 1999, we identified the homeobox gene Prox1 as the first specific marker of lymphatic endothelial cells. Functional inactivation of Prox1 in mice demonstrated that lymphangiogenesis requires the activity of this gene in a subpopulation of endothelial cells in embryonic veins. Prox1 promotes the development of the lymphatic vasculature by determining the final lymphatic fate of budding venous endothelial cells. On the basis of our findings, we propose a stepwise model of lymphangiogenesis in which lymphatic vasculature development is initiated by the specific expression of Prox1 in a subpopulation of vascular endothelial cells that subsequently adopt a lymphatic vasculature phenotype.
The Role of Interstitial Stress in Lymphatic Function and Lymphangiogenesis
Authors: SWARTZ MELODY A. , BOARDMAN KENDRICK C.
Published: July 2009

Abstract: The management and control of tissue fluid balance depends on the highly regulated orchestration of various interstitial factors. In particular, lymphatic function, lymphatic biology, and development (lymphangiogenesis), and the extracellular matrix all contribute to interstitial fluid balance. In light of the dynamic interdependence of these factors, our lab has been working towards establishing a mechanical‐molecular picture of the process of lymphangiogenesis—that is, bridging the physiological context of lymphangiogenesis with its molecular regulation by studying the coordination of mechanical forces, ECM development, lymphatic biology, and lymphatic capillary organization and development. Our working hypothesis is that the physiological driving force for lymphangiogenesis is the need for organized interstitial fluid flow. This paper will outline the rationale and background for such an approach and highlight some of the recently published findings of our lab and others that support this concept.
Using Fuzzy Logic to Confirm the Integrity of a Pattern Recognition Algorithm for Long Genomic Sequences
Authors: CORK DOUGLAS J. , TOGUEM ANDRE
Published: July 2009

Abstract:The W‐curve is a numerical mapping algorithm that provides tertiary information content of long and short genomic sequences. The most popular genomic pattern recognition algorithms depend on string matching of the primary information content of short genomic sequences. Herein, we describe a way to define the fuzzy properties of the W‐curve. This approach improves a distance (dissimilarity) between two or more homologous long genomic sequences. Fourier analysis of W‐curves delivers a smoother function for gap‐stripped regions. Calculation of respective Fourier energies may improve the accuracy of the distance metric used to generate a phylogenetic tree of analyzed genomic sequences. This is especially the case for long genomic sequences that have been gap‐stripped and aligned with the aid of previously published heuristic methods. These previous methods involved W‐curve alignments used in concert with such programs as Clustal that use linear dynamic programming to align multiple gap‐stripped W‐curves.
Pattern Recognition Techniques in Microarray Data Analysis
Authors: VALAFAR FARAMARZ
Published: July 2009

Abstract:Recent development of technologies (e.g., microarray technology) that are capable of producing massive amounts of genetic data has highlighted the need for new pattern recognition techniques that can mine and discoverbiologically meaningfulknowledge in large data sets. Many researchers have begun an endeavor in this direction to devise such data‐mining techniques. As such, there is a need for survey articles that periodically review and summarize the work that has been done in the area. This article presents one such survey. The first portion of the paper is meant to provide the basic biology (mostly for non‐biologists) that is required in such a project. This part is only meant to be a starting point for those experts in the technical fields who wish to embark on this new area of bioinformatics. The second portion of the paper is a survey of various data‐mining techniques that have been used in mining microarray data for biological knowledge and information (such as sequence information). This survey is not meant to be treated as complete in any form, since the area is currently one of the most active, and the body of research is very large. Furthermore, the applications of the techniques mentioned here are not meant to be taken as the most significant applications of the techniques, but simply as examples among many.
Mammography and Computerized Decision Systems
Authors: ROQUE ANTÔNIO C. , ANDRÉ TÚLIO C.S.S.
Published: July 2009

Abstract:Computer‐aided diagnosis (CAD) systems in mammography have been developed and investigated for several years and recently they have left the research stage to enter the clinical stage. The purpose of this article is to review the present situation of mammography for breast cancer detection and the role played by CAD systems. Results from the recent literature show that CAD systems have the potential to improve the sensitivities of radiologists in the detection of malignant clustered microcalcifications and masses, while keeping specificities at acceptable levels. This leads to the conclusion that CAD systems can be incorporated into clinical practice as a double reading option to radiologists. However, some issues have yet to be tackled for CAD systems to gain better acceptance and more widespread use worldwide.
Comparison of Feature Extraction and Selection Methods in Mammogram Recognition
Authors: SWINIARSKI R. , SWINIARSKA A.
Published: July 2009

Abstract: This paper presents a comparison of feature extraction and selection methods in the design of mammogram recognition systems. Mammographic images were classified into two categories, normal and cancerous. The following methods of feature extraction were investigated: two‐dimensional Haar wavelets, histograms, and singular value decomposition. The feature patterns were reduced and selected using principal component analysis (PCA) and rough sets. The rough sets methods were applied to the final selection of the pattern features. Classification of mammograms was realized using an error backpropagation neural network.