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Senile Plaques (senile + plaque)
Selected AbstractsAlzheimer's disease: Mechanisms and development of therapeutic strategiesGERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 4 2003Takeshi Tabira Senile plaques are the most characteristic change in Alzheimer's disease (AD). In senile plaques, , amyloid is deposited, which is composed of aggregated amyloid , protein (A,) derived from amyloid precursor protein (APP). Therefore, it is suggested that there exists a mechanism of increase of A, production or a decrease of A, degradation and/or clearance of , amyloid in AD. Mutations in familial Alzheimer's disease (FAD) genes such as APP, presenilin 1 (PS1) and presenilin 2 (PS2) result in an increase of A, production. Apolipoprotein E (ApoE), a genetic risk factor for AD, is involved in A, production and/or its clearance. Thus, it is suggested that an inhibition of A, production and a facilitation of , amyloid degradation and clearance delay the clinical onset and progression of AD, and it is possible to cure AD even after an onset of the disease, if it is still at an early phase. Researchers studied the fine mechanisms of A, production and identified enzymes that cleave-out A, from APP. Inhibitors of the cleaving enzymes are proven to be effective in ameliorating AD-like conditions in its animal models and are now being applied to humans. Researchers also found an efficient way of clearing , amyloid deposits using the immune system, which was effective in animal models. When it was applied to humans, some patients developed meningoencephalitis as a side-effect. Therefore, safer vaccines are now being developed. It did not require 20 years for researchers to develop therapeutic strategies since the discovery of A, in 1984. Now that AD is becoming a treatable disease, early diagnosis and early treatment will soon become the rule. Notably, AD may not be a psychiatric disorder any more, and mainly neurologists and geriatricians will see patients. Thus, neurogeriatrics will become more and more important. [source] Modulation of A, peptides by estrogen in mouse modelsJOURNAL OF NEUROCHEMISTRY, Issue 1 2002H. Zheng Abstract Clinical studies have shown that estrogen deprivation through menopause is a risk factor in both the initiation and progression of Alzheimer's disease (AD) and that estrogen replacement therapy may be protective. One of the major pathological features in the human AD brain is the senile plaque, a proteinaceous structure composed mainly of heterogeneous peptides collectively known as A-beta (A,). In vitro studies have linked estrogen with A, modulation, suggesting that one-way that estrogen depletion at menopause may exacerbate the features of AD is through A, accumulation. To test this, two studies were performed on transgenic models of amyloidosis. Firstly, transgenic mice without detectable amyloid aggregates were subjected to ovariectomy and estradiol supplementation, and A, levels were assessed. Secondly, the effects of estrogen modulation were assessed in mice at an age when plaques would be forming initially. Overall, A, levels were higher in estrogen-deprived mice than intact mice, and this effect could be reversed through the administration of estradiol. These data suggest that, in vivo, estrogen depletion leads to the accumulation of A, in the CNS, which can be reversed through replacement of estradiol. These results provide evidence that post-menopausal estrogen depletion may be linked to an increased risk of AD through A, modulation. [source] Neuropathology of Alzheimer's DiseaseMOUNT SINAI JOURNAL OF MEDICINE: A JOURNAL OF PERSONALIZED AND TRANSLATIONAL MEDICINE, Issue 1 2010Daniel P. Perl MD Abstract Alois Alzheimer first pointed out that the disease which would later bear his name has a distinct and recognizable neuropathological substrate. Since then, much has been added to our understanding of the pathological lesions associated with the condition. The 2 primary cardinal lesions associated with Alzheimer's disease are the neurofibrillary tangle and the senile plaque. The neurofibrillary tangle consists of abnormal accumulations of abnormally phosphorylated tau within the perikaryal cytoplasm of certain neurons. The senile plaque consists of a central core of beta-amyloid, a 4-kD peptide, surrounded by abnormally configured neuronal processes or neurites. Other neuropathological lesions are encountered in cases of Alzheimer's disease, but the disease is defined and recognized by these 2 cardinal lesions. Other lesions include poorly understood changes such as granulovacuolar degeneration and eosinophilic rodlike bodies (Hirano bodies). The loss of synaptic components is a change that clearly has a significant impact on cognitive function and represents another important morphological alteration. It is important to recognize that distinguishing between Alzheimer's disease, especially in its early stages, and normal aging may be very difficult, particularly if one is examining the brains of patients who died at an advanced old age. It is also noted that instances of pure forms of Alzheimer's disease, in the absence of other coexistent brain disease processes, such as infarctions or Parkinson's disease,related lesions, are relatively uncommon, and this must be taken into account by researchers who employ postmortem brain tissues for research. Mt Sinai J Med 77:32&–42, 2010. © 2010 Mount Sinai School of Medicine [source] Involvement of apoptosis and cholinergic dysfunction in Alzheimer's diseasePSYCHOGERIATRICS, Issue 2006Shinji TAGAMI Abstract As Alzheimer's disease (AD) progresses, brain atrophy becomes conspicuous, and histologically there is neuronal loss, primarily with a deficit of cholinergic neurons observed. Hitherto, the view has been that cell death, apoptosis, plays a role in this neuronal loss. Apoptosis is characterized by the morphological changes of nuclear fragmentation, chromatin condensation and cell shrinkage, with activation of caspases, members of the cysteine protease family, resulting in considerable substrate cleavage. TUNEL positive neurons have in fact been detected in AD brain, indicating increased caspase activity and resulting substrate cleavage. In AD brain, amyloid beta peptides (A,), the main constituent of senile plaque, are a specific pathological hallmark observed in extracellular spaces. In contrast, the main constituent of intracellularly observed neurofibrillary tangles (NFT) is hyperphosphorylated tau, which is observed in various neurodegenerative disorders other than AD. The viewpoint of many studies is that the A, and NFT that cause these neuropathological changes probably participate in neuronal death. However, up until now it has been thought that there was no hypothesis offering a comprehensive explanation of how the accumulation of extracellular A, and intracellular NFT leads to neuronal death. This report first covers the mechanism of apoptosis as clarified by molecular biological methods, and provides an explanation of how apoptosis could be involved in AD pathology. The subject of autophagic cell death, a type of cell death morphology that has recently been the focus of attention, is also addressed. [source] Involvement of astroglial ceramide in palmitic acid-induced Alzheimer-like changes in primary neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2007Sachin Patil Abstract A high-fat diet has been shown to significantly increase the risk of the development of Alzheimer's disease (AD), a neurodegenerative disease histochemically characterized by the accumulation of amyloid beta (A,) protein in senile plaques and hyperphosphorylated tau in neurofibrillary tangles. Previously, we have shown that saturated free fatty acids (FFAs), palmitic and stearic acids, caused increased amyloidogenesis and tau hyperphosphorylaion in primary rat cortical neurons. These FFA-induced effects observed in neurons were found to be mediated by astroglial FFA metabolism. Therefore, in the present study we investigated the basic mechanism relating astroglial FFA metabolism and AD-like changes observed in neurons. We found that palmitic acid significantly increased de-novo synthesis of ceramide in astroglia, which in turn was involved in inducing both increased production of the A, protein and hyperphosphorylation of the tau protein. Increased amyloidogenesis and hyperphoshorylation of tau lead to formation of the two most important pathophysiological characteristics associated with AD, A, or senile plaques and neurofibrillary tangles, respectively. In addition to these pathophysiological changes, AD is also characterized by certain metabolic changes; abnormal cerebral glucose metabolism is one of the distinct characteristics of AD. In this context, we found that palmitic acid significantly decreased the levels of astroglial glucose transporter (GLUT1) and down-regulated glucose uptake and lactate release by astroglia. Our present data establish an underlying mechanism by which saturated fatty acids induce AD-associated pathophysiological as well as metabolic changes, placing ,astroglial fatty acid metabolism' at the center of the pathogenic cascade in AD. [source] Alzheimer's disease: Mechanisms and development of therapeutic strategiesGERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 4 2003Takeshi Tabira Senile plaques are the most characteristic change in Alzheimer's disease (AD). In senile plaques, , amyloid is deposited, which is composed of aggregated amyloid , protein (A,) derived from amyloid precursor protein (APP). Therefore, it is suggested that there exists a mechanism of increase of A, production or a decrease of A, degradation and/or clearance of , amyloid in AD. Mutations in familial Alzheimer's disease (FAD) genes such as APP, presenilin 1 (PS1) and presenilin 2 (PS2) result in an increase of A, production. Apolipoprotein E (ApoE), a genetic risk factor for AD, is involved in A, production and/or its clearance. Thus, it is suggested that an inhibition of A, production and a facilitation of , amyloid degradation and clearance delay the clinical onset and progression of AD, and it is possible to cure AD even after an onset of the disease, if it is still at an early phase. Researchers studied the fine mechanisms of A, production and identified enzymes that cleave-out A, from APP. Inhibitors of the cleaving enzymes are proven to be effective in ameliorating AD-like conditions in its animal models and are now being applied to humans. Researchers also found an efficient way of clearing , amyloid deposits using the immune system, which was effective in animal models. When it was applied to humans, some patients developed meningoencephalitis as a side-effect. Therefore, safer vaccines are now being developed. It did not require 20 years for researchers to develop therapeutic strategies since the discovery of A, in 1984. Now that AD is becoming a treatable disease, early diagnosis and early treatment will soon become the rule. Notably, AD may not be a psychiatric disorder any more, and mainly neurologists and geriatricians will see patients. Thus, neurogeriatrics will become more and more important. [source] Microglial dystrophy in the aged and Alzheimer's disease brain is associated with ferritin immunoreactivityGLIA, Issue 10 2008Kryslaine O. Lopes Abstract Degeneration of microglial cells may be important for understanding the pathogenesis of aging-related neurodegeneration and neurodegenerative diseases. In this study, we analyzed the morphological characteristics of microglial cells in the nondemented and Alzheimer's disease (AD) human brain using ferritin immunohistochemistry. The central hypothesis was that expression of the iron storage protein ferritin increases the susceptibility of microglia to degeneration, particularly in the aged brain since senescent microglia might become less efficient in maintaining iron homeostasis and free iron can promote oxidative damage. In a primary set of 24 subjects (age range 34,97 years) examined, microglial cells immunoreactive for ferritin were found to constitute a subpopulation of the larger microglial pool labeled with an antibody for HLA-DR antigens. The majority of these ferritin-positive microglia exhibited aberrant morphological (dystrophic) changes in the aged and particularly in the AD brain. No spatial correlation was found between ferritin-positive dystrophic microglia and senile plaques in AD tissues. Analysis of a secondary set of human postmortem brain tissues with a wide range of postmortem intervals (PMI, average 10.94 ± 5.69 h) showed that the occurrence of microglial dystrophy was independent of PMI and consequently not a product of tissue autolysis. Collectively, these results suggest that microglial involvement in iron storage and metabolism contributes to their degeneration, possibly through increased exposure of the cells to oxidative stress. We conclude that ferritin immunohistochemistry may be a useful method for detecting degenerating microglia in the human brain. © 2008 Wiley-Liss, Inc. [source] Transplanted astrocytes internalize deposited ,-amyloid peptides in a transgenic mouse model of Alzheimer's diseaseGLIA, Issue 2 2008Rea Pihlaja Abstract Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders. The neuropathological hallmarks include extracellular senile plaques consisting of deposited ,-amyloid (A,) peptides and intraneuronal neurofibrillary tangles. Neuroinflammation and activation of astrocytes are also well-established features of AD neuropathology; however, the relationships between astrocytes and A, deposition remain unclear. Previous studies have shown that adult mouse astrocytes internalize and degrade A, deposits in brain sections prepared from human amyloid precursor protein (APP) transgenic mice. In the present study, we demonstrate that cultured adult, but not neonatal mouse astrocytes, respond morphologically and degrade A, deposits present in human AD brain. We also transplanted astrocytes isolated from enhanced green fluorescent protein expressing adult and neonatal mice into the hippocampi of human A, plaque-bearing transgenic APPSwe+PS1dE9 (APdE9) mice and their wild-type littermates and followed the migration and localization of these astrocytes by confocal microscopy upto 7 days after transplantation. Posttransplantation the astrocytes localized as aggregates or thin strings of many cells within the hippocampi of APdE9 and wild-type mice and showed limited migration from the injection site. Interestingly, most of the transplanted astrocytes were found near A, deposits in the hippocampi of APdE9 mice. In contrast to findings in ex vivo degradation assay, confocal microscopy revealed that both adult and neonatal transplanted astrocytes internalized human A, immunoreactive material in vivo. These results support the role of astrocytes as active A, clearing cells in the CNS that may have important implications for future development of therapeutic strategies for AD. © 2007 Wiley-Liss, Inc. [source] Proteomic identification of nitrated brain proteins in early Alzheimer's disease inferior parietal lobuleJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 8b 2009Tanea T. Reed Abstract Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive decline in multiple cognitive domains. Its pathological hallmarks include senile plaques and neurofibrillary tangles. Mild cognitive impairment (MCI) is the earliest detectable stage of AD with limited symptomology and no dementia. The yearly conversion rate of patients from MCI to AD is 10,15%, although conversion back to normal is possible in a small percentage. Early diagnosis of AD is important in an attempt to intervene or slow the advancement of the disease. Early AD (EAD) is a stage following MCI and characterized by full-blown dementia; however, information involving EAD is limited. Oxidative stress is well-established in MCI and AD, including protein oxidation. Protein nitration also is an important oxidative modification observed in MCI and AD, and proteomic analysis from our laboratory identified nitrated proteins in both MCI and AD. Therefore, in the current study, a proteomics approach was used to identify nitrated brain proteins in the inferior parietal lobule from four subjects with EAD. Eight proteins were found to be significantly nitrated in EAD: peroxiredoxin 2, triose phosphate isomerase, glutamate dehydrogenase, neuropolypeptide h3, phosphoglycerate mutase1, H+, transporting ATPase, ,-enolase and fructose-1,6-bisphosphate aldolase. Many of these proteins are also nitrated in MCI and late-stage AD, making this study the first to our knowledge to link nitrated proteins in all stages of AD. These results are discussed in terms of potential involvement in the progression of this dementing disorder. [source] Activation of MKK6, an upstream activator of p38, in Alzheimer's diseaseJOURNAL OF NEUROCHEMISTRY, Issue 2 2001Xiongwei Zhu Mitogen-activated protein kinase (MAPK) p38 has been implicated in the pathogenesis of Alzheimer's disease, but the upstream cascade leading to p38 activation has not been elucidated in the disease. In the present study, we focused on mitogen-activated protein kinase kinase 6 (MKK6), one of the upstream activators of p38 MAPK. We found that MKK6 was not only increased but also specifically associated with granular structures in the susceptible neurons in the hippocampus and cortex of Alzheimer's disease patients, but was only weakly diffuse in the cytoplasm in neurons in control cases. Immunoblot analysis demonstrated a significant increase of MKK6 level in Alzheimer's disease compared with age-matched controls. In this regard, in hippocampal and cortical regions of individuals with Alzheimer's disease, the activated phospho-MKK6 was localized exclusively in association with pathological alterations including neurofibrillary tangles, senile plaques, neuropil threads and granular structures, overlapping with activated p38 MAPK suggesting both a functional and mechanic link. By immunoblot analysis, phospho-MKK6 is also significantly increased in AD compared with control cases. Together, these findings lend further credence to the notion that the p38 MAPK pathway is dysregulated in Alzheimer's disease and also indicates an active role for this pathway in disease pathogenesis. [source] In Vivo Visualization of Senile-Plaque-Like Pathology in Alzheimer's Disease Patients by MR Microscopy on a 7T SystemJOURNAL OF NEUROIMAGING, Issue 2 2008Tsutomu Nakada MD ABSTRACT BACKGROUND Microscopic application of magnetic resonance imaging (MRI) has entered the era of clinical application. One of the most important targets is the visualization of pathological findings such as senile plaques (SP), in vivo, in patients with Alzheimer's disease (AD). Such an application provides not only the most accurate diagnostic tool for clinicians but also a solid basis for scientists for developing effective treatment and preventive strategies for AD. METHODS Focused microscopic studies were performed on parietal association cortex at the level of the centrum semiovale identified on conventional axial slices using a system constructed based on General Electric Signa LX (Waukesha, WI) equipped with a 900-mm clear bore superconducting magnet operating at 7.0 T in 10 patients (67-83-year old, five males, five females) who fulfilled the NINCD and the SADRDA criteria for probable AD, 10 age-matched controls (71-85-year old, five males, five females), and 20 young adults (22-35-year old, 10 males, 10 females) using a susceptibility weighted imaging (SWI) algorithm. RESULTS SWI microscopy consistently provided images with SP-like pathology extending within the entire parietal cortex in all cases of AD and 2 out of 10 age-matched volunteers. CONCLUSIONS Although the precise mechanisms leading to the higher susceptibility rendering SP-like pathology observable within the cortical mantle are not totally understood, the study unambiguously demonstrated that MR microscopy is capable of directly visualizing cortical pathology in AD patients in vivo. [source] Decreased levels of PSD95 and two associated proteins and increased levels of BCl2 and caspase 3 in hippocampus from subjects with amnestic mild cognitive impairment: Insights into their potential roles for loss of synapses and memory, accumulation of A,, and neurodegeneration in a prodromal stage of Alzheimer's diseaseJOURNAL OF NEUROSCIENCE RESEARCH, Issue 3 2010Rukhsana Sultana Abstract Alzheimer's disease (AD) is the most common form of dementia and is pathologically characterized by senile plaques, neurofibrillary tangles, synaptic disruption and loss, and progressive neuronal deficits. The exact mechanism(s) of AD pathogenesis largely remain unknown. With advances in technology diagnosis of a pre-AD stage referred to as amnestic mild cognitive impairment (MCI) has become possible. Amnestic MCI is characterized clinically by memory deficit, but normal activities of daily living and no dementia. In the present study, compared to controls, we observed in hippocampus from subjects with MCI a significantly decreased level of PSD95, a key synaptic protein, and also decreased levels of two proteins associated with PSD95, the N-methyl-D-aspartate receptor, subunit 2A (NR2A) and the low-density lipoprotein receptor-1 (LRP1). PSD95 and NR2A are involved in long-term potentiation, a key component of memory formation, and LRP1 is involved in efflux of amyloid beta-peptide (1-42). A, (1-42) conceivably is critical to the pathogenesis of MCI and AD, including the oxidative stress under which brain in both conditions exist. The data obtained from the current study suggest a possible involvement of these proteins in synaptic alterations, apoptosis and consequent decrements in learning and memory associated with the progression of MCI to AD. © 2009 Wiley-Liss, Inc. [source] Presenilin 1 is involved in the maturation of ,-site amyloid precursor protein-cleaving enzyme 1 (BACE1)JOURNAL OF NEUROSCIENCE RESEARCH, Issue 1 2007Akira Kuzuya Abstract One of the pathologic hallmarks of Alzheimer's disease is the excessive deposition of ,-amyloid peptides (A,) in senile plaques. A, is generated when ,-amyloid precursor protein (APP) is cleaved sequentially by ,-secretase, identified as ,-site APP-cleaving enzyme 1 (BACE1), and ,-secretase, a putative enzymatic complex containing presenilin 1 (PS1). However, functional interaction between PS1 and BACE1 has never been known. In addition to this classical role in the generation of A, peptides, it has also been proposed that PS1 affects the intracellular trafficking and maturation of selected membrane proteins. We show that the levels of exogenous and endogenous mature BACE1 expressed in presenilin-deficient mouse embryonic fibroblasts (PS,/,MEFs) were reduced significantly compared to those in wild-type MEFs. Moreover, the levels of mature BACE1 were increased in human neuroblastoma cell line, SH-SY5Y, stably expressing wild-type PS1, compared to native cells. Conversely, the maturation of BACE1 was compromised under the stable expression of dominant,negative mutant PS1 overexpression. Immunoprecipitation assay showed that PS1 preferably interacts with proBACE1 rather than mature BACE1, indicating that PS1 can be directly involved in the maturation process of BACE1. Further, endogenous PS1 was immunoprecipitated with endogenous BACE1 in SH-SY5Y cells and mouse brain tissue. We conclude that PS1 is directly involved in the maturation of BACE1, thus possibly functioning as a regulator of both ,- and ,-secretase in A, generation. © 2006 Wiley-Liss, Inc. [source] Interaction of a ,-sheet breaker peptide with lipid membranesJOURNAL OF PEPTIDE SCIENCE, Issue 2 2010Giuseppe Vitiello Abstract Aggregation of ,-amyloid peptides into senile plaques has been identified as one of the hallmarks of Alzheimer's disease. An attractive therapeutic strategy for Alzheimer's disease is the inhibition of the soluble ,-amyloid aggregation using synthetic ,-sheet breaker peptides that are capable of binding A, but are unable to become part of a ,-sheet structure. As the early stages of the A, aggregation process are supposed to occur close to the neuronal membrane, it is strategic to define the ,-sheet breaker peptide positioning with respect to lipid bilayers. In this work, we have focused on the interaction between the ,-sheet breaker peptide acetyl-LPFFD-amide, iA,5p, and lipid membranes, studied by ESR spectroscopy, using either peptides alternatively labeled at the C- and at the N-terminus or phospholipids spin-labeled in different positions of the acyl chain. Our results show that iA,5p interacts directly with membranes formed by the zwitterionic phospholipid dioleoyl phosphatidylcholine and this interaction is modulated by inclusion of cholesterol in the lipid bilayer formulation, in terms of both peptide partition coefficient and the solubilization site. In particular, cholesterol decreases the peptide partition coefficient between the membrane and the aqueous medium. Moreover, in the absence of cholesterol, iA,5p is located between the outer part of the hydrophobic core and the external hydrophilic layer of the membrane, while in the presence of cholesterol it penetrates more deeply into the lipid bilayer. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd. [source] Synthesis of A,[1-42] and its derivatives with improved efficiencyJOURNAL OF PEPTIDE SCIENCE, Issue 2 2007Márta Zarándi Abstract It has been proved that the principal component of senile plaques is aggregates of ,-amyloid peptide (A,) in cases of one of the most common forms of age-related neurodegenerative disorders, Alzheimer's disease (AD). Although the synthetic methods for the synthesis of A, peptides have been developed since their first syntheses, A,[1-42] is still problematic to prepare. The highly hydrophobic composition of A,[1-42] results in aggregation between resin-bound peptide chains or intrachain aggregation which leads to a decrease in the rates of deprotection and repetitive incomplete coupling reactions during 9-flurenylmethoxycarbonyl (Fmoc) synthesis. In order to avoid aggregation and/or disrupt internal aggregation during stepwise Fmoc solid phase synthesis and to improve the quality of crude products, several attempts have been made. Since highly pure A, peptides in large quantities are used in biological experiments, we wanted to develop a method for a rational synthesis of human A,[1-42] with high purity and adequate yield. This paper reports a convenient methodology with a novel solvent system for the synthesis of A,[1-42], its N -terminally truncated derivatives A,[4-42] and A,[5-42], and A,[1-42] labeled with 7-amino-4-methyl-3-coumarinylacetic acid (AMCA) at the N -terminus using Fmoc strategy. The use of 10% anisole in Dimethylformamide/Dichloromethane (DMF/DCM) can substantially improve the purity and yield of crude A,[1-42] and has been shown to be an optimal coupling condition for the synthesis of A,[1-42]. Anisole is a cheap and simple aid in the synthesis of ,difficult sequences' where other solvents are less successful in the prevention of aggregation during the synthesis. Copyright © 2006 European Peptide Society and John Wiley & Sons, Ltd. [source] Progressive supranuclear palsy combined with Alzheimer's disease: A clinicopathological study of two autopsy casesNEUROPATHOLOGY, Issue 3 2009Rieko Sakamoto We present here the clinicopathological characteristics of two autopsy-confirmed cases comorbid of progressive supranuclear palsy (PSP) and Alzheimer's disease (AD). Histopathologically, the amount and distribution of neurofibrillary tangles (NFTs) in the basal ganglia and brainstem fulfilled the pathological criteria of PSP proposed by the National Institute of Neurological Disorders and Stroke , The Society for PSP (NINDS-SPSP). The Braak stages of senile plaques and NFTs were stage C and stage V in Case 1, and stage C and stage IV in Case 2. These neuropathological findings confirmed that the two patients had combined PSP with AD. Our patients presented clinically with executive dysfunction prior to memory disturbance as an early symptom. Not only neurological symptoms such as gait disturbance, supranuclear ophthalmoplegia and pseudobulbar palsy, but emotional and personality changes and delirium were prominent. Therefore, symptoms of subcortical dementia of PSP were more predominant than AD-related symptoms in the present two patients. Comorbid PSP and AD further complicates the clinical picture and makes clinical diagnosis even more difficult. [source] Quantitative analysis of neurofibrillary pathology in a general population to reappraise neuropathological criteria for senile dementia of the neurofibrillary tangle type (tangle-only dementia): The Hisayama studyNEUROPATHOLOGY, Issue 6 2006Kazuhito Noda Senile dementia of the neurofibrillary tangle type (SD-NFT) is characterized by numerous neurofibrillary tangles (NFT) in the hippocampal region and the absence or minimal presence of senile plaques throughout the brain. We analyzed 207 demented subjects and 68 non-demented subjects autopsied in the Hisayama study to investigate the clinicopathological aspects of SD-NFT in the general Japanese population. The prevalence of SD-NFT in the consecutive autopsy cases was 8/207 (3.9%), comprising three men and five women. The average age at onset and death was 83.8 ± 6.8 (mean ± SD; standard deviation) and 88.1 ± 7.6 years, respectively. A mild memory disturbance preceded a decrease in the ability to undertake the activities of daily living and the diagnosis of dementia. Focal cerebral symptoms, such as aphasia and paralysis, did not appear during the disease course of any subject. Gross examination of the brains showed moderate to severe diffuse cerebral atrophy with brain weight loss (mean ± SD; standard deviation: 1118.1 ± 124.0 g). Histologically, there were abundant NFT and neuropil threads predominantly in or limited to the limbic cortex. The density of NFT in the CA1/subiculum in SD-NFT was much higher than the densities in the other hippocampal regions. The average density of NFT in CA1 in SD-NFT subjects was 115.4 per 100× field (range 23,247), that in Alzheimer disease (AD) subjects was 80.1 (range 1,227), and that in non-demented elderly subjects was 37.2 (range 0,203). Although many previous papers have reported that the densities of NFT in the limbic system in SD-NFT were significantly higher than those in AD, there was considerable overlap of NFT densities in CA1 among the non-demented elderly, AD subjects and SD-NFT subjects. [source] Neurofibrillary tangles and deposition of oxidative products in the brain in cases of myotonic dystrophyNEUROPATHOLOGY, Issue 2 2006Reiko Oyamada Myotonic dystrophy (MyD) is a neuromuscular degenerative disorder that is neuropathologically characterized by minor changes, such as the presence of neurofibrillary tangles (NFT), thalamic inclusions and functional brainstem lesions. In the current study, we conducted an immunohistochemical analysis to examine the distribution of NFT and formation of oxidative products in the brain specimens of 12 patients with MyD. Neurofibrillary tangles were found in the limbic system and/or the brainstem of all the cases examined but there were no senile plaques. The density of distribution of the NFT was not significantly correlated with clinicopathological findings, although cases with fewer NFT in the brain frequently showed sleep disturbances and lack of spontaneity. Nuclear and cytoplasmic immunoreactivities for 8-hydroxy-2,-deoxyguanosine and advanced glycation end products were observed in the glial cells and/or neurons in the brainstem, but not in the cerebral cortex. On the other hand, 10 out of the 12 cases showed cytoplasmic immunoreactivity for 4-hydroxy-2-nonenal-modified protein (4-HNE) in neurons of the temporal cortex and raphe nucleus. Deposition of 4-HNE was also recognized in the hippocampus and mesencephalic central gray matter, but not in the subiculum. The distribution pattern of the immunoreactivity for 4-HNE showed no clear correlation with either the psychological disturbances or the distribution of the NFT. Altered expression of monoaminergic neurons in the brainstem of MyD patients has already been reported, and it is worth noting that most of our cases showed NFT in the brainstem. The selective deposition of 4-HNE in the limbic system and brainstem suggests that lipid peroxidation may be involved in the neurodegenerative process in MyD. Using immunohistochemical analysis to determine the distribution of neurotransmitters in the mesencephalic central gray matter and/or pontine raphe nucleus may help elucidate the relationship between the clinical abnormalities, distribuion of NFT, and 4-HNE deposition in the brain in patients with MyD. [source] Untangling Alzheimer's disease from fibrous lesions of neurofibrillary tangles and senile plaquesNEUROPATHOLOGY, Issue 2000Hiroshi Mori Neuropathological evidence suggests that the two fibril lesions of neurofibrillary tangles (NFT) and senile plaques are the major findings in brain tissue of Alzheimer's disease (AD) and that their occurrence is strongly associated with the symptoms of dementia. Genetic findings have indicated that the pathological molecules from the lesions function as causal agents. There is little evidence, however, to directly indicate that fibril lesions themselves kill neuronal cells in vivo. In spite of such limitations it is important to consider the molecular events involved in AD etiology. In this review of the contribution of Japanese neuropathologists to studies of AD, I will introduce briefly their work and highlight some current topics for consideration on the etiology of AD, and the basis of cell death, and will offer my perspective on outstanding conflicting issues. [source] Specific association of small heat shock proteins with the pathological hallmarks of Alzheimer's disease brainsNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 2 2006M. M. M. Wilhelmus The small heat shock protein family (sHsp) comprises molecular chaperones able to interact with incorrectly folded proteins. Alzheimer's disease (AD) is characterized by pathological lesions such as senile plaques (SPs), cerebral amyloid angiopathy (CAA) and neurofibrillary tangles (NFTs), predominantly consisting of the incorrectly folded proteins amyloid-, (A,) and tau respectively. The aim of this study was to investigate the association of the chaperones Hsp20, HspB2, ,B-crystallin and Hsp27 with the pathological lesions of AD brains. For this purpose, a panel of well-characterized antibodies directed against these sHsps was used in immunohistochemistry and immunoblotting. We observed extracellular expression of Hsp20, Hsp27 and HspB2 in classic SPs, and Hsp20 expression in diffuse SPs. In addition, extracellular expression of HspB2 was observed in CAA. Both Hsp27 and ,B-crystallin were also observed in astrocytes associated with both SPs and CAA. Furthermore, none of the sHsps were observed in NFTs in AD brains. We conclude that specific sHsp species may be involved in the pathogenesis of either SPs or CAA in AD. [source] Ballooned neurones in the limbic lobe are associated with Alzheimer type pathology and lack diagnostic specificityNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 6 2004Y. Fujino Ballooned neurones (BNs) are one of the pathological hallmarks of several neurodegenerative diseases, including Pick's disease, corticobasal degeneration and argyrophilic grain disease (AGD). They have also been described in Alzheimer disease (AD), but the frequency of BNs in AD has not been systematically addressed. In the present study, immunohistochemistry for ,B-crystallin was used as a sensitive method to detect BNs to determine the frequency of BNs in the limbic lobe in AD. At least a few BNs were detected in the limbic lobe of virtually all AD cases, and their density correlated with Braak stage, as well as the density of neurofibrillary tangles and senile plaques in the limbic lobe. The density of BN tended to be greater in AD cases with concurrent AGD than in pure AD. Given the high prevalence of AD in brain banks for neurodegenerative disease and the frequent presence of BNs in these areas with ,B-crystallin immunohistochemistry, the present findings further indicate that BNs confined to the limbic lobe lack specificity in diagnostic neuropathology. [source] Selective PrP-like protein, doppel immunoreactivity in dystrophic neurites of senile plaques in Alzheimer's diseaseNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 4 2004I. Ferrer Doppel (Dpl) is a prion-like protein encoded by the gene PRND, which has been found downstream of the prion gene PRNP in several species. The present study examines by immunohistochemistry Dpl expression in brain samples from 10 patients with Alzheimer's disease (AD), three patients with Pick's disease, four patients with Parkinson's disease, eight patients with diffuse Lewy body disease (DLBD), six patients with sporadic Creutzfeldt,Jakob disease (CJD) methionine/methionine at the codon 129, two patients with sporadic CJD methionine/valine at the codon 129 and numerous kuru plaques in the cerebellum, one patient with fatal familial insomnia (FFI), and 10 age-matched controls. In the adult human brain, Dpl immunoreactivity was restricted to scattered granule cells of the cerebellum and scattered small granules in the cerebral cortex. Dpl immunoreactivity was seen around ,A4 amyloid deposits in neuritic plaques, but not in diffuse plaques, AD and the common form of DLBD. Neurofibrillary tangles, Pick bodies and Lewy bodies were not stained with anti-Dpl antibodies. No modifications in Dpl immunoreactivity were observed in CJD excepting those associated with accompanying senile plaques. No Dpl-positive deposits were seen in FFI. Whether Dpl in neuritic plaques may attenuate amyloid-induced oxidative stress and participate in the glial response around amyloid cores is discussed in light of the few available data on Dpl functions. [source] Neuroprotective effects of Triticum aestivum L. against ,-Amyloid-induced cell death and memory impairmentsPHYTOTHERAPY RESEARCH, Issue 1 2010Jung-Hee Jang Abstract ,-Amyloid (A,) is a key component of senile plaques, neuropathological hallmarks of Alzheimer's disease (AD) and has been reported to induce cell death via oxidative stress. This study investigated the protective effects of Triticum aestivum L. (TAL) on A,-induced apoptosis in SH-SY5Y cells and cognitive dysfunctions in Sprague-Dawley (SD) rats. Cells treated with A, exhibited decreased viability and apoptotic features, such as DNA fragmentation, alterations in mitochondria and an increased Bax/Bcl-2 ratio, which were attenuated by TAL extract (TALE) pretreatment. To elucidate the neuroprotective mechanisms of TALE, the study examined A,-induced oxidative stress and cellular defense. TALE pretreatment suppressed A,-increased intracellular accumulation of reactive oxygen species (ROS) via up-regulation of glutathione, an essential endogenous antioxidant. To further verify the effect of TALE on memory impairments, A, or scopolamine was injected in SD rats and a water maze task conducted as a spatial memory test. A, or scopolamine treatment increased the time taken to find the platform during training trials, which was decreased by TALE pretreatment. Furthermore, one of the active components of TALE, total dietary fiber also effectively inhibited A,-induced cytotoxicity and scopolamine-caused memory deficits. These results suggest that TALE may have preventive and/or therapeutic potential in the management of AD. Copyright © 2009 John Wiley & Sons, Ltd. [source] Protective effect of Toki-shakuyaku-san on amyloid ,25,35 -induced neuronal damage in cultured rat cortical neuronsPHYTOTHERAPY RESEARCH, Issue 5 2005Nobuaki Egashira Abstract Amyloid , protein (A,) is the major component of senile plaques, the pathological hallmark of the neurodegeneration associated with Alzheimer's disease (AD). This study investigated the effect of Toki-shakuyaku-san (TSS), a traditional medicine, on A,25,35 -induced neuronal death and lipid peroxidation assessed by measuring lactate dehydrogenase (LDH) and malondialdehyde (MDA), respectively. A,25,35 at 10 µM induced neuronal damage and increased the LDH and MDA. TSS at concentrations of 100 and 300 µg/mL significantly reduced the A,25,35 -induced neuronal death and the lipid peroxidation. These results suggest that TSS has a protective effect against A,25,35 -induced neuronal damage. TSS may be beneficial for the treatment of AD. Copyright © 2005 John Wiley & Sons, Ltd. [source] Redox proteomics studies of in vivo amyloid beta-peptide animal models of Alzheimer's disease: Insight into the role of oxidative stressPROTEOMICS - CLINICAL APPLICATIONS, Issue 5 2008Rukhsana Sultana Abstract Alzheimer's disease (AD) is an age-related neurodegenerative disease. AD is characterized by the presence of senile plaques, neurofibrillary tangles, and synaptic loss. Amyloid ,-peptide (A,), a component of senile plaques, has been proposed to play an important role in oxidative stress in AD brain and could be one of the key factors in the pathogenesis of AD. In the present review, we discuss some of the AD animal models that express A,, and compare the proteomics-identified oxidatively modified proteins between AD brain and those of A, models. Such a comparison would allow better understanding of the role of A, in AD pathogenesis thereby helping in developing potential therapeutics to treat or delay AD. [source] Apolipoprotein E,dependent accumulation of Alzheimer disease,related lesions begins in middle age,ANNALS OF NEUROLOGY, Issue 6 2009Eloise Kok BScHons Objective To study the prevalence and age dependency of senile plaques (SP) and neurofibrillary tangles (NFT), the brain changes characteristic of Alzheimer disease (AD), and their association with apolipoprotein E (APOE) genotypes in a community-dwelling normal population. Methods This neuropathological study used both silver staining and A, immunohistochemistry in brain tissue microarrays, including SP coverage and NFT counts from frontal cortex and hippocampus, and APOE genotyping, and was performed on a consecutive prospective series of 603 subjects (aged between 0 and 97 years) of an unselected population living outside of institutions. Cases were subjected to autopsy following sudden or unexpected out-of-hospital death, covering 22.1% of the mortality of Tampere, Finland and its surroundings. None died of AD, although 22 (3.7%) were demented and 10 (1.7%) had memory problems. Results Of the series, 30.8% had SP, and 42.1% had NFT; these occurred more commonly among females and showed a strong relationship with age. Both changes had already appeared at around 30 years of age, reaching an occurrence of almost 100% in the oldest. SP were more frequent in APOE ,4-carriers compared with noncarriers in every age group except the oldest (>90 years). The difference was most evident during the ages 50 to 59 years, where 40.7% of ,4-carriers had SP, compared with 8.2% in noncarriers (odds ratio, 8.39; 95% confidence interval, 2.55,27.62). The difference in NFT prevalence between APOE genotypes was not statistically significant in any age group. Interpretation The brain changes associated with AD may already begin developing early in middle age, especially among APOE ,4 carriers. Ann Neurol 2009;65:650,657 [source] Immunoglobulins and complement in postmortem multiple sclerosis tissue,ANNALS OF NEUROLOGY, Issue 1 2009Michael H. Barnett MBBS Objective To identify evidence of a discrete, specific immune response in multiple sclerosis (MS) by analyzing the distribution of immunoglobulins and complement in tissue derived from cases of MS, and from control inflammatory white matter diseases known to express viral and autoantigens in the brain and spinal cord. Methods Autopsy tissue from 25 MS patients and 24 patients with other neurological diseases was examined immunohistochemically for immunoglobulins and activated complement (C3d and C9neo). Results In tissue remote from focal lesions in MS and other neurological diseases, IgG was detected in many normal structures but not in myelin or ramified microglia. Disrupted myelin in areas of active myelin breakdown and in phagocytes stained positively for C3d and C9neo, and equivocally for IgG in MS and all other neurological diseases examined, including ischemic infarcts. Disease-specific deposits of IgG or complement were detected in virus-infected cells in progressive multifocal leukoencephalopathy, subacute sclerosing panencephalitis, and cytomegalovirus encephalitis; in glial-limiting membranes in neuromyelitis optica; and in senile plaques in Alzheimer's dementia. Specific to MS were unusual microglial nodules containing short, linear deposits of activated complement (C3d) on partly demyelinated axons located in normal-appearing periplaque white matter. Interpretation IgG and complement immunostaining of disrupted myelin in MS lesions, frequently cited as an indication of pathogenic anti-myelin antibodies, is a nonspecific feature that cannot be interpreted as evidence of a distinct pathogenesis or serve to define particular variants of the disease. The unusual microglial nodules described in this study may constitute a specific biomarker with pathogenetic significance in MS. Ann Neurol 2009;65:32,46 [source] CCR1 is an early and specific marker of Alzheimer's diseaseANNALS OF NEUROLOGY, Issue 5 2003Meredith Halks-Miller MD Chemokines are a diverse group of small proteins that effect cell signaling by binding to G-protein,coupled, seven-trans-membrane receptors. Our group had found previously that the chemokine receptor CCR1 was present in neurons and dystrophic processes in a small sample of Alzheimer's disease cases. This expanded immunohistochemical study shows that the number of CCR1-positive plaque-like structures in the hippocampus and entorhinal cortex is highly correlated to dementia state as measured by the clinical dementia rating score. CCR1 immunoreactivity is found in dystrophic, neurofilament-positive, synaptophysin-negative neurites that are associated with senile plaques containing amyloid beta peptides of the 1-42 species (A,42). CCR1 was not, however, associated with diffuse deposits of A,42. There was limited expression of CCR1 in neurofibrillary tangle-bearing neuritic processes. Astrocytes and microglia were typically negative for CCR1. Human brains from age-matched, nondemented individuals rarely displayed either CCR1 or A,42 immunoreactivity. Seven other types of dementing neurodegenerative diseases were examined, and all failed to demonstrate CCR1 immunopositivity unless A,42-positive plaques were also present. Thus, neuronal CCR1 is not a generalized marker of neurodegeneration. Rather, it appears to be part of the neuroimmune response to A,42-positive neuritic plaques. [source] Rationally designed dehydroalanine (,Ala)-containing peptides inhibit amyloid-, (A,) peptide aggregationBIOPOLYMERS, Issue 6 2009Vijayaraghavan Rangachari Abstract Among the pathological hallmarks of Alzheimer's disease (AD) is the deposition of amyloid-, (A,) peptides, primarily A, (1,40) and A, (1,42), in the brain as senile plaques. A large body of evidence suggests that cognitive decline and dementia in AD patients arise from the formation of various aggregated forms of A,, including oligomers, protofibrils and fibrils. Hence, there is increasing interest in designing molecular agents that can impede the aggregation process and that can lead to the development of therapeutically viable compounds. Here, we demonstrate the ability of the specifically designed ,,,-dehydroalanine (,Ala)-containing peptides P1 (K-L-V-F-,A-I-,A) and P2 (K-F-,A-,A-,A-F) to inhibit A, (1,42) aggregation. The mechanism of interaction of the two peptides with A, (1,42) seemed to be different and distinct. Overall, the data reveal a novel application of ,Ala-containing peptides as tools to disrupt A, aggregation that may lead to the development of anti-amyloid therapies not only for AD but also for many other protein misfolding diseases. © 2009 Wiley Periodicals, Inc. Biopolymers 91: 456,465, 2009. This article was originally published online as an accepted preprint. The "Published Online" date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com [source] A1 Adenosine Receptors Accumulate in Neurodegenerative Structures in Alzheimer's Disease and Mediate Both Amyloid Precursor Protein Processing and Tau Phosphorylation and TranslocationBRAIN PATHOLOGY, Issue 4 2003Ester Angulo Immunostaining of adenosine receptors in the hippocampus and cerebral cortex from necropsies of Alzheimer's disease (AD) patients shows that there is a change in the pattern of expression and a redistribution of receptors in these brain areas when compared with samples from controls. Adenosine A1 receptor (A1R) immunoreactivity was found in degenerating neurons with neurofibrillary tangles and in dystrophic neurites of senile plaques. A high degree of colocalization for A1R and pA4 amyloid in senile plaques and for A1R and tau in neurons with tau deposition, but without tangles, was seen. Additionally, adenosine A2A receptors, located mainly in striatal neurons in controls, appeared in glial cells in the hippocampus and cerebral cortex of patients. On comparing similar samples from controls and patients, no significant change was evident for metabotropic glutamate receptors. In the human neuroblastoma SH-SY5Y cell line, agonists for A1R led to a dose-dependent increase in the production of soluble forms of amyloid precursor protein in a process mediated by PKC. A1R agonist induced p21 Ras activation and ERK1/2 phosphorylation. Furthermore, activation of A1R led to and ERK-dependent increase of tau phosphorylation and translocation towards the cytoskeleton. These results indicate that adenosine receptors are potential targets for AD. [source] | |||||||||||||||||||||||||||||||