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Neurofibrillary Tangles (neurofibrillary + tangle)
Selected AbstractsMitotic Epitopes are Incorporated into Age-dependent Neurofibrillary Tangles in Niemann,Pick Disease Type CBRAIN PATHOLOGY, Issue 2 2010Min Zhang MD Abstract The mechanism underlying neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) and other neurodegenerative disorders remains elusive. Niemann,Pick disease type C (NPC) is a kind of genetic neurovisceral disorder in which the intracellular sequestration of cholesterol and other lipids in neurons, NFT formation and neuronal degeneration in brain are the neuropathology hallmarks. The age of onset and progression of the disease vary dramatically. We have analyzed the hippocampus from 17 NPC cases, aged from 7 months to 55 years, to depict the temporal characteristics of NFT formation. Unexpectedly, classic NFT was observed in about 4-year-old NPC brain, suggesting that NFT is not aging dependent, and that juvenile brain neurons satisfy the requirements for NFT formation. NFT in the hippocampus of NPC was significantly increased in number with the advance of age. More importantly, multiple mitotic phase markers, which are not usually found in normal mature neurons, were abundant in the affected neurons and incorporated into NFT. The unusual activation of cdc2/cyclin B kinase and downstream mitotic indices are closely associated with the age-dependent NFT formation, signifying the contribution of abortive cell cycle to neurodegeneration. The cdc2 inhibitors may be therapeutically used for early intervention of neurodegeneration and NFT formation in NPC. [source] Active c-jun N-terminal kinase induces caspase cleavage of tau and additional phosphorylation by GSK-3, is required for tau aggregationEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2008Naruhiko Sahara Abstract Neurofibrillary tangles (NFTs), comprising human intracellular microtubule-associated protein tau, are one of the hallmarks of tauopathies, including Alzheimer's disease. Recently, a report that caspase-cleaved tau is present in NFTs has led to the hypothesis that the mechanisms underlying NFT formation may involve the apoptosis cascade. Here, we show that adenoviral infection of tau into COS-7 cells induces activation of c-jun N-terminal kinase (JNK), followed by excessive phosphorylation of tau and its cleavage by caspase. However, JNK activation alone was insufficient to induce sodium dodecyl sulfate (SDS)-insoluble tau aggregation and additional phosphorylation by GSK-3, was required. In SH-SY5Y neuroblastoma cells, overexpression of active JNK and GSK-3, increased caspase-3 activation and cytotoxicity more than overexpression of tau alone. Taken together, these results indicate that, although JNK activation may be a primary inducing factor, further phosphorylation of tau is required for neuronal death and NFT formation in neurodegenerative diseases, including those characterized by tauopathy. [source] The small heat shock protein Hsp27 protects cortical neurons against the toxic effects of ,-amyloid peptideJOURNAL OF NEUROSCIENCE RESEARCH, Issue 14 2009Michael King Abstract Neurofibrillary tangles and amyloid plaques are considered to be hallmarks of Alzheimer's disease (AD), and the toxic effects of amyloid-, peptide (A,) lead to activation of stress-related signaling and neuronal loss. The small heat shock protein Hsp27 is reported to be increased in AD brains and to accumulate in plaques, but whether this represents a potentially protective response to stress or is part of the disease process is not known. We hypothesized that increased expression of Hsp27 in neurons can promote neuronal survival and stabilize the cytoskeleton in the face of A, exposure. By using neonatal rat cortical neurons, we investigated the potential role of Hsp27 in neuronal cultures in the presence or absence of A,. We initially tested whether a heat stress (HS) would be sufficient to induce endogenous Hsp27 expression. HS not only did not result in neuronal Hsp27 up-regulation but made the cells more vulnerable to A, exposure. We then used cDNA transfection to overexpress EGFP-Hsp27 (or the empty vector) in cultures and then assessed neuronal survival and growth. Transfected neurons appeared healthy and had robust neuritic outgrowth. A, treatment induced significant cell death by 48,72 hr in nontransfected and empty-vector-expressing cultures. In contrast, cultures expressing Hsp27 did not display significant apoptosis. Our results show that Hsp27-expressing neurons were selectively protected against the deleterious effects of A, treatment; neuronal degeneration was prevented, and A,-induced alterations in mitochondrial size were attenuated. We also demonstrate that Hsp27 expression can enhance neurite growth in cortical neurons compared with control vector-transfected cells. Overall, our study provides new evidence that Hsp27 can provide a protective influence in primary cortical neurons in the face of toxic concentrations of amyloid. © 2009 Wiley-Liss, Inc. [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] 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] 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] Cytosolic protein-protein interactions that regulate the amyloid precursor proteinDRUG DEVELOPMENT RESEARCH, Issue 2 2002Shasta L. Sabo Abstract Alzheimer disease (AD), a progressive neurodegenerative disease, is the most common cause of dementia in the elderly and is among the leading causes of death in adults. AD is characterized by two major pathological hallmarks, amyloid plaques and neurofibrillary tangles. For a number of reasons, amyloid plaque accumulation is widely thought to be the probable cause of AD. The amyloid plaque core is largely composed of an approximately 4-kDa peptide referred to as A,. A, is derived from its precursor, the Alzheimer amyloid protein precursor (APP), by endoproteolytic processing. APP is a type I integral membrane protein, with a long extracellular domain, one transmembrane domain, and a short (,50 amino acid) cytoplasmic tail. Despite intense efforts to decipher the function of APP, its normal physiological role has remained elusive. The carboxy-terminus of APP contains the sequence YENPTY, which is absolutely conserved across APP homologues and across species. The YENPTY sequence is important for regulation of APP processing and trafficking. Given the importance of the cytoplasmic domain in APP physiology, a number of laboratories have hypothesized that proteins that bind to the YENPTY sequence in the cytoplasmic domain of APP might regulate APP processing, trafficking, and/or function. In this article, we will discuss data revealing which proteins bind to the cytoplasmic domain of APP, how these binding-proteins regulate APP metabolism and function, and why such protein-protein interactions provide an exciting new target for therapeutic intervention in AD. Drug Dev. Res. 56:228,241, 2002. © 2002 Wiley-Liss, Inc. [source] Truncated tau expression levels determine life span of a rat model of tauopathy without causing neuronal loss or correlating with terminal neurofibrillary tangle loadEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2008Peter Koson Abstract We have previously demonstrated in a transgenic rat model of tauopathy that human misfolded truncated tau derived from Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo. We employed this model to investigate the impact of truncated tau expression levels on life span, neuronal loss and the final load of neurofibrillary tangles (NFTs) in transgenic rats. Two independent transgenic lines (SHR72, SHR318), that display different expression levels of truncated tau, were utilized in this study. We found that transgene expression levels in the brain of SHR72 rats were 44% higher than in SHR318 rats and that truncated tau protein levels determined the survival rate of transgenic rats. The line with higher expression levels of truncated tau (SHR72) showed decreased median survival (222.5 days) when compared with the line with lower expression (SHR318; 294.5 days). Interestingly, NFT loads (total NFT/total neurons) were very similar in terminal stages of disease in both transgenic lines (SHR72 , 10.9%; SHR318 , 11.6%), despite significantly different expression levels of truncated tau. Moreover, mean neuron numbers in the hippocampus (CA1,3) and brain stem (gigantocellular reticular nucleus) in the two transgenic rat strains in the terminal stages of disease were similar, and did not differ significantly from those observed in age-matched non-transgenic controls. These findings suggest that the expression levels of misfolded truncated tau determine the life span in a transgenic rat model of tauopathy without causing neuronal loss or correlating with terminal NFT load. [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] Altered subcellular location of phosphorylated Smads in Alzheimer's diseaseEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2006Uwe Ueberham Abstract A number of growth factors and cytokines, such as transforming growth factor beta 1 (TGF-,1), is elevated in Alzheimer's disease (AD), giving rise to activated intracellular mitogenic signaling cascades. Activated mitogenic signaling involving the mitogen-activated protein kinases (MAPKs) and other protein kinases might alter the phosphorylation states of structural proteins such as tau, resulting in hyperphosphorylated deposits. Many intracellular signaling proteins are potential targets of misregulated phosphorylation and dephosphorylation. Recently, a crosstalk between MAPKs and Smad proteins, both involved in mediating TGF-,1 signaling, has been reported. Although TGF-,1 has previously been shown to be involved in the pathogenesis of AD, the role of Smad proteins has not been investigated. In this study we thus analysed the subcellular distribution of phosphorylated Smad2 and Smad3 in the hippocampus of both normal and AD brains. Here we report on strong nuclear detection of phosphorylated Smad2 and Smad3 in neurons of control brains. In AD brains these phosphorylated proteins were additionally found in cytoplasmic granules in hippocampal neurons, within amyloid plaques and attached to neurofibrillary tangles. Our data suggest a critical role of Smad proteins in the pathogenesis of AD. [source] Impaired spatial reference memory and increased exploratory behavior in P301L tau transgenic miceGENES, BRAIN AND BEHAVIOR, Issue 5 2006L. Pennanen The neuropathological hallmark shared between Alzheimer's disease (AD) and familial frontotemporal dementia (FTDP-17) are neurofibrillary tangles (NFT) which are composed of filamentous aggregates of the microtubule-associated protein tau. Their formation has been reproduced in transgenic mice, which express the FTDP-17-associated mutation P301L of tau. In these mice, tau aggregates are found in many brain areas including the hippocampus and the amygdala, both of which are characterized by NFT formation in AD. Previous studies using an amygdala-specific test battery revealed an increase in exploratory behavior and an accelerated extinction of conditioned taste aversion in these mice. Here, we assessed P301L mice in behavioral tests known to depend on an intact hippocampus. Morris water maze and Y-maze revealed intact spatial working memory but impairment in spatial reference memory at 6 and 11 months of age. In addition, a modest disinhibition of exploratory behavior at 6 months of age was confirmed in the open field and the elevated O-maze and was more pronounced during aging. [source] Changes in age-associated neurodegenerative diseases in the last half centuryGERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 3 2002Asao Hirano Age-associated neurodegenerative diseases are a serious and growing problem for mankind, and their etiologies are still unknown. The author has been studying the neuropathology of fatal neurodegenerative diseases endemic to the native Chamorro population on Guam during the last half a century. During this time, remarkable advances in scientific technology, such as the application of electron microscopy, immunohistochemistry and molecular genetics, have contributed to numerous discoveries in classic neurological diseases. In addition, various new diseases have been recognized. This communication reviews Alzheimer's neurofibrillary tangles and Cu/Zn superoxide dismutase positive Lewy body-like inclusions in the anterior horn cells, in order to elucidate these pathological findings as well as remarkable changes observed in certain other age-related neurodegenerative diseases. [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] Cleavage and conformational changes of tau protein follow phosphorylation during Alzheimer's diseaseINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 2 2008Siddhartha Mondragón-Rodríguez Summary Phosphorylation, cleavage and conformational changes in tau protein all play pivotal roles during Alzheimer's disease (AD). In an effort to determine the chronological sequence of these changes, in this study, using confocal microscopy, we compared phosphorylation at several sites (Ser199/202/396/404/422 -Thr205 and the second repeat domain), cleavage of tau (D421) and the canonical conformational Alz-50 epitope. While all of these posttranslational modifications are found in neurofibrillary tangles (NFTs) at all stages of the disease, we found significantly higher numbers of phospho-tau positive NFTs when compared with cleaved tau (P = 0.006 in Braak III; P = 0.002 in Braak IV; P = 0.012 in Braak V) or compared with the Alz-50 epitope (P < 0.05). Consistent with these findings, in a double transgenic mice model (Tet/GSK-3,/VLW) overexpressing the enzyme glycogen synthase kinase-3, (GSK-3,) and tau with a triple FTDP-17 mutation (VLW) with AD-like neurodegeneration, phosphorylation at sites Ser199/202 -Thr205 was greater than truncated tau. Taken together, these data strongly support the notion that the conformational changes and truncation of tau occur after the phosphorylation of tau. We propose two probable pathways for the pathological processing of tau protein during AD, either phosphorylation and cleavage of tau followed by the Alz-50 conformational change or phosphorylation followed by the conformational change and cleavage as the last step. [source] Blood Pressure and Brain Injury in Older Adults: Findings from a Community-Based Autopsy StudyJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 11 2009Lucy Y. Wang MD OBJECTIVES: To examine correlations between blood pressure (BP) and dementia-related pathological brain changes in a community-based autopsy sample. DESIGN: Prospective cohort study. SETTING: A large health maintenance organization in Seattle, Washington. PARTICIPANTS: A cohort of 250 participants aged 65 and older and cognitively normal at time of enrollment in the Adult Changes in Thought (ACT) Study and who underwent autopsy. MEASUREMENTS: BP and history of antihypertensive treatment were taken at enrollment. A linear regression model was used to examine the relationship between BP (systolic (SBP) and diastolic (DBP)) at enrollment and pathological changes in the cerebrum (cystic macroscopic infarcts, microinfarcts, neuritic plaques, neurofibrillary tangles, and cortical Lewy bodies). RESULTS: The presence of more than 2 microinfarcts, but not any other pathological change, was independently associated with SBP in younger participants (65,80, n=137) but not in older participants (>80, n=91). The relative risk (RR) for more than two microinfarcts with each 10-mmHg increase in SBP was 1.15 (95% confidence interval (CI)=1.00,1.33) in the younger participants, adjusted for age at entry, sex, and time to death. This RR was particularly strong in younger participants not taking antihypertensive medications (RR=1.48, 95% CI=1.21, 1.81); significant associations were not observed in participants treated for hypertension. Findings for DBP were negative. CONCLUSION: The association between high SBP and cerebrovascular damage in untreated older adults (65,80) suggests that adequate hypertension treatment may reduce dementia risk by minimizing microvascular injury to cerebrum. [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] S100B induces tau protein hyperphosphorylation via Dickopff-1 up-regulation and disrupts the Wnt pathway in human neural stem cellsJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 3 2008Giuseppe Esposito Abstract Previous studies suggest that levels of the astrocyte-derived S100B protein, such as those occurring in brain extra-cellular spaces consequent to persistent astroglial activation, may have a pathogenetic role in Alzheimer's disease (AD). Although S100B was reported to promote , amyloid precursor protein overexpression, no clear mechanistic relationship between S100B and formation of neurofibrillary tangles (NFTs) is established. This in vitro study has been aimed at investigating whether S100B is able to disrupt Wnt pathway and lead to tau protein hyperphosphorylation. Utilizing Western blot, electrophoretic mobility shift assay, supershift and reverse transcriptase-polymerase chain reaction techniques, it has been demonstrated that micromolar S100B concentrations stimulate c-Jun N-terminal kinase (JNK) phosphorylation through the receptor for advanced glycation ending products, and subsequently activate nuclear AP-1/cJun transcription, in cultured human neural stem cells. In addition, as revealed by Western blot, small interfering RNA and immunofluorescence analysis, S100B-induced JNK activation increased expression of Dickopff-1 that, in turn, promoted glycogen synthase kinase 3, phosphorylation and ,-catenin degradation, causing canonical Wnt pathway disruption and tau protein hyperphosphorylation. These findings propose a previously unrecognized link between S100B and tau hyperphosphorylation, suggesting S100B can contribute to NFT formation in AD and in all other conditions in which neuroinflammation may have a crucial role. [source] Synthesis and 11C-labelling of (E,E)-1-(3,,4,-dihydroxystyryl)-4-(3,-methoxy-4,-hydroxystyryl) benzene for PET imaging of amyloid deposits,,JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 8 2002Yanming Wang Abstract Carboxylic acid derivatives of the amyloid-binding dye Congo red do not enter the brain well and are thus unable to serve as in vivo amyloid-imaging agents. A neutral amyloid probe, (E,E)-1-(3,,4,-dihydroxystyryl)-4-(3,-methoxy-4,-hydroxystyryl)benzene (3), devoid of any carboxylate groups has been designed and synthesized via a 12-step reaction sequence with a total yield of 30%. The unsymmetric compound 3 has also been labelled with C-11 via [11C]methyl iodide ([11C]CH3I) methylation of a symmetric 4,4,-dimesyl protected precursor followed by deprotection. Preliminary evaluation indicated that compound 3 selectively stained plaques and neurofibrillary tangles in post-mortem AD brain, and exhibited good binding affinity (Ki=38±8 nM) for A,(1,40) fibrils in vitro. In vivo pharmacokinetic studies indicated that [11C]3 exhibited higher brain uptake than its carboxylic acid analogs and good clearance from normal control mouse brain. [11C]3 also exhibited specific in vivo binding to pancreatic amyloid deposits in the NOR-beta transgenic mouse model. These results justify further investigation of 3 and similar derivatives as surrogate markers for in vivo quantitation of amyloid deposits. Copyright © 2002 John Wiley & Sons, Ltd. [source] A novel effect of rivastigmine on pre-synaptic proteins and neuronal viability in a neurodegeneration model of fetal rat primary cortical cultures and its implication in Alzheimer's diseaseJOURNAL OF NEUROCHEMISTRY, Issue 4 2010Jason A. Bailey J. Neurochem. (2010) 112, 843,853. Abstract Alzheimer's disease (AD) is characterized by deposition of amyloid-, peptide plaque, disrupted amyloid-,-precursor protein (APP) metabolism, hyperphosphorylation of Tau leading to neurofibrillary tangles and associated neurotoxicity. Moreover, there is synaptic loss in AD, which occurs early and may precede frank amyloidosis. The central cholinergic system is especially vulnerable to the toxic events associated with AD, and reduced acetylcholine levels in specific brain regions is thought to be central to memory deficits in AD. First-generation cholinesterase inhibitors have provided only symptomatic relief to patients with AD by prolonging the action of remaining acetylcholine with little or no change in the course of the disease. Some second-generation cholinesterase inhibitors are multifunctional drugs that may provide more than purely palliative results. To evaluate the effects of the dual acetylcholinesterase and butyrylcholinesterase inhibitor rivastigmine on key aspects of AD, embryonic day 16 rat primary cortical cultures were treated with rivastigmine under media conditions observed to induce time-dependent neurodegeneration. Samples were subjected to western blotting and immunocytochemistry techniques to determine what influence this drug may have on synaptic proteins and neuronal morphology. There was a strong increase in relative cell viability associated with rivastigmine treatment. Significant dose-dependent increases were observed in the levels of synaptic markers synaptosomal-associated protein of 25 kDa (SNAP-25) and synaptophysin, as well as the neuron-specific form of enolase. Together with an observed enhancement of neuronal morphology, our results suggest a rivastigmine-mediated novel neuroprotective and/or neurorestorative effects involving the synapse. Our observations may explain the potential for rivastigmine to alter the course of AD, and warrant further investigations into using butyrylcholinesterase inhibition as a therapeutic strategy for AD, especially with regard to restoration of synaptic function. [source] Complement component C1q inhibits ,-amyloid- and serum amyloid P-induced neurotoxicity via caspase- and calpain-independent mechanismsJOURNAL OF NEUROCHEMISTRY, Issue 3 2008Karntipa Pisalyaput Abstract Alzheimer's disease is a neurodegenerative disorder characterized by neuronal loss, ,-amyloid (A,) plaques, and neurofibrillary tangles. Complement protein C1q has been found associated with fibrillar A, deposits, however the exact contributions of C1q to Alzheimer's disease is still unknown. There is evidence that C1q, as an initiator of the inflammatory complement cascade, may accelerate disease progression. However, neuronal C1q synthesis is induced after injury/infection suggesting that it may be a beneficial response to injury. In this study, we report that C1q enhances the viability of neurons in culture and protects neurons against A,- and serum amyloid P (SAP)-induced neurotoxicity. Investigation of potential signaling pathways indicates that caspase and calpain are activated by A,, but C1q had no effect on either of these pathways. Interestingly, SAP did not induce caspase and calpain activation, suggesting that C1q neuroprotection is in distinct from caspase and calpain pathways. In contrast to A,- and SAP-induced neurotoxicity, neurotoxicity induced by etoposide or FCCP was unaffected by the addition of C1q, indicating pathway selectivity for C1q neuroprotection. These data support a neuroprotective role for C1q which should be further investigated to uncover mechanisms which may be therapeutically targeted to slow neurodegeneration via direct inhibition of neuronal loss. [source] Chronic lithium administration to FTDP-17 tau and GSK-3, overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre-formed neurofibrillary tangles do not revertJOURNAL OF NEUROCHEMISTRY, Issue 6 2006Tobias Engel Abstract Glycogen synthase kinase-3 (GSK-3) has been proposed as the main kinase able to aberrantly phosphorylate tau in Alzheimer's disease (AD) and related tauopathies, raising the possibility of designing novel therapeutic interventions for AD based on GSK-3 inhibition. Lithium, a widely used drug for affective disorders, inhibits GSK-3 at therapeutically relevant concentrations. Therefore, it was of great interest to test the possible protective effects of lithium in an AD animal model based on GSK-3 overexpression. We had previously generated a double transgenic model, overexpressing GSK-3, in a conditional manner, using the Tet-off system and tau protein carrying a triple FTDP-17 (frontotemporal dementia and parkinsonism linked to chromosome 17) mutation. This transgenic line shows tau hyperphosphorylation in hippocampal neurones accompanied by neurofibrillary tangles (NFTs). We used this transgenic model to address two issues: first, whether chronic lithium treatment is able to prevent the formation of aberrant tau aggregates that result from the overexpression of FTDP-17 tau and GSK-3,; second, whether lithium is able to change back already formed NFTs in aged animals. Our data suggest that progression of the tauopathy can be prevented by administration of lithium when the first signs of neuropathology appear. Furthermore, it is still possible to partially reverse tau pathology in advanced stages of the disease, although NFT-like structures cannot be changed. The same results were obtained after shut-down of GSK-3, overexpression, supporting the possibility that GSK-3 inhibition is not sufficient to reverse NFT-like aggregates. [source] Pseudophosphorylation of tau at serine 422 inhibits caspase cleavage: in vitro evidence and implications for tangle formation in vivoJOURNAL OF NEUROCHEMISTRY, Issue 4 2006Angela L. Guillozet-Bongaarts Abstract The tangles of Alzheimer's disease (AD) are comprised of the tau protein displaying numerous alterations, including phosphorylation at serine 422 (S422) and truncation at aspartic acid 421 (D421). Truncation at the latter site appears to result from activation of caspases, a class of proteases that cleave specifically at aspartic acid residues. It has been proposed that phosphorylation at or near caspase cleavage sites could regulate the ability of the protease to cleave at those sites. Here, we use tau pseudophosphorylated at S422 (S422E) to examine the effects of tau phosphorylation on its cleavage by caspase 3. We find that S422E tau is more resistant to proteolysis by caspase 3 than non-pseudophosphorylated tau. Additionally, we use antibodies directed against the phosphorylation site and against the truncation epitope to assess the presence of these epitopes in neurofibrillary tangles in the aged human brain. We show that phosphorylation precedes truncation during tangle maturation. Moreover, the distribution of the two epitopes suggests that a significant length of time (perhaps as much as two decades) elapses between S422 phosphorylation and cleavage at D421. We further conclude that tau phosphorylation at S422 may be a protective mechanism that inhibits cleavage in vivo. [source] Presenilin function and ,-secretase activityJOURNAL OF NEUROCHEMISTRY, Issue 4 2005A. L. Brunkan Abstract Alzheimer's disease (AD) is the most common form of dementia and is characterized pathologically by the accumulation of ,-amyloid (A,) plaques and neurofibrillary tangles in the brain. Genetic studies of AD first highlighted the importance of the presenilins (PS). Subsequent functional studies have demonstrated that PS form the catalytic subunit of the ,-secretase complex that produces the A, peptide, confirming the central role of PS in AD biology. Here, we review the studies that have characterized PS function in the ,-secretase complex in Caenorhabditis elegans, mice and in in vitro cell culture systems, including studies of PS structure, PS interactions with substrates and other ,-secretase complex members, and the evidence supporting the hypothesis that PS are aspartyl proteases that are active in intramembranous proteolysis. A thorough knowledge of the mechanism of PS cleavage in the context of the ,-secretase complex will further our understanding of the molecular mechanisms that cause AD, and may allow the development of therapeutics that can alter A, production and modify the risk for AD. [source] Iron (III) induces aggregation of hyperphosphorylated , and its reduction to iron (II) reverses the aggregation: implications in the formation of neurofibrillary tangles of Alzheimer's diseaseJOURNAL OF NEUROCHEMISTRY, Issue 6 2003Akira Yamamoto No abstract is available for this article. [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] 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] Medicinal chemistry approaches for the treatment and prevention of Alzheimer's diseaseMEDICINAL RESEARCH REVIEWS, Issue 1 2003S.O. Bachurin Abstract Alzheimer's disease (AD) is the most common form of dementia, which is characterised by progressive deterioration of memory and higher cortical functions that ultimately result in total degradation of intellectual and mental activities. Modern strategies in the search of new therapeutic approaches are based on the morphological and biochemical characteristics of AD, and focused on following directions: agents that compensate the hypofunction of cholinergic system, agents that interfere with the metabolism of beta-amyloid peptide, agents that protect nerve cells from toxic metabolites formed in neurodegenerative processes, agents that activate other neurotransmitter systems that indirectly compensate for the deficit of cholinergic functions, agents that affect the process of the formation of neurofibrillary tangles, anti-inflammatory agents that prevent the negative response of nerve cells to the pathological process. The goal of the present review is the validation and an analysis from the point of view of medicinal chemistry of the principles of the directed search of drugs for the treatment and prevention of AD and related neurodegenerative disorders. It is based on systematization of the data on biochemical and structural similarities in the interaction between physiologically active compounds and their biological targets related to the development of such pathologies. The main emphasis is on cholinomimetic, anti-amyloid and anti-metabolic agents, using the data that were published during the last 3 to 4 years, as well as the results of clinical trials presented on corresponding websites. © 2002 Wiley Periodicals, Inc. Med Res Rev, 23, No. 1, 48,88, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/med.10026 [source] Vaccination as a Therapeutic Approach to Alzheimer's DiseaseMOUNT SINAI JOURNAL OF MEDICINE: A JOURNAL OF PERSONALIZED AND TRANSLATIONAL MEDICINE, Issue 1 2010Thomas Wisniewski MD Abstract Alzheimer's disease is the most common cause of dementia worldwide. Alzheimer's disease is a member of a broad range of neurodegenerative diseases characterized pathologically by the conformational change of a normal protein into a pathological conformer with a high ,-sheet content that renders it neurotoxic. In the case of Alzheimer's disease, the normal soluble amyloid , peptide is converted into oligomeric/fibrillar amyloid ,. The oligomeric forms of amyloid , have been hypothesized to be the most toxic, whereas fibrillar amyloid , becomes deposited as amyloid plaques and congophilic angiopathy, which both serve as neuropathological markers of the disease. In addition, the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is a critical part of the pathology. Numerous therapeutic interventions are under investigation to prevent and treat Alzheimer's disease. Among the most exciting and advanced of these approaches is vaccination. Immunomodulation is being tried for a range of neurodegenerative disorders, with great success being reported in most model animal trials; however, the much more limited human data have shown more modest clinical success so far, with encephalitis occurring in a minority of patients treated with active immunization. The immunomodulatory approaches for neurodegenerative diseases involve targeting a self-protein, albeit in an abnormal conformation; hence, effective enhanced clearance of the disease-associated conformer has to be balanced with the potential risk of stimulating excessive toxic inflammation within the central nervous system. The design of future immunomodulatory approaches that are more focused is dependent on addressing a number of questions, including when is the best time to start immunization, what are the most appropriate targets for vaccination, and is amyloid central to the pathogenesis of Alzheimer's disease or is it critical to target tau-related pathology also. In this review, we discuss the past experience with vaccination for Alzheimer's disease and the development of possible future strategies that target both amyloid ,,related and tau-related pathologies. Mt Sinai J Med 77:17&–31, 2010. © 2010 Mount Sinai School of Medicine [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] Diagnostic clues and more from photographsNEUROPATHOLOGY, Issue 1 2007Asao Hirano During over 50 years of the first author's career in neuropathology at Montefiore Medical Center in New York, we have come across certain interesting neuropathological findings. In this communication, some photographs showing macroscopic, microscopic and electron microscopic significant findings are selected to illustrate usefulness not only for the diagnosis but also for understanding of the nervous system. The six topics presented in this paper are: (i) unattached presynaptic terminals in cerebellar neuroblastoma; (ii) neurofibrillary tangle formation in the nucleus basalis of Meynert ipsilateral to a massive cerebral infarct; (iii) orderly arrangement of tumor cells in leptomeningeal carcinomatosis; (iv) interface between craniopharyngioma and brain tissue; (v) neurofibrillary tangles and Lewy bodies in a single neuron; and (vi) Cu/Zn superoxide dismutase positive Lewy body-like hyaline inclusions in anterior horn cells in familial motor neuron diseases. Analyses of these findings are presented for an educational purpose. [source] | ||||||||||||||||||||||||||||||||||