Showing papers by "John Q. Trojanowski published in 1997"
TL;DR: Strong staining of Lewy bodies from idiopathic Parkinson's disease with antibodies for α-synuclein, a presynaptic protein of unknown function which is mutated in some familial cases of the disease, indicates that the LewY bodies from these two diseases may have identical compositions.
Abstract: Lewy bodies, a defining pathological characteristic of Parkinson's disease and dementia with Lewy bodies (DLB)1,2,3,4, constitute the second most common nerve cell pathology, after the neurofibrillary lesions of Alzheimer's disease. Their formation may cause neurodegeneration, but their biochemical composition is unknown. Neurofilaments and ubiquitin are present5,6,7,8, but it is unclear whether they are major components of the filamentous material of the Lewy body9,10. Here we describe strong staining of Lewy bodies from idiopathic Parkinson's disease with antibodies for α-synuclein, a presynaptic protein of unknown function which is mutated in some familial cases of the disease11. α-Synuclein may be the main component of the Lewy body in Parkinson's disease. We also show staining for α-synuclein of Lewy bodies from DLB, indicating that the Lewy bodies from these two diseases may have identical compositions.
6,923 citations
TL;DR: The consensus recommendations for improving the neuropathological criteria for the postmortem diagnosis of Alzheimer's disease are reported here, and the "position papers" by members of the Working Group that accompany this report elaborate on the research findings and concepts upon which these recommendations were based.
Abstract: THE NATIONAL INSTITUTE ON AGING AND REAGAN INSTITUTE WORKING GROUP ON DIAGNOSTIC CRITERIA FOR THE NEUROPATHOLOGICAL ASSESSMENT OF ALZHEIMER'S DISEASE.Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. NEUROBIOL AGING18(S4) S1-S2, 1997.—This report summarizes the consensus recommenda- tions of a panel of neuropathologists from the United States and Europe to improve the postmortem diagnostic criteria for Alzheimer's disease. The recommendations followed from a two-day workshop sponsored by the National Institute on Aging (NIA) and the Ronald and Nancy Reagan Institute of the Alzheimer's Association to reassess the original NIA criteria for the postmortem diagnosis of Alzheimer's disease published in 1985 (2). The consensus recommendations for improving the neuropathological criteria for the postmortem diagnosis of Alzheimer's disease are reported here, and the "position papers" by members of the Working Group that accompany this report elaborate on the research findings and concepts upon which these recommendations were based. Further, commentaries by other experts in the field also are included here to provide additional perspectives on these recommendations. Finally, it is anticipated that future meetings of the Working Group will reassess these recommendations and the implementation of postmortem diagnostic criteria for Alzheimer's disease. © 1997 Elsevier Science Inc.
1,572 citations
TL;DR: The consensus recommendations for improving the neuropathological criteria for the postmortem diagnosis of Alzheimer's disease are reported here, and the "position papers" by members of the Working Group that accompany this report elaborate on the research findings and concepts upon which these recommendations were based.
1,080 citations
TL;DR: It is suggested that intranuclear aggregation of the expanded protein is a unifying feature of CAG/polyglutamine diseases and may be initiated or catalyzed by a glutamine-containing fragment of the disease protein.
823 citations
TL;DR: The results suggest that a chronically progressive degenerative process may be initiated by brain trauma and there is a temporally broad window within which to introduce novel therapeutic strategies designed to ameliorate the short and long-term consequences of brain trauma.
Abstract: Although atrophic changes have been well described following traumatic brain injury (TBI) in humans, little is known concerning the mechanisms or progression of brain tissue loss. In the present study, we evaluated the temporal profile of histopathological changes following parasagittal fluid-percussion (FP) brain injury in rats over 1 year postinjury. Anesthetized 3-4 month-old Sprague-Dawley Rats (n = 51) were subjected to FP brain injury of high severity (2.5-2.9 atm, n = 51) or sham treatment (n = 27). At 1 h, 2 h, 48 h, 1 week, 2 weeks, 1 month, 2 months, 6 months and 1 year after brain injury or sham treatment, these animals were humanely euthanized. Brain sections were analyzed with image-processing techniques to determine the extent of cortical tissue loss and shrinkage of the hippocampal pyramidal cell layer. In addition, cell counting was performed to determine the number of neurons in the dentate hilus of the hippocampus, and glial fibrillary acidic protein (GFAP) immunostaining was used to reveal reactive astrocytosis. Examination of the injured brains revealed substantial and progressive tissue loss with concomitant ventriculomegaly in the hemisphere ipsilateral to injury. The regions with the most notable progressive atrophy included the cortex, hippocampus, thalamus, and septum. Quantitative analysis demonstrated a significantly progressive loss of cortical tissue as well as shrinkage of the hippocampal pyramidal cell layer ipsilateral to injury over 1 year following injury. In addition, reactive astrocytosis in regions of atrophy and progressive bilateral death of neurons in the dentate hilus was observed for 1 year following injury. These results suggest that a chronically progressive degenerative process may be initiated by brain trauma. Thus, there is a temporally broad window within which to introduce novel therapeutic strategies designed to ameliorate the short and long-term consequences of brain trauma.
431 citations
TL;DR: A dinucleotide repeat polymorphism in a tau intron was identified and used in a case-control study to analyze the genetic association of tau with several neurodegenerative diseases with tau pathology as discussed by the authors.
Abstract: A dinucleotide repeat polymorphism in a tau intron was identified and used in a case-control study to analyze the genetic association of tau with several neurodegenerative diseases with tau pathology. Subjects with the homozygous tau AO alleles were excessively represented in the progressive supranuclear palsy (PSP) group, compared with the age-matched healthy control group. Consequently, this allele is more frequently found in PSP than in a group of healthy subjects. This trend was not found in Alzheimer's disease or parkinsonism-dementia complex of Guam, both of which are accompanied by major tau pathology. The result suggests a possible involvement of tau in the pathogenesis of PSP.
389 citations
TL;DR: This is the first demonstration of impaired axonal transport in a mouse model of ALS, and it is inferred that similar impairments occur in authentic ALS.
Abstract: Mice engineered to express a transgene encoding a human Cu/Zn superoxide dismutase (SOD1) with a Gly93 --> Ala (G93A) mutation found in patients who succumb to familial amyotrophic lateral sclerosis (FALS) develop a rapidly progressive and fatal motor neuron disease (MND) similar to amyotrophic lateral sclerosis (ALS). Hallmark ALS lesions such as fragmentation of the Golgi apparatus and neurofilament (NF)-rich inclusions in surviving spinal cord motor neurons as well as the selective degeneration of this population of neurons were also observed in these animals. Since the mechanism whereby mutations in SOD1 lead to MND remains enigmatic, we asked whether NF inclusions in motor neurons compromise axonal transport during the onset and progression of MND in a line of mice that contained approximately 30% fewer copies of the transgene than the original G93A (Gurney et al., 1994). The onset of MND was delayed in these mice compared to the original G93A mice, but they developed the same neuropathologic abnormalities seen in the original G93A mice, albeit at a later time point with fewer vacuoles and more NF inclusions. Quantitative Western blot analyses showed a progressive decrease in the level of NF proteins in the L5 ventral roots of G93A mice and a concomitant reduction in axon caliber with the onset of motor weakness. By approximately 200 d, both fast and slow axonal transports were impaired in the ventral roots of these mice coincidental with the appearance of NF inclusions and vacuoles in the axons and perikarya of vulnerable motor neurons. This is the first demonstration of impaired axonal transport in a mouse model of ALS, and we infer that similar impairments occur in authentic ALS. Based on the temporal correlation of these impairments with the onset of motor weakness and the appearance of NF inclusions and vacuoles in vulnerable motor neurons, the latter lesions may be the proximal cause of motor neuron dysfunction and degeneration in the G93A mice and in FALS patients with SOD1 mutations.
308 citations
TL;DR: In this paper, the authors reported that traumatic brain injury evokes local changes in axolemma's permeability, in concert with local cytoskeletal changes involving neurofilament (NF) compaction and sidearm loss, all of which contribute to the genesis of reactive axonal change.
Abstract: Recently we reported that traumatic brain injury evokes local changes in the axolemma's permeability, in concert with local cytoskeletal changes involving neurofilament (NF) compaction and sidearm loss, all of which contribute to the genesis of reactive axonal change. Since it was of concern that these events may be either injury model- or species-specific, we sought to address these phenomena in a different but well-characterized animal model and species. Further, to provide more compelling insight into the potential for NF compaction and sidearm alteration, we also employed antibodies specific for the NF rod domains, which are readily visualized only when the NF sidearms are disturbed. Rats were subjected to impact acceleration injury. To assess the potential for altered axolemmal permeability, 5 animals received intrathecal horseradish peroxidase (HRP), normally excluded by the intact axolemma. To assess the potential for NF sidearm alteration, another 14 animals were processed for the visualization of antibodies targeting the NF rod domain at 5 minutes (min) to 24 hours (h) postinjury. All animals were evaluated at the LM and EM levels. Those animals receiving intrathecal HRP showed immediate focal alterations in the axolemma's permeability to the normally excluded tracer. Over a 2 h period, these axons demonstrated NF compaction. Antibodies targeted to the rod domains revealed focal intra-axonal immunoreactivity in sites closely correlated with those showing altered axolemmal permeability. These same sites also demonstrated evidence of NF compaction and sidearm loss/perturbation. Collectively, these findings suggest that occurrence of altered axolemmal permeability and concomitant cytoskeletal change are features common to traumatic brain injury in various animal models and species. Further, these studies underscore the utility of antibodies targeting the rod domain for the early detection of traumatically induced reactive change.
199 citations
TL;DR: A Midwestern American pedigree spanning four generations in which 15 individuals were affected by early‐onset dementia with long disease duration, with an autosomal dominant inheritance pattern, and with α‐rich neurofibrillary pathology found in the brain post mortem is presented.
Abstract: Several familial dementing conditions with atypical features have been characterized, but only rarely is the neuropathology dominated solely by neurofibrillary lesions. We present a Midwestern American pedigree spanning four generations in which 15 individuals were affected by early-onset dementia with long disease duration, with an autosomal dominant inheritance pattern, and with tau-rich neurofibrillary pathology found in the brain post mortem. The average age at presentation was 55 years with gradual onset and progression of memory loss and personality change. After 30 years' disease duration, the proband's neuropathologic examination demonstrated abundant intraneuronal neurofibrillary tangles (NFTs) involving the hippocampus, pallidum, subthalamic nucleus, substantia nigra, pons, and medulla. Only sparse neocortical tangles were present and amyloid plaques were absent. The tangles were recognized by antibodies specific for phosphorylation-independent (Tau-2, T46, 133, and Alz-50) and phosphorylation-dependent epitopes (AT8, T3P, PHF-1, 12E8, AT6, AT18, AT30) in tau proteins. Electron microscopy of NFTs in the dentate gyrus and midbrain demonstrated paired helical filaments. Although the clinical phenotype resembles Alzheimer's disease, and the neuropathologic phenotype resembles progressive supranuclear palsy, an alternative consideration is that this familial disorder may be a new or distinct disease entity.
181 citations
TL;DR: The studies imply that inactivation of PP2A in vulnerable neurons of the AD brain may play a mechanistic role in the conversion of normal tau into PHFtau, in the depolymerization of stable MTs, and in the degeneration of axons emanating from tangle-bearing neurons.
Abstract: Paired helical filaments (PHFs) in the neurofibrillary tangles (NFTs) in Alzheimer’s disease (AD) brains are composed of highly phosphorylated isoforms of tau (PHFtau) that fail to bind microtubules (MTs), and the levels of MT-binding competent tau are decreased in AD brains with abundant PHFtau. Because this loss of MT binding could compromise the viability of tangle-bearing AD neurons by destabilizing MTs, we asked whether these events could be initiated by inhibiting protein phosphatase 1 (PP1) and PP2A in cultured human neurons (NT2N cells) using okadaic acid (OK) and calyculin-A (CL-A). The treatment of NT2N cells with OK and CL-A increased tau phosphorylation, decreased the binding of tau to MTs, and selectively depolymerized the more stable detyrosinated MTs but not the more labile tyrosinated MTs. Significantly, this led to the rapid degeneration of axons, which are enriched in the more stable detyrosinated MTs, and PP2A was implicated in the initiation of this cascade of events because PP2A but not PP1 was closely associated with MTs in the NT2N cells. These studies imply that inactivation of PP2A in vulnerable neurons of the AD brain may play a mechanistic role in the conversion of normal tau into PHFtau, in the depolymerization of stable MTs, and in the degeneration of axons emanating from tangle-bearing neurons.
156 citations
TL;DR: Quantitative analysis of double‐labeled sections demonstrated that approximately 80% of TS‐positive NFTs also were AO‐positive, whereas approximately 55% ofTS‐stained SPs contained AO labeling, demonstrating the relative specificity of AO for RNA species.
Abstract: The polypeptide composition of neurofibrillary tangles (NFTs) and senile plaques (SPs) has been characterized extensively within the Alzheimer's disease (AD) brain. Because few data exist on the nonproteinaceous components of these lesions, we sought to determine if NFTs, neuropil threads (NTs), and SPs contain RNA species. To accomplish this, acridine orange (AO) histofluorescence was employed, alone or in combination with thioflavine S (TS) staining and immunohistochemistry to identify RNAs in paraffin-embedded tissue sections of hippocampus and entorhinal cortex. Postmortem brain samples came from 32 subjects including AD and elderly Down's syndrome (DS) patients, age-matched normal controls, and non-AD diseased controls. AO stained the cytoplasm of normal hippocampal and entorhinal neurons in all of the cases, while NFTs, NTs, and SPs were AO-positive in the same regions of AD and DS brains. Cytoplasmic AO histofluorescence was abolished with RNase, but not DNase or proteinase K, indicating the relative specificity of AO for RNA species. Quantitative analysis of double-labeled sections demonstrated that approximately 80% of TS-positive NFTs also were AO-positive, whereas approximately 55% of TS-stained SPs contained AO labeling. These novel observations demonstrate the presence of RNAs in NFTs, NTs, and SPs.
TL;DR: This study suggests that tau may accumulate in the CSF of patients with certain neurodegenerative diseases other than AD and that measurement of CSF-tau may not distinguish AD from DLB.
TL;DR: The rats receiving NGF infusions had significantly higher memory scores than vehicle-treated animals and significantly attenuated loss of these cholinergic neurons after injury.
Abstract: ✓ This study explores the effects of infusion of nerve growth factor (NGF) on behavioral outcome and cell death in the septal region using the clinically relevant model of fluid-percussion brain injury in the rat. Animals were subjected to fluid-percussion brain injury and 24 hours later a miniosmotic pump was implanted to infuse NGF (12 animals) or vehicle (12 animals) directly into the region of maximum injury for 2 weeks. Four weeks postinjury the animals were tested for cognitive function using a Morris Water Maze paradigm. Neurological motor function was evaluated over a 4-week postinjury period. The rats receiving NGF infusions had significantly higher memory scores than vehicle-treated animals. Examination of the cholinergic neurons in the medial septal region using choline acetyltransferase immunohistochemistry demonstrated significant cell loss after injury. Infusion of NGF significantly attenuated loss of these cholinergic neurons. A second group of animals was subjected to fluid-percussion brai...
TL;DR: Controversial issues relating to the pathobiology and classification of central nervous system primitive neuroectodermal tumors (PNETs) have plagued neuropathologists for more than 70 years despite a growing body of information discrediting these ideas from neuroembryologists, oncologists, neuroscien‐tists and pathologists.
Abstract: Controversial issues relating to the pathobiology and classification of central nervous system primitive neuroectodermal tumors (PNETs) have plagued neuropathologists for more than 70 years. Hypotheses advanced in the mid-1920's have remained as fixed concepts in contemporary literature, largely consequent to repetitious support by a small number of neuropathologists despite a growing body of information discrediting these ideas from neuroembryologists, oncologists, neuroscien-tists and pathologists.
Attention has largely focused upon PNETs arising in the cerebellum (commonly known as medul-loblastomas [MBs]), because about 80% of central nervous system (CNS) PNETs originate in this site. It has been asserted that the 20% which do not are biologically different, although most individuals agree that the histological features of PNETs that occur in different sites throughout the CNS are indistinguishable from those growing in the cerebellum.
The historical aspects of this controversy are examined in the face of evidence that there is, in fact, a unique class of CNS tumors which should appropriately be regarded as primitive neuroectodermal in nature. Specifically, a number of different approaches to the problem have yielded data supporting this hypothesis. These approaches include the identification of patterns of expression among a variety of cellular antigens (demonstrated by the use of immunopathological techniques), molecular analyses of cell lines derived from these tumors, experimental production of PNETs and molecular genetic analyses.
Differences of opinion among surgeons, oncologists and radiotherapists are typically resolved by conducting cooperative studies of patients with these tumors who are diagnosed and treated at multiple centers.
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TL;DR: Recent insights into mechanisms of motor neuron degeneration in ALS that have emerged from studies of these new animal models of this neurodegenerative disease are summarized.
TL;DR: The findings suggest that a NGF/TrkA signal transduction pathway could activate apoptotic cell death programs in CNS neuroepithelial progenitor cells and in childhood brain tumors.
Abstract: Neurotrophins act through their cognate receptors to promote the differentiation and/or survival of neuronal progenitor cells, immature neurons, and other cells. Here, we examined the effects of nerve growth factor (NGF) and its cognate receptor (Trk or TrkA) on the survival of a common childhood brain tumor, i.e., medulloblastoma, a tumor that resembles CNS neuroepithelial progenitor cells. To do this, we engineered two human medulloblastoma cell lines (i.e., D283MED and DAOY cells) to express human TrkA using a retroviral expression vector. Surprisingly, NGF-treated medulloblastoma cells expressing the TrkA receptor (D283trk and DAOYtrk cells) grown in the presence or absence of serum underwent massive apoptosis, but similar treatment did not induce apoptosis in wild-type uninfected cells, cells expressing an empty vector, or cells expressing the TrkC receptor. Furthermore, D283MED cells engineered to express the human p75 NGF receptor (D283p75) also did not undergo apoptosis. Significantly, NGF-induced apoptosis in D283trk and DAOYtrk cells can be inhibited by anti-NGF antibodies and by K-252a, an inhibitor of TrkA tyrosine phosphorylation and mimicked by high concentrations of NT3. Because NGF treatment primarily eliminated D283trk cells from the S phase of the cell cycle, this form of NGF-mediated apoptosis is cell cycle-dependent. These findings suggest that a NGF/TrkA signal transduction pathway could activate apoptotic cell death programs in CNS neuroepithelial progenitor cells and in childhood brain tumors.
TL;DR: It is concluded that grafted NT2N cells could serve as a suitable platform for the delivery of exogenous proteins into the CNS for gene therapy of human nervous system diseases.
TL;DR: The normal rat brain could produce enzymes that mediate the conversion of Aβ 1–40/1-42 into processed variants similar to those in AD, and a factor or factors might exist in the rat brain that inhibit the fibrillar assembly of soluble Aβ1–42.
Abstract: Two major C-terminal variants ending at Val40 and Ala42 constitute the majority of amyloid beta-protein (Abeta), which undergoes postsecretory aggregation and deposition in the Alzheimer disease (AD) brain. To probe the differential pathobiology of the two Abeta variants, we used an in vivo paradigm in which freshly solubilized Abeta1-40 or Abeta1-42 was injected into rat brains, followed by examination using Congo red birefringence, Abeta immunohistochemistry, and electron microscopy. In the rat brain, soluble Abeta 1-40 and Abeta1-42 formed aggregates, and the Abeta1-40 but not the Abeta1-42 aggregates showed Congo red birefringence. Electron microscopy revealed that the Abeta1-40 aggregates contained fibrillar structures similar to the amyloid fibrils of AD, whereas the Abeta1-42 aggregates contained nonfibrillar amorphous material. Preincubation of Abeta1-42 solution in vitro led to the formation of birefringent aggregates, and after injection of the preincubated Abeta1-42, the aggregates remained birefringent in the rat brain. Thus, a factor or factors might exist in the rat brain that inhibit the fibrillar assembly of soluble Abeta1-42. To analyze the postsecretory processing of Abeta, we used the same in vivo paradigm and showed that Abeta1-40 and Abeta1-42 were processed at their N termini to yield variants starting at pyroglutamate, and at their C termini to yield variants ending at Val40 and at Val39. Thus the normal rat brain could produce enzymes that mediate the conversion of Abeta 1-40/1-42 into processed variants similar to those in AD. This experimental paradigm may facilitate efforts to elucidate mechanisms of Abeta deposition evolving into amyloid plaques in AD.
TL;DR: The findings suggest that the cytoarchitectural abnormalities in CD may reflect pathophysiological changes in the developing brain that disrupt expression of several key components of the neuronal cytoskeleton and may contribute to impaired migration of cortical neurons.
Abstract: Cortical dysplasias (CD) are characterized histologically by disorganized cortical lamination and abnormally shaped neurons. We hypothesized that neurons within CD have failed to differentiate fully and may express proteins such as cytoskeletal elements characteristic of immature cells. Disrupted expression of certain cytoskeletal proteins, which have been implicated in neuronal polarity, process outgrowth, and migration, could result in disorganized cortical lamination. Thus, we probed two CD subtypes, focal CD (FCD) and hemimegalencephaly (HME), with antibodies specific for cytoskeletal proteins that are developmentally regulated in neural progenitor cells and neurons to define more fully the developmental phenotype of neurons within CD. Microtubule-associated protein 1B (MAP1B) and the intermediate filament (IF) protein nestin are enriched in neural progenitors, whereas MAP2B, phosphorylated and non-phosphorylated forms of medium (NFM) and high (NFH) molecular weight neurofilament (NF) proteins, as well as the light NF subunit (NFL) and the IF protein α internexin are expressed in developing and mature neurons. Immunolabeling for internexin and MAP1B was more abundant in the most abnormally shaped neurons that populated dysplastic regions than in adjacent regions exhibiting milder cytoarchitectural abnormalities or control cortex. Nestin immunoreactivity was noted in large dysplastic and heterotopic neurons within the deeper cortical layers of CD specimens but not in normal cortex. In contrast, neurons in CD specimens also expressed cytoskeletal markers characteristic of differentiated neurons such as NF subunits and MAP2B. These findings suggest that the cytoarchitectural abnormalities in CD may reflect pathophysiological changes in the developing brain that disrupt expression of several key components of the neuronal cytoskeleton and may contribute to impaired migration of cortical neurons.
TL;DR: The sequestration of cellular organelles in type II inclusions may isolate and impair the function of these organlles, thereby rendering Purkinje cells selectively vulnerable to degeneration with age as in neurodegenerative diseases of the elderly characterized by accumulation of LBs.
Abstract: Transgenic (NFHLacZ) mice expressing a fusion protein composed of a truncated high-molecular-weight mouse neurofilament (NF) protein (NFH) fused to beta-galactosidase (LacZ) develop inclusions in neurons throughout the CNS. These inclusions persist from birth to advanced age and contain massive filamentous aggregates including all three endogenous NF proteins and the NFHLacZ fusion protein. Further, the levels of endogenous NF proteins are selectively reduced in NFHLacZ mice. Because these inclusions resemble NF-rich Lewy bodies (LBs) in Parkinson's disease and LB dementia, we asked whether these lesions compromised the viability of affected neurons during aging. We studied hippocampal CA1 neurons, nearly all of which harbored inclusions (type I) devoid of cellular organelles, and cerebellar Purkinje cells, nearly all of which accumulated inclusions (type II) containing numerous entrapped organelles. Purkinje cells with type II inclusions began to degenerate in the NFHLacZ mice at approximately 1 year of age, and most were eliminated by 18 months of age. In contrast, there was no significant loss of type I inclusion-bearing CA1 neurons with age. These data suggest that the sequestration of cellular organelles in type II inclusions may isolate and impair the function of these organelles, thereby rendering Purkinje cells selectively vulnerable to degeneration with age as in neurodegenerative diseases of the elderly characterized by accumulation of LBs.
TL;DR: Results support the hypothesis that NF subunits are integral components of LBs and lead to novel strategies for the antemortem diagnosis of LB disorders as well as to insight into the role LBs play in the degeneration of affected neurons in these disorders.
Abstract: Lewy bodies (LBs) are filamentous intraneuronal inclusions that are hallmark lesions of Parkinson's disease, and LBs have been shown, by immunohistochemistry, to contain cytoskeletal as well as other cellular proteins. Similar LBs also occur in the cortical neurons of a subset of patients with Alzheimer's disease (AD), and cortical LBs are the predominant or sole lesions in the brains of patients with an AD-like dementia known as diffuse Lewy-body disease (DLBD). To gain insight into the biochemical composition of LBs, we generated monoclonal antibodies (mAbs) to LBs purified from the brains of patients with DLBD. Here, we describe three of these new mAbs (LB48, LB202, and LB204) that stained LBs by immunohistochemistry and recognized the medium molecular mass neurofilament (NF) protein in western blots. These results support the hypothesis that NF subunits are integral components of LBs. Continued efforts to clarify the composition of LBs are likely to lead to novel strategies for the antemortem diagnosis of LB disorders as well as to insight into the role LBs play in the degeneration of affected neurons in these disorders.
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TL;DR: The initial characterization of a 100-kd protein recognized by four new monoclonal antibodies that reveal abundant and unique plaque-like lesions throughout gray matter of Alzheimer's disease brains concludes that the AMY117-positive plaques described here for the first time are major lesions of the Alzheimer's Disease brain.
Abstract: Here we describe the initial characterization of a 100-kd protein recognized by four new monoclonal antibodies that reveal abundant and unique plaque-like lesions throughout gray matter of Alzheimer's disease brains. This 100-kd protein and these new plaque-like lesions were identified by four monoclonal antibodies raised to immunogens extracted from Alzheimer's disease neurofibrillary abnormalities. However, these antibodies did not recognize hyperphosphorylated tau in Western blots or neurofibrillary lesions by immunohistochemistry. As all of these antibodies displayed similar properties, one, AMY117, was used to characterize the new plaque-like lesions in detail. These studies demonstrated that AMY117-positive plaques were not visualized by amyloid stains and never co-localized with A beta deposits, although AMY117-positive and A beta-positive lesions frequently occurred in the same cortical and subcortical gray matter regions. Abundant AMY117-positive plaques were found in the brains of all 32 sporadic Alzheimer's disease patients and all 6 elderly Down's syndrome subjects. Although AMY117-positive plaques also were seen in the brains of nondemented patients with numerous A beta deposits. AMY117-positive plaques were rare or absent in the brains of other elderly controls and patients with other neurodegenerative or neuropsychiatric disorders. We conclude that the AMY117-positive plaques described here for the first time are major lesions of the Alzheimer's disease brain. Thus, it will be important to elucidate the role played by the 100-kd protein and the AMY117 plaques in the etiology and pathogenesis of Alzheimer's disease.
TL;DR: An examination of ApoE in relation to clinical and neurobiological features of schizophrenia suggests that it modifies the phenotypic expression of the disease.
Abstract: Apolipoprotein E (ApoE) genotype has been found to affect the expression of a variety of neuropsychiatric disorders. We determined ApoE genotype frequencies and their relationship to clinical and pathological features in a diverse cohort of individuals with schizophrenia. There were no differences in ApoE genotype frequencies between schizophrenics and controls. However, the ApoE epsilon 4 genotype was associated with a younger age of onset of schizophrenia, and in an elderly subsample, individuals with the epsilon 4 allele more frequently exhibited co-existent dementia and had more neurofibrillary pathology (although none of the cases met criteria for Alzheimer's disease). This examination of ApoE in relation to clinical and neurobiological features of schizophrenia suggests that it modifies the phenotypic expression of the disease.
TL;DR: The rationale for emphasizing the detection of both beta amyloid-rich plaques and tau-rich tangles in the next iteration of the neuropathological criteria for the postmortem diagnosis of AD that has been recommended by the Working Group on Consensus Criteria for the Postmortem Diagnosis of AD is discussed.
TL;DR: NGF administration beginning 24 hours after fluid-percussion brain injury has a beneficial effect on cognition and results in sparing of cholinergic septal neurons, and improvements persist after cessation of NGF administration.
Abstract: ✓ This study explores the effects of infusion of nerve growth factor (NGF) on behavioral outcome and cell death in the septal region using the clinically relevant model of fluid-percussion brain injury in the rat. Animals were subjected to fluid-percussion brain injury and 24 hours later a miniosmotic pump was implanted to infuse NGF (12 animals) or vehicle (12 animals) directly into the region of maximum injury for 2 weeks. Four weeks postinjury the animals were tested for cognitive function using a Morris Water Maze paradigm. Neurological motor function was evaluated over a 4-week postinjury period. The rats receiving NGF infusions had significantly higher memory scores than vehicle-treated animals. Examination of the cholinergic neurons in the medial septal region using choline acetyltransferase immunohistochemistry demonstrated significant cell loss after injury. Infusion of NGF significantly attenuated loss of these cholinergic neurons. A second group of animals was subjected to fluid-percussion brai...
TL;DR: The age-dependent and coordinate diminution in cell proliferative activity and cell death events may serve to maintain the thickness of the OE as mice mature and age.
TL;DR: Recent developments in the understanding of the role of neurotrophins in medulloblastomas are focused on, especially the ability of nerve growth factor to induce apoptosis in vitro in medulla oblastomas.
Abstract: The members of the neurotrophin family play key biological roles in the development of the nervous system. Based on studies initially in cell lines (e.g., the rat pheochromocytoma PC12 cells), neurotrophins have been found to be important mediators of proliferation, differentiation, and survival in the normal brain, but their role in brain tumors remains unclear. Since neurotrophins and neurotrophin receptors are frequently detected in biopsy samples of central nervous system medulloblastomas, efforts have been undertaken in several laboratories to elucidate the potential effects of neurotrophins on the growth and differentiation of these tumors. Results from these studies may have both basic and clinical implications because medulloblastomas resemble embryonic neuroectodermal stem cells and/or their immature neuronal and glial progeny. This review focuses on recent developments in our understanding of the role of neurotrophins in medulloblastomas, especially the ability of nerve growth factor to induce apoptosis in vitro in medulloblastomas. J. Neurosci. Res. 49:522–527, 1997. © 1997 Wiley-Liss, Inc.
TL;DR: This study was undertaken to gain insights into the clinical utility of measuring cerebrospinal fluid tau protein to aid in the diagnosis of Alzheimer's disease.
Abstract: OBJECTIVE: This study was undertaken to gain insights into the clinical utility of measuring cerebrospinal fluid tau protein (CSF-tau) to aid in the diagnosis of Alzheimer's disease (AD).
SETTING: AD patients from Tohoku University Hospital, Sendai Japan were sampled.
SUBJECTS AND METHODS: CSF-tau levels were examined by sandwich enzyme-linked immunosorbent assay in a total of 62 patients carrying different α1 -antichymotrypsin (ACT) and presenilin-1 (PS-1) polymorphic alleles. Further, the CSF-tau levels were followed up on two occasions during the progression of the disease in 17 AD patients.
RESULTS: There was no evident gradient for tau protein in CSF. Neither the ACT/A allele nor the PS-1/1 allele affected the CSF-tau levels. Although CSF-tau levels changed to a variable extent over time, the CSF-tau levels were significantly increased (P <.01) during the follow-up period. Three of the AD patients demonstrated decreasing values, whereas 14 patients showed increasing values. Finally, these temporal changes in CSF-tau levels were not influenced by the apolipoprotein E ∍4, ACT/A or PS-1/1 alleles during the progression of AD.
CONCLUSION: Regardless of the mechanisms leading to the degeneration of neurons in AD, our findings provide further evidences that monitoring CSF-tau levels may provide useful information about AD irrespective of the background of genetic risks and disease progression. J Am Geriatr Soc 45:1228–1231,1997.
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