Showing papers by "John Q. Trojanowski published in 2004"
TL;DR: Understanding of mechanisms regulating protein processing and aggregation, as well as of the toxic effects of misfolded neurodegenerative disease proteins, will facilitate development of rationally designed therapies to treat and prevent these disorders.
Abstract: A wide variety of neurodegenerative diseases are characterized by the accumulation of intracellular or extracellular protein aggregates. More recently, the genetic identification of mutations in familial counterparts to the sporadic disorders, leading to the development of in vitro and in vivo model systems, has provided insights into disease pathogenesis. The effect of many of these mutations is the abnormal processing of misfolded proteins that overwhelms the quality-control systems of the cell, resulting in the deposition of protein aggregates in the nucleus, cytosol and/or extracellular space. Further understanding of mechanisms regulating protein processing and aggregation, as well as of the toxic effects of misfolded neurodegenerative disease proteins, will facilitate development of rationally designed therapies to treat and prevent these disorders.
679 citations
TL;DR: It is found that presynaptic dysbindin-1 reductions independent of the dystrophin glycoprotein complex are frequent in schizophrenia and are related to glutamatergic alterations in intrinsic hippocampal formation connections, which may contribute to the cognitive deficits common in schizophrenia.
Abstract: Eleven studies now report significant associations between schizophrenia and certain haplotypes of single-nucleotide polymorphisms in the gene encoding dysbindin-1 at 6p22.3. Dysbindin-1 is best known as dystrobrevin-binding protein 1 (DTNBP1) and may thus be associated with the dystrophin glycoprotein complex found at certain postsynaptic sites in the brain. Contrary to expectations, however, we found that when compared to matched, nonpsychiatric controls, 73-93% of cases in two schizophrenia populations displayed presynaptic dysbindin-1 reductions averaging 18-42% (P = 0.027-0.0001) at hippocampal formation sites lacking neuronal dystrobrevin (i.e., beta-dystrobrevin). The reductions, which were not observed in the anterior cingulate of the same schizophrenia cases, occurred specifically in terminal fields of intrinsic, glutamatergic afferents of the subiculum, the hippocampus proper, and especially the inner molecular layer of the dentate gyrus (DGiml). An inversely correlated increase in vesicular glutamate transporter-1 (VGluT-1) occurred in DGiml of the same schizophrenia cases. Those changes occurred without evidence of axon terminal loss or neuroleptic effects on dysbindin-1 or VGluT-1. Our findings indicate that presynaptic dysbindin-1 reductions independent of the dystrophin glycoprotein complex are frequent in schizophrenia and are related to glutamatergic alterations in intrinsic hippocampal formation connections. Such changes may contribute to the cognitive deficits common in schizophrenia.
435 citations
TL;DR: The results demonstrate a differential distribution and course of intra- and extra-cellular AD-like changes during the acute phase following severe TBI in humans, and provide insight into the molecular mechanisms that initiate these pathological cascades very early during severe brain injury.
386 citations
TL;DR: The hypothesis that oxidative stress is an important early event in AD pathogenesis, and antioxidant therapy may be beneficial only if given at this stage of the disease process is supported.
Abstract: Increased brain oxidative stress is a key feature of Alzheimer's disease (AD) and manifests predominantly as lipid peroxidation. However, clinical evidence that antioxidants can affect the clinical course of the disease is limited. In the present study, we investigated the effect of the antioxidant Vitamin E on the AD-like phenotype when given to a transgenic mouse model (Tg2576) of the disease before or after the amyloid plaques are deposited. One group of Tg2576 received Vitamin E starting at 5 months of age until they were 13 months old, the second group started at 14 months of age until they were 20 months old. Brain levels of 8,12-iso-iPF2alpha-VI, a specific marker of lipid peroxidation, were significantly reduced in both groups of mice receiving Vitamin E compared with placebo. Tg2576 administered with Vitamin E at a younger age showed a significant reduction in Abeta levels and amyloid deposition. By contrast, mice receiving the diet supplemented with Vitamin E at a later age did not show any significant difference in either marker when compared with placebo. These results support the hypothesis that oxidative stress is an important early event in AD pathogenesis, and antioxidant therapy may be beneficial only if given at this stage of the disease process.
300 citations
TL;DR: In this article, the authors evaluated the potential source of this Aβ and long-term mechanisms that could lead to its production in pigs via head rotational acceleration of 110° over 20 ms in the coronal plane.
Abstract: Plaques composed of amyloid β (Aβ) have been found within days following brain trauma in humans, similar to the hallmark plaque pathology of Alzheimer's disease (AD) Here, we evaluated the potential source of this Aβ and long-term mechanisms that could lead to its production Inertial brain injury was induced in pigs via head rotational acceleration of 110° over 20 ms in the coronal plane Animals were euthanized at 3 hours, 3 days, 7 days, and 6 months post-injury Immunohistochemistry and Western blot analyses of the brains were performed using antibodies specific for amyloid precursor protein (APP), Aβ peptides, β-site APP-cleaving enzyme (BACE), presenilin-1 (PS-1), caspase-3, and caspase-mediated cleavage of APP (CCA) Substantial co-accumulation for all of these factors was found in swollen axons at all time points up to 6 months following injury Western blot analysis of injured brains confirmed a substantial increase in the protein levels of these factors, particularly in the white matter These data suggest that impaired axonal transport due to trauma induces long-term pathological co-accumulation of APP with BACE, PS-1, and activated caspase The abnormal concentration of these factors may lead to APP proteolysis and Aβ formation within the axonal membrane compartment
246 citations
TL;DR: In this paper, the authors investigated the protein levels and activity of 12/15-LOX in different brain regions of histopathologically confirmed Alzheimer's disease and control cases, using quantitative Western blot analysis.
Abstract: Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that impairs cognition and behavior. Although the initiating molecular events are not known, increasing evidence suggests that oxidative stress could play a functional role in its pathogenesis. Lipoxygenase (LOX) enzymes by oxidizing polyunsaturated fatty acids synthesize hydroperoxyacids, which are potent pro-oxidant mediators. Because circumstantial evidence suggests that 12/15-LOX is a major source of oxidative stress, we investigated the protein levels and activity of this enzyme in different brain regions of histopathologically confirmed AD and control cases. Using quantitative Western blot analysis we demonstrated that in affected frontal and temporal regions of AD brains the amount of 12/15-LOX was higher compared with controls, whereas no difference between the two groups was detected in the cerebellum. This observation was confirmed by immunohistochemical studies. Levels of 12/15-hydroxyeicosatetraenoic acids, metabolic products of 12/15-LOX, were also markedly elevated in AD brains compared to controls. This increase directly correlated with brain lipid peroxidation, and inversely with vitamin E levels. Finally, genetic deletion of this enzyme in vitro resulted in a reduction of the cellular oxidative stress response after incubation with H2O2 or amyloid β. These data show that the 12/15-LOX metabolic pathway is increased and correlates with an oxidative imbalance in the AD brain, implying that this enzyme might contribute to the pathogenesis of this neurodegenerative disorder.
208 citations
TL;DR: Data indicate that the R406W mutation causes reduced binding of this mutant tau to microtubules, resulting in slower axonal transport, which leads to increased accumulation and reduced solubility of RW tau in an age-dependent manner, culminating in the formation of filamentous intraneuronal tau aggregates similar to that observed in tauopathy patients.
Abstract: Intracellular accumulations of filamentous tau inclusions are neuropathological hallmarks of neurodegenerative diseases known as tauopathies. The discovery of multiple pathogenic tau gene mutations in many kindreds with familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) unequivocally confirmed the central role of tau abnormalities in the etiology of neurodegenerative disorders. To examine the effects of tau gene mutations and the role of tau abnormalities in neurodegenerative tauopathies, transgenic (Tg) mice were engineered to express the longest human tau isoform (T40) with or without the R406W mutation (RW and hWT Tg mice, respectively) that is pathogenic for FTDP-17 in several kindreds. RW but not hWT tau Tg mice developed an age-dependent accumulation of insoluble filamentous tau aggregates in neuronal perikarya of the cerebral cortex, hippocampus, cerebellum, and spinal cord. Significantly, CNS axons in RW mice contained reduced levels of tau when compared with hWT mice, and this was linked to retarded axonal transport and increased accumulation of an insoluble pool of RW but not hWT tau. Furthermore, RW but not hWT mice demonstrated neurodegeneration and a reduced lifespan. These data indicate that the R406W mutation causes reduced binding of this mutant tau to microtubules, resulting in slower axonal transport. This altered tau function caused by the RW mutation leads to increased accumulation and reduced solubility of RW tau in an age-dependent manner, culminating in the formation of filamentous intraneuronal tau aggregates similar to that observed in tauopathy patients.
193 citations
TL;DR: Emerging evidence indicates that there is frequent overlap of the pathological and clinical features of patients with tauopathies and synucleinopathies, thereby re-enforcing the notion that these disorders might be linked mechanistically.
175 citations
TL;DR: The identification of molecular genetic defects and biochemical alterations in cytoskeletal proteins of human neurodegenerative diseases has facilitated experimental studies and will promote the development of assays of molecules which inhibit abnormal neuronal IF and tau protein inclusions.
Abstract: Abundant abnormal aggregates of cytoskeletal proteins are neuropathological signatures of many neurodegenerative diseases that are broadly classified by filamentous aggregates of neuronal intermediate filament (IF) proteins, or by inclusions containing the microtubule-associated protein (MAP) tau The discovery of mutations in neuronal IF and tau genes firmly establishes the importance of neuronal IF proteins and tau in the pathogenesis of neurodegenerative diseases Multiple IF gene mutations are pathogenic for Charcot-Marie-Tooth (CMT) disease and amyotrophic lateral sclerosis (ALS)--in addition to those in the copper/zinc superoxide dismutase-1 (SOD1) gene Tau gene mutations are pathogenic for frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), and tau polymorphisms are genetic risk factors for sporadic progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) Thus, IF and tau abnormalities are linked directly to the aetiology and pathogenesis of neurodegenerative diseases In vitro and transgenic animal models are being used to demonstrate that different mutations impair protein function, promote tau fibrilization, or perturb tau gene splicing, leading to aberrant and distinct tau aggregates For recognition of these disorders at neuropathological examination, immunohistochemistry is needed, and this may be combined with biochemistry and molecular genetics to properly determine the nosology of a particular case As reviewed here, the identification of molecular genetic defects and biochemical alterations in cytoskeletal proteins of human neurodegenerative diseases has facilitated experimental studies and will promote the development of assays of molecules which inhibit abnormal neuronal IF and tau protein inclusions
169 citations
TL;DR: It is suggested that the exacerbation of brain oxidative stress following RCBI plays a mechanistic role in accelerating Αβ accumulation and behavioral impairments in the Tg2576 mice.
Abstract: Traumatic brain injury is a well-recognized environmental risk factor for developing Alzheimer's disease. Repetitive concussive brain injury (RCBI) exacerbates brain lipid peroxidation, accelerates amyloid (Abeta) formation and deposition, as well as cognitive impairments in Tg2576 mice. This study evaluated the effects of vitamin E on these four parameters in Tg2576 mice following RCBI. Eleven-month-old mice were randomized to receive either regular chow or chow-supplemented with vitamin E for 4 weeks, and subjected to RCBI (two injuries, 24 h apart) using a modified controlled cortical impact model of closed head injury. The same dietary regimens were maintained up to 8 weeks post-injury, when the animals were killed for biochemical and immunohistochemical analyses after behavioral evaluation. Vitamin E-treated animals showed a significant increase in brain vitamin E levels and a significant decrease in brain lipid peroxidation levels. After RBCI, compared with the group on regular chow, animals receiving vitamin E did not show the increase in Abeta peptides, and had a significant attenuation of learning deficits. This study suggests that the exacerbation of brain oxidative stress following RCBI plays a mechanistic role in accelerating Alphabeta accumulation and behavioral impairments in the Tg2576 mice.
162 citations
TL;DR: Mutations in the β-synuclein gene may predispose to DLB, and histopathology and immunohistochemistry analysis of index case brain sections revealed widespread Lewy body pathology and α-syn nuclein aggregation without evidence of β- synuclein aggregation.
Abstract: Objective: To determine whether mutations in the genes for α-synuclein or β-synuclein are responsible for dementia with Lewy bodies (DLB), a disorder closely related to Parkinson disease (PD). Methods: The authors ascertained 33 sporadic cases of DLB and 10 kindreds segregating DLB. DNA samples from the 43 index cases were screened for alterations in the genes for α-synuclein and β-synuclein, as α-synuclein alterations cause PD and β-synuclein may modulate α-synuclein aggregation and neurotoxicity. Results: Two amino acid alterations were identified in unrelated DLB index cases: a valine to methionine substitution at codon 70 (V70M) and a proline to histidine substitution at codon 123 (P123H), both in the β-synuclein gene. These amino acid substitutions occur at conserved residues in highly conserved regions of the β-synuclein protein. Screening of at least 660 chromosomes from control subjects matched to the patients’ population groups failed to identify another V70M or P123H allele. Cosegregation analysis of an extended pedigree segregating the P123H β-synuclein alteration suggested that it is a dominant trait with reduced penetrance or a risk factor polymorphism. Histopathology and immunohistochemistry analysis of index case brain sections revealed widespread Lewy body pathology and α-synuclein aggregation without evidence of β-synuclein aggregation. Conclusion: Mutations in the β-synuclein gene may predispose to DLB.
TL;DR: The data implicate fibrillization of α-syn and tau in the pathogenesis of PD, and suggest that distinct amyloidogenic proteins may cross-seed each other in neurodegenerative diseases.
TL;DR: It is indicated that chronic administration of indomethacin by blocking the activation of the NF-κB significantly reduces the amyloid pathology in Tg2576 mice, and insights into the mechanisms by which this drug could slow progression of AD are provided.
Abstract: Epidemiological studies show that some nonsteroidal anti-inflammatory drugs, nonspecific inhibitors of the cyclooxygenase enzyme, reduce the incidence of Alzheimer's disease (AD). We determined the impact of two nonsteroidal anti-inflammatory drugs on Aβ levels, deposition, and metabolism in a mouse model (the Tg2576) of AD-like amyloidosis. To this end, mice were treated with indomethacin and nimesulide continuously from 8 months of age until they were 15 months old. At the end of the study, indomethacin significantly reduced Aβ 1-40 and Aβ 1-42 levels in both cortex and hippocampus. This decrease was coincidental with a significant reduction of the nuclear factor (NF)-κB activity. By contrast, nimesulide had no effect on both Aβ peptides and NF-κB. Consistently, mice receiving indomethacin, but no nimesulide, showed a significant reduction in the amyloid burden compared with placebo. Neither drug had an effect on plasma levels of Aβ peptides or the Aβ precursor protein metabolism. In vitro studies confirmed that genetic absence of this factor reduces the anti-amyloidogenic effect of indomethacin. These findings indicate that chronic administration of indomethacin by blocking the activation of the NF-κB significantly reduces the amyloid pathology in Tg2576 mice, and provide insights into the mechanisms by which this drug could slow progression of AD.
TL;DR: NIFID is a neuropathologically distinct, clinically heterogeneous variant of frontotemporal dementia (FTD) that may include parkinsonism or MND that may also include FTD with MND and FTD tauopathies.
Abstract: BACKGROUND: Recently described neuronal intermediate filament inclusion disease (NIFID) shows considerable clinical heterogeneity. OBJECTIVE: To assess the spectrum of the clinical and neuropathological features in 10 NIFID cases. METHODS: Retrospective chart and comprehensive neuropathological review of these NIFID cases was conducted. RESULTS: The mean age at onset was 40.8 (range 23 to 56) years, mean disease duration was 4.5 (range 2.7 to 13) years, and mean age at death was 45.3 (range 28 to 61) years. The most common presenting symptoms were behavioral and personality changes in 7 of 10 cases and, less often, memory loss, cognitive impairment, language deficits, and motor weakness. Extrapyramidal features were present in 8 of 10 patients. Language impairment, perseveration, executive dysfunction, hyperreflexia, and primitive reflexes were frequent signs, whereas a minority had buccofacial apraxia, supranuclear ophthalmoplegia, upper motor neuron disease (MND), and limb dystonia. Frontotemporal and caudate atrophy were common. Histologic changes were extensive in many cortical areas, deep gray matter, cerebellum, and spinal cord. The hallmark lesions of NIFID were unique neuronal IF inclusions detected most robustly by antibodies to neurofilament triplet proteins and alpha-internexin. CONCLUSION: NIFID is a neuropathologically distinct, clinically heterogeneous variant of frontotemporal dementia (FTD) that may include parkinsonism or MND. Neuronal IF inclusions are the neuropathological signatures of NIFID that distinguish it from all other FTD variants including FTD with MND and FTD tauopathies.
TL;DR: The view that different neurodegenerative diseases may have similar pathological mechanisms, and that these processes likely include DJ‐1, is extended to include tauopathies.
Abstract: Two novel mutations recently have been identified in the DJ-1 gene that cause a new form of autosomal recessive, early-onset parkinsonism. Because the pathological role of this protein is unknown, we examined the issue here and report the colocalization of DJ-1 protein within a subset of pathological tau inclusions in a diverse group of neurodegenerative disorders known as tauopathies. Our study extends the view that different neurodegenerative diseases may have similar pathological mechanisms, and that these processes likely include DJ-1.
TL;DR: It is reported here for the first time that alpha-internexin, a neuronal IF protein, is present within the inclusions of NIFID as are all three neurofilament subunits: heavy, medium, and light.
Abstract: Neuronal intermediate filament (IF) inclusion disease (NIFID) is a novel neurological disease of early onset with a variable clinical phenotype including frontotemporal dementia, pyramidal, and extrapyramidal signs. Pathologically, in affected areas, there is neuronal loss, astrocytosis, and neuronal intracytoplasmic aggregates of abnormal neuronal IFs that contain neither tau nor α-synuclein. Thus, to characterize the neuronal IF protein profile of inclusions in NIFID, immunohistochemistry (IHC) was performed on 10 cases of NIFID, four normal aged controls (NL), and two cases of Alzheimer's disease (AD) using a panel of anti-neuronal IF proteins. Immunoelectron microscopy was performed on selected cases and frozen tissue from the frontal lobe of four cases was used for biochemical studies including sequential extractions and Western blotting. Based on these studies, we report here for the first time that α-internexin, a neuronal IF protein, is present within the inclusions of NIFID as are all three neurofilament subunits: heavy, medium, and light. Thus, all class IV neuronal IF proteins are present within the pathological inclusions of this disease. Biochemistry revealed that IF aggregates were soluble in sodium dodecyl sulfate (SDS) and no post-translational modification was detected when compared with Alzheimer's disease or aged control brains. Hence, we conclude that NIFID is characterized by the pathological cytoplasmic aggregation of all class IV neuronal IF proteins in brain. The discovery of α-internexin in the cytoplasmic inclusions implicates novel mechanisms of pathogenesis in NIFID and other neurological diseases with pathological accumulations of IFs.
TL;DR: Abnormal alpha-synuclein aggregation in the amygdala is disease selective, but not restricted to disorders of alpha- synuclein and beta-amyloid, and compatible with the notion that tau aggregates predispose neurons to develop secondary LBs.
Abstract: Background Increased attention has been given to α-synuclein aggregation in nonsynucleinopathies because α-synuclein–containing Lewy bodies (LBs) influence symptoms. However, the spectrum of disorders in which secondary inclusions are likely to occur has not been defined. Amygdala neurons commonly develop large numbers of secondary LBs, making it a practical region for studying this phenomenon. Objective To characterize the spectrum of diseases associated with LB formation in the amygdala of neurodegenerative disease and control cases. Design An autopsy series of 101 neurodegenerative disease and 34 aged control cases. Using immunohistochemistry studies, we examined the amygdala for α-synuclein aggregates. Results Lewy bodies were often abundant in classic Pick disease, argyrophilic grain disease, Alzheimer disease, and dementia with LBs but not in cases with amygdala degeneration lacking tau-based inclusions, control cases, preclinical disease carriers, or degenerative diseases lacking pathologic involvement of the amygdala. The exposed α-synuclein epitopes were similar in all cases containing LBs. Conclusions Abnormal α-synuclein aggregation in the amygdala is disease selective, but not restricted to disorders of α-synuclein and β-amyloid. Our data are compatible with the notion that tau aggregates predispose neurons to develop secondary LBs.
TL;DR: It is demonstrated that PS1 deficiency also leads to the formation of degradative vacuoles and to the aberrant translocation of presynaptic α- and β-synuclein proteins to these organelles in the perikarya of primary neurons, concomitant with significant increases in the levels of both synucleins.
Abstract: Presenilin-1 null mutation (PS1 −/−) in mice is associated with morphological alterations and defects in cleavage of transmembrane proteins. Here, we demonstrate that PS1 deficiency also leads to the formation of degradative vacuoles and to the aberrant translocation of presynaptic α- and β-synuclein proteins to these organelles in the perikarya of primary neurons, concomitant with significant increases in the levels of both synucleins. Stimulation of autophagy in control neurons produced a similar mislocalization of synucleins as genetic ablation of PS1. These effects were not the result of the loss of PS1 γ-secretase activity; however, dysregulation of calcium channels in PS1 −/− cells may be involved. Finally, colocalization of α-synuclein and degradative organelles was observed in brains from patients with the Lewy body variant of AD. Thus, aberrant accumulation of α- and β-synuclein in degradative organelles are novel features of PS1 −/− neurons, and similar events may promote the formation of α-synuclein inclusions associated with neurodegenerative diseases.
TL;DR: The following is a compendium of new and exciting studies, including a critical discussion of the rationale and caveats associated with cellular transplantation techniques in experimental TBI research.
Abstract: Experimental research during the past decade has greatly increased our understanding of the pathophysiology of traumatic brain injury (TBI) and allowed us to develop neuroprotective pharmacological therapies. Encouraging results of experimental pharmacological interventions, however, have not been translated into successful clinical trials, to date. Traumatic brain injury is now believed to be a progressive degenerative disease characterized by cell loss. The limited capacity for self-repair of the brain suggests that functional recovery following TBI is likely to require cellular transplantation of exogenous cells to replace those lost to trauma. Recent advances in central nervous system transplantation techniques involve technical and experimental refinements and the analysis of the feasibility and efficacy of transplantation of a range of stem cells, progenitor cells and postmitotic cells. Cellular transplantation has begun to be evaluated in several models of experimental TBI, with promising results. The following is a compendium of these new and exciting studies, including a critical discussion of the rationale and caveats associated with cellular transplantation techniques in experimental TBI research. Further refinements in future research are likely to improve results from transplantation-based treatments for TBI.
01 Jan 2004
TL;DR: The clinical features and neuroanatomical basis of dementia, and the practical approach to the pathological diagnosis of dementia: important anatomical landmarks in the brain in dementia, are defined.
Abstract: 1. Definition, clinical features and neuroanatomical basis of dementia T. J. Grabowski, and A. R. Damasio 2. Practical approach to the pathological diagnosis of dementia: important anatomical landmarks in the brain in dementia M. M. Esiri, and J. H. Morris 3. Practical approach to pathological diagnosis M. M. Esiri, and J. H. Morris 4a. Alzheimer's disease M. M. Esiri, and J. H. Morris 4b. Neuropathological changes of Alzheimer's disease in persons with Down's syndrome D. Mann 5. Vascular dementia M. M. Esiri, and J. H. Morris 6. Parkinson's disease and dementia M. M. Esiri, and R. McShane 7. Amyotrophic lateral sclerosis/Parkinsonism-dementia complex of Guam D. P. Perl 8. Pick's disease J. H. Morris, and M. M. Esiri 9. Huntington disease J. P. G. von Sattel, P. Ge, and L. Kelley 10. Other neurodegenerative diseases causing dementia M. M. Esiri, and J. H. Morris 11. Familial cerebral amyloid angiopathies G. T. Plant, and M. M. Esiri 12. Human prion disease K. Hsiao 13. Alcoholism and dementia C. Harper, and D. Corbett 14. Dementia due to other metabolic diseases and toxins M. M. Esiri 15. Hydrocephalus and dementia M. M. Esiri 16. Head injury and dementia C. J. Bruton 17. Infectious diseases causing dementias F. Scaravilli, and M. J. G. Harrison 18. Schizophrenia and its dementia P. J. Harrison 19. Other diseases that cause dementia M. M. Esiri, and J. H. Morris Appendix 1. Morphometric methods and dementia J. M. Anderson Appendix 2. Addresses of dementia brain banks M. M. Esiri, and J. H. Morris Appendix 3. Safety precautions in laboratories involved in dementia diagnosis and research M. M. Esiri, and J. H. Morris.
TL;DR: The potential power of single-cell gene expression studies within the CNS in relation to neurodegenerative and neuropsychiatric disorders such as Alzheimer's disease (AD) and schizophrenia, respectively are illustrated.
Abstract: Technical and experimental advances in microaspiration techniques, RNA amplification, quantitative real-time polymerase chain reaction (qPCR), and cDNA microarray analysis have led to an increase in the number of studies of single-cell gene expression. In particular, the central nervous system (CNS) is an ideal structure to apply single-cell gene expression paradigms. Unlike an organ that is composed of one principal cell type, the brain contains a constellation of neuronal and noneuronal populations of cells. A goal is to sample gene expression from similar cell types within a defined region without potential contamination by expression profiles of adjacent neuronal subpopulations and noneuronal cells. The unprecedented resolution afforded by single-cell RNA analysis in combination with cDNA microarrays and qPCR-based analyses allows for relative gene expression level comparisons across cell types under different experimental conditions and disease states. The ability to analyze single cells is an important distinction from global and regional assessments of mRNA expression and can be applied to optimally prepared tissues from animal models as well as postmortem human brain tissues. This focused review illustrates the potential power of single-cell gene expression studies within the CNS in relation to neurodegenerative and neuropsychiatric disorders such as Alzheimer's disease (AD) and schizophrenia, respectively.
TL;DR: It is suggested that oxidative damage is involved in the pathological mechanisms of the tau Tg mice and that treatment with antioxidative agents like α-tocopherol may prevent neurodegenerative tauopathies.
TL;DR: The results of the present study support the concept that brain oxidative stress and inflammation coexist in this animal model of AD-like brain amyloidosis, but they represent two distinct therapeutic targets in the disease pathogenesis.
Abstract: BACKGROUND: An increasing body of evidence implicates both brain inflammation and oxidative stress in the pathogenesis of Alzheimer's disease (AD). The relevance of their interaction in vivo, however, is unknown. Previously, we have shown that separate pharmacological targeting of these two components results in amelioration of the amyloidogenic phenotype of a transgenic mouse model of AD-like brain amyloidosis (Tg2576). METHODS: In the present study, we investigated the therapeutic effects of a combination of an anti-inflammatory agent, indomethacin, and a natural anti-oxidant, vitamin E, in the Tg2576 mice. For this reason, animals were treated continuously from 8 (prior to Abeta deposition) through 15 (when Abeta deposits are abundant) months of age. RESULTS: At the end of the study, these therapeutic interventions suppressed brain inflammatory and oxidative stress responses in the mice. This effect was accompanied by significant reductions of soluble and insoluble Abeta1-40 and Abeta1-42 in neocortex and hippocampus, wherein the burden of Abeta deposits also was significantly decreased. CONCLUSIONS: The results of the present study support the concept that brain oxidative stress and inflammation coexist in this animal model of AD-like brain amyloidosis, but they represent two distinct therapeutic targets in the disease pathogenesis. We propose that a combination of anti-inflammatory and anti-oxidant drugs may be a useful strategy for treating AD.
TL;DR: The hypothesis that NGF-expressing human NT2N neurons transplanted into the basal forebrain of brain-injured mice can attenuate long-term cognitive dysfunction associated with TBI is tested and NGF gene therapy using transduced NT2n neurons (as a source of delivery) may selectively improve cognitive function following TBI.
Abstract: Infusion of nerve growth factor (NGF) has been shown to be neuroprotective following traumatic brain injury (TBI). In this study, we tested the hypothesis that NGF-expressing human NT2N neurons transplanted into the basal forebrain of brain-injured mice can attenuate long-term cognitive dysfunction associated with TBI. Undifferentiated NT2 cells were transduced in vitro with a lentiviral vector to release NGF, differentiated into NT2N neurons by exposure to retinoic acid and transplanted into the medial septum of mice 24 h following controlled cortical impact (CCI) brain injury or sham injury. Adult mice (n = 78) were randomly assigned to one of four groups: (1) sham-injured and vehicle (serum-free medium)-treated, (2) brain-injured and vehicle-treated, (3) brain-injured engrafted with untransduced NT2N neurons, and (4) brain-injured engrafted with transduced NGF-NT2N neurons. All groups were immunosuppressed daily with cyclosporin A (CsA) for 4 weeks. At 1 month post-transplantation, animals engrafted with NGF-expressing NT2N neurons showed significantly improved learning ability (evaluated with the Morris water maze) compared to brain-injured mice receiving either vehicle (p < 0.05) or untransduced NT2N neurons (p < 0.01). No effect of NGF-secreting NT2N cells on motor function deficits at 1-4 weeks post-transplantation was observed. These data suggest that NGF gene therapy using transduced NT2N neurons (as a source of delivery) may selectively improve cognitive function following TBI.
TL;DR: The condition affecting members of San Francisco family A is clinically, pathologically, and genetically distinct from previous familial forms of FTD and ALS.
Abstract: Background Frontotemporal dementia (FTD) is a clinically heterogeneous condition that can be associated with clinical manifestations of an extrapyramidal disorder or motor neuron disease. A range of histologic patterns has been described in patients with FTD. The most common familial form of this condition is caused by mutations in the microtubule-associated protein tau gene ( MAPτ ) and is associated with neuronal or glial tau inclusions. Objectives To determine the clinical, anatomic, and pathological features of San Francisco family A and to map the mutation responsible for disease in this family. Design A systematic clinical, neuropsychologic, neuroimaging, and chromosome segregation analysis of San Francisco family A was performed. A pathological and biochemical assessment of a family member was made. Setting Family study. Patients San Francisco family A, with FTD, variable extrapyramidal symptoms, and prominent motor neuron disease. Afflicted family members donot have a MAPτ coding or splice regulatory sequence mutation, and the MAPτ is genetically excluded. Main Outcome Measures Comparison of clinical, neuropsychologic, neuroimaging, and linkage findings of San Francisco family A with other familial forms of FTD and amyotrophic lateral sclerosis (ALS). Results The most probable location for the mutation responsible for this condition is on chromosome arm 17q, distal to the MAPτ. All previously identified susceptibility loci for FTD and ALS are excluded. Autopsy findings from an afflicted family member show distinctive tau and α-synuclein inclusions. Another unique feature is that the insoluble tau protein consists predominantly of the 4R/0N isoform. Conclusion The condition affecting members of San Francisco family A is clinically, pathologically, and genetically distinct from previous familial forms of FTD and ALS.
TL;DR: The ABCA2 transfected cell line expressed resistance to a free radical initiator, confirming involvement in protection against reactive oxygen species and suggesting a further possible link to AD.
Abstract: SPECIFIC AIMSThe ATP binding cassette, subfamily A transporter 2 (ABCA2) gene is localized in the endolysosomal compartment of the cell and expressed at high levels in brain tissue. ABCA2 expressio...
TL;DR: This case demonstrates the ineffectiveness of DBS in MSA, even when the patient is responsive to levodopa, and emphasizes the need for diagnostic modalities that can be used to distinguish PD from MSA and other parkinsonian syndromes in which thelevodopa response pattern is typical of PD.
Abstract: ✓ The authors report the clinicopathological findings in a patient in whom levodopa-responsive parkinsonism developed at 45 years of age. The patient experienced asymmetrical onset of symptoms, sustained benefit from levodopa, and motor fluctuations and dyskinesias, but there were no prominent autonomic, cerebellar, or pyramidal signs. He was diagnosed clinically with Parkinson disease (PD) and underwent bilateral subthalamic nucleus deep brain stimulation (DBS) surgery 9 years after symptom onset. He did not respond to stimulation or medication postoperatively, however, and died 12 weeks after surgery of repeated aspiration pneumonias. Postmortem examination revealed neuron loss in the substantia nigra and basal ganglia, and numerous α-synuclein—positive glial cytoplasmic inclusions in the subcortical nuclei, cerebellum, and brainstem, findings that established a neuropathological diagnosis of multiple system atrophy (MSA). Furthermore, there was an atypical and robust inflammatory reaction, as well as n...
TL;DR: Evaluating the olfactory function of T alpha 1-3RT transgenic mice that overexpress tau and comparing such function to that of wild-type controls lent support to the notion that tau may be involved in the pathogenesis of theOlfactory dysfunction of some neurodegenerative diseases.
TL;DR: The results indicate that class IV IF proteins are present within the pleomorphic inclusions of all cases of NIFID and small subsets of abnormal neuronal inclusions in Alzheimer’s disease, Lewy body diseases, and motor neuron disease also contain epitopes of α-internexin.
Abstract: Abnormal neuronal aggregates of alpha-internexin and the three neurofilament (NF) subunits, NF-L, NF-M, and NF-H have recently been identified as the pathological hallmarks of neuronal intermediate filament (IF) inclusion disease (NIFID), a novel neurological disease of early onset with a variable clinical phenotype including frontotemporal dementia, pyramidal and extrapyramidal signs. alpha-Internexin, a class IV IF protein, a major component of inclusions in NIFID, has not previously been identified as a component of the pathological protein aggregates of any other neurodegenerative disease. Therefore, to determine the specificity of this protein, alpha-internexin immunohistochemistry was undertaken on cases of NIFID, non-tau frontotemporal dementias, motor neuron disease, alpha-synucleinopathies, tauopathies, and normal aged control brains. Our results indicate that class IV IF proteins are present within the pleomorphic inclusions of all cases of NIFID. Small subsets of abnormal neuronal inclusions in Alzheimer's disease, Lewy body diseases, and motor neuron disease also contain epitopes of alpha-internexin. Thus, alpha-internexin is a major component of the neuronal inclusions in NIFID and a relatively minor component of inclusions in other neurodegenerative diseases. The discovery of alpha-internexin in neuronal cytoplasmic inclusions implicates novel mechanisms of pathogenesis in NIFID and other neurological diseases with pathological filamentous neuronal inclusions.
TL;DR: Evidence is provided that the MAPT +16 splice mutation cases from around the world analyzed in this study are indeed related and represent a single pedigree that probably originated in the North Wales area of the UK.
Abstract: The +16 exon 10 splice mutation of the tau gene (microtubule-associated protein tau, MAPT) has been reported in numerous families with frontotemporal dementia (FTD). To date, the majority of these families are from England and Wales in the UK, although families with this mutation have been reported from Australia and the USA. Our own analysis has identified eight families with the +16 MAPT splice mutation from around the Manchester and North Wales areas of the UK. Given the proximity of the UK families to one another it is likely that they are related and represent a single extended pedigree. In order to investigate this possibility, and the possibility that the families with this mutation from London, the USA, and Australia are related, we genotyped 11 microsatellite markers around the tau locus. In most cases (20/25, 80%), a common haplotype, approximately 3 cM in size, was identified. In the remaining cases, this haplotype appears to have been varyingly reduced in size by recombination. We demonstrate that the +16 mutation is on the H1 tau haplotype and that H1 specific polymorphisms are also shared by these families. These data provide evidence that the MAPT +16 splice mutation cases from around the world analyzed in this study are indeed related and represent a single pedigree that probably originated in the North Wales area of the UK. Furthermore, this single large pedigree may be of use in the identification of disease modifying loci in FTD.