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Showing papers by "John Q. Trojanowski published in 1998"


Journal ArticleDOI
18 Jun 1998-Nature
TL;DR: In this paper, the authors sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon in
Abstract: Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)(1-9), historically termed Pick's disease(10) Most FTDP-17 cases show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule-associated protein Tau, although the Tau pathology varies considerably in both its quantity (or severity) and characteristics(1-8,12) Previous studies have mapped the FTDP-17 locus to a 2-centimorgan region on chromosome 17q2111; the tau gene also lies within this region We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon in The splice-site mutations all destabilize a potential stem-loop structure which is probably involved in regulating the alternative splicing of exon10 (ref 13) This causes more frequent usage of the 5' splice site and an increased proportion of tan transcripts that include exon 10 The increase in exon 10(+) messenger RNA will increase the proportion of Tau containing four microtubule-binding repeats, which is consistent with the neuropathology described in several families with FTDP-17 (refs 12, 14)

3,366 citations


Journal Article
TL;DR: Western blot analyses of highly purified LBs from DLB brains showed that full-length as well as partially truncated and insoluble aggregates of alpha-synuclein are deposited in LBs, which strongly implicate alpha- Synuclein in the formation of LBs and the selective degeneration of neurons in sporadic PD and DLB.
Abstract: Lewy bodies (LBs) are hallmark lesions of degenerating neurons in the brains of patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Recently, a point mutation in the gene encoding the presynaptic alpha-synuclein protein was identified in some autosomal-dominantly inherited familial PD pedigrees, and light microscopic studies demonstrated alpha-synuclein immunoreactivity in LBs of sporadic PD and DLB. To characterize alpha-synuclein in LBs, we raised monoclonal antibodies (MAbs) to LBs purified from DLB brains and obtained a MAb specific for alpha-synuclein that intensely labeled LBs. Light and electron microscopic immunocytochemical studies performed with this MAb as well as other antibodies to alpha-and beta-synuclein showed that alpha-synuclein, but not beta-synuclein, is a component of LBs in sporadic PD and DLB. Western blot analyses of highly purified LBs from DLB brains showed that full-length as well as partially truncated and insoluble aggregates of alpha-synuclein are deposited in LBs. Thus, these data strongly implicate alpha-synuclein in the formation of LBs and the selective degeneration of neurons in sporadic PD and DLB.

1,529 citations


Journal ArticleDOI
04 Dec 1998-Science
TL;DR: Functional assays of recombinant tau proteins with different FTDP-17 missense mutations implicated all but one of these mutations in disease pathogenesis by reducing the ability of tau to bind microtubules and promote microtubule assembly.
Abstract: Tau proteins aggregate as cytoplasmic inclusions in a number of neurodegenerative diseases, including Alzheimer's disease and hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Over 10 exonic and intronic mutations in the tau gene have been identified in about 20 FTDP-17 families. Analyses of soluble and insoluble tau proteins from brains of FTDP-17 patients indicated that different pathogenic mutations differentially altered distinct biochemical properties and stoichiometry of brain tau isoforms. Functional assays of recombinant tau proteins with different FTDP-17 missense mutations implicated all but one of these mutations in disease pathogenesis by reducing the ability of tau to bind microtubules and promote microtubule assembly.

949 citations


Journal ArticleDOI
TL;DR: Examination of brains from patients with multiple system atrophy suggested that a reduction in the solubility of α‐synuclein may induce this protein to form filaments that aggregate into cytoplasmic inclusions, which contribute to the dysfunction or death of glial cells as well as neurons in neurodegenerative disorders with different phenotypes.
Abstract: Recently, alpha-synuclein was shown to be a structural component of the filaments in Lewy bodies (LBs) of Parkinson's disease (PD), dementia with LBs (DLB) as well as the LB variant of Alzheimer's disease, and this suggests that alpha-synuclein could play a mechanistic role in the pathogenesis of these disorders. To determine whether alpha-synuclein is a building block of inclusions in other neurodegenerative movement disorders, we examined brains from patients with multiple system atrophy (MSA) and detected alpha-synuclein, but not beta- or gamma-synuclein, in glial cytoplasmic inclusions (GCIs) throughout the MSA brain. In MSA white matter, alpha-synuclein-positive GCIs were restricted to oligodendrocytes, and alpha-synuclein was localized to the filaments in GCIs by immunoelectron microscopy. Finally, we demonstrated that insoluble alpha-synuclein accumulated selectively in MSA white matter with alpha-synuclein-positive GCIs. Taken together with evidence that LBs contain insoluble alpha-synuclein, our data suggest that a reduction in the solubility of alpha-synuclein may induce this protein to form filaments that aggregate into cytoplasmic inclusions, which contribute to the dysfunction or death of glial cells as well as neurons in neurodegenerative disorders with different phenotypes.

634 citations


Journal ArticleDOI
TL;DR: Cerebrospinal fluid assays showing low levels of Aβ 42 and high levels of tau come closest to fulfilling criteria for a useful biomarker, and apolipoprotein E e4 allele can add confidence to the clinical diagnosis.

593 citations


Journal ArticleDOI
TL;DR: The data suggest that the apoptotic response to trauma is regionally distinct and may be involved in both acute and delayed patterns of cell death.
Abstract: The temporal pattern of apoptosis in the adult rat brain after lateral fluid-percussion (FP) brain injury was characterized using terminal deoxynucleotidyl-transferase-mediated biotin-dUTP nick end labeling (TUNEL) histochemistry and agarose gel electrophoresis. Male Sprague Dawley rats were subjected to brain injury and killed for histological analysis at intervals from 12 hr to 2 months after injury (n = 3/time point). Sham (uninjured) controls were subjected to anesthesia with (n = 3) or without (n = 3) surgery. Apoptotic TUNEL-positive cells were defined using stringent morphological criteria including nuclear shrinkage and fragmentation and condensation of chromatin and cytoplasm. Double-labeled immunocytochemistry was performed to identify TUNEL-positive neurons (anti-neurofilament monoclonal antibody RM044), astrocytes (anti-glial fibrillary acidic protein polyclonal antibody), and oligodendrocytes (anti-cyclic nucleotide phosphohydrolase polyclonal antibody). Compared with that seen with sham controls, in the injured cortex, significant apoptosis occurred at 24 hr (65 +/- 19 cells; p < 0.05) with a second, more pronounced response at 1 week after injury (91 +/- 24 cells; p < 0.05). The number of apoptotic cells in the white matter was increased as early as 12 hr after injury and peaked by 1 week (33 +/- 6 cells; p < 0.05). An increase in apoptotic cells was observed in the hippocampus at 48 hr (13 +/- 8), whereas in the thalamus, the apoptotic response was delayed, peaking at 2 weeks after injury (151 +/- 71 cells; p < 0.05). By 2 months, the number of apoptotic cells in most regions had returned to uninjured levels. At 24 hr after injury, TUNEL-labeled neurons and oligodendrocytes were localized primarily to injured cortex. By 1 week after injury, populations of TUNEL-labeled astrocytes and oligodendrocytes were present in the injured cortex, while double-labeled neurons were present predominantly in injured cortex and thalamus, with a few scattered in the hippocampus. DNA agarose gels confirmed morphological identification of apoptosis. These data suggest that the apoptotic response to trauma is regionally distinct and may be involved in both acute and delayed patterns of cell death.

524 citations


Journal ArticleDOI
TL;DR: It is suggested that insoluble alpha-synuclein aggregates into filaments that form LBs in many FAD patients, and it is speculated that these inclusions may compromise the function and/or viability of affected neurons in the FAD brain.
Abstract: Missense mutations in the α-synuclein gene cause familial Parkinson's disease (PD), and α-synuclein is a major component of Lewy bodies (LBs) in sporadic PD, dementia with LBs (DLB), and the LB variant of Alzheimer's disease (AD). To determine whether α-synuclein is a component of LBs in familial AD (FAD) patients with known mutations in presenilin ( n = 65) or amyloid precursor protein ( n = 9) genes, studies were conducted with antibodies to α-, β-, and γ-synuclein. LBs were detected with α- but not β- or γ-synuclein antibodies in 22% of FAD brains, and α-synuclein-positive LBs were most numerous in amygdala where some LBs co-localized with tau-positive neurofibrillary tangles. As 12 (63%) of 19 FAD amygdala samples contained α-synuclein-positive LBs, these inclusions may be more common in FAD brains than previously reported. Furthermore, α-synuclein antibodies decorated LB filaments by immunoelectron microscopy, and Western blots revealed that the solubility of α-synuclein was reduced compared with control brains. The presence of α-synuclein-positive LBs was not associated with any specific FAD mutation. These studies suggest that insoluble α-synuclein aggregates into filaments that form LBs in many FAD patients, and we speculate that these inclusions may compromise the function and/or viability of affected neurons in the FAD brain.

507 citations


Journal ArticleDOI
TL;DR: In this paper, two missense mutations in exon 10 of the tau gene that segregate with disease, Asn279(Lys) in the Pallido-ponto-nigral degeneration (PPND) kindred and Pro301(Leu) in four other FTDP-17 kindred were found.
Abstract: Pallido-ponto-nigral degeneration (PPND) is one of the most well characterized familial neurodegenerative disorders linked to chromosome 17q21-22. These hereditary disorders are known collectively as frontotemporal dementia (FTD) and parkinsonism linked to chromosome 17 (FTDP-17). Although the clinical features and associated regional variations in the neuronal loss observed in different FTDP-17 kindreds are diverse, the diagnostic lesions of FTDP-17 brains are tau-rich filaments in the cytoplasm of specific subpopulations of neurons and glial cells. The microtubule associated protein (tau) gene is located on chromosome 17q21-22. For these reasons, we investigated the possibility that PPND and other FTDP-17 syndromes might be caused by mutations in the tau gene. Two missense mutations in exon 10 of the tau gene that segregate with disease, Asn279(Lys) in the PPND kindred and Pro301(Leu) in four other FTDP-17 kindreds, were found. A third mutation was found in the intron adjacent to the 3' splice site of exon 10 in patients from another FTDP-17 family. Transcripts that contain exon 10 encode tau isoforms with four microtubule (MT)-binding repeats (4Rtau) as opposed to tau isoforms with three MT-binding repeats (3Rtau). The insoluble tau aggregates isolated from brains of patients with each mutation were analyzed by immunoblotting using tau-specific antibodies. For each of three mutations, abnormal tau with an apparent Mr of 64 and 69 was observed. The dephosphorylated material comigrated with tau isoforms containing exon 10 having four MT-binding repeats but not with 3Rtau. Thus, the brains of patients with both the missense mutations and the splice junction mutation contain aggregates of insoluble 4Rtau in filamentous inclusions, which may lead to neurodegeneration.

472 citations


Journal ArticleDOI
TL;DR: The data suggest that specific isoprostane analysis may reflect increased oxidative stress in AD, and increased F2‐isoprostanes in Alzheimer's disease: evidence for enhanced lipid peroxidation in vivo.
Abstract: Alzheimer's disease (AD) includes a group of dementing neurodegenerative disorders that have diverse etiologies but the same hallmark brain lesions. Since oxidative stress may play a role in the pathogenesis of AD and isoprostanes are chemically stable peroxidation products of arachidonic acid, we measured both iPF2alpha-III and iPF2alpha -VI using gas chromatography-mass spectrometry in AD and control brains. The levels of both isoprostanes, but not of 6-keto PGF1alpha, an index of prostaglandin production, were markedly elevated in both frontal and temporal poles of AD brains compared to the corresponding cerebella. Levels were also elevated compared to corresponding areas of brains from patients who had died with schizophrenia or Parkinson's disease or from nonneuropsychiatric disorders. iPF2alpha -IV, but not iPF2alpha-III, levels were higher in ventricular CSF of AD brains relative to the non-AD brains. These data suggest that specific isoprostane analysis may reflect increased oxidative stress in AD.

412 citations


Journal ArticleDOI
TL;DR: Findings indicate that experimental traumatic brain injury can cause long-term cognitive and neurologic motor dysfunction accompanied by continuing neurodegeneration.

374 citations


Journal ArticleDOI
TL;DR: The long-term viability of cryopreserved NT2N cell Xenografts in vivo and their sustained effectiveness in promoting behavioral recovery suggest potential utilization of xenografting and Cryopreservation as useful protocols for establishing clone cell lines as graft source in neural transplantation therapies for central nervous system disorders.

Journal ArticleDOI
TL;DR: Increased understanding of the protein composition and pathological significance of LBs may provide insight into mechanisms of neuron dysfunction and death in other neurodegenerative disorders characterized by brain lesions containing massive deposits of proteinacious fibrils.
Abstract: The abnormal aggregation of proteins into fibrillar lesions is a neuropathological hallmark of several sporadic and hereditary neurodegenerative diseases For example, Lewy bodies (LBs) are intracytoplasmic filamentous inclusions that accumulate primarily in subcortical neurons of patients with Parkinson's disease (PD), or predominantly in neocortical neurons in a subtype of Alzheimer's disease (AD) known as the LB variant of AD (LBVAD) and in dementia with LBs (DLB) Aggregated neurofilament subunits and α-synuclein are major protein components of LBs, and these inclusions may contribute mechanistically to the degeneration of neurons in PD, DLB and LBVAD Here we review recent studies of the protein building blocks of LBs, as well as the role LBs play in the onset and progression of PD, DLB and LBVAD Increased understanding of the protein composition and pathological significance of LBs may provide insight into mechanisms of neuron dysfunction and death in other neurodegenerative disorders characterized by brain lesions containing massive deposits of proteinacious fibrils

Journal ArticleDOI
TL;DR: Ulastructural examination of Lewy bodies has revealed masses of aggregated 7-to 25-nm-diameter filaments that appear similar to neurofilaments (NFs), but the precise molecular composition of LBs, including the abnormal filaments in these intracytoplasmic neuronal inclusions, remains to be clarified.
Abstract: The presence of Lewy bodies (LBs) in dopaminergic neurons of the substantia nigra pars compacta, as well as neuron loss and gliosis, is a diagnostic hallmark of Parkinson disease (PD), but LBs also are seen in other cortical and subcortical neurons of the PD brain. Additionally, LBs also occur in similar populations of neurons in the brains of patients with the classic clinical and pathological features of Alzheimer disease (AD). Furthermore, the presence of numerous cortical intraneuronal LBs, but only rare AD neurofibrillary tangles and senile plaques in the brains of patients with an AD-like dementia, defines a neurodegenerative disorder known as dementia with LBs (DLB). Ultrastructural examination of LBs has revealed masses of aggregated 7-to 25-nm-diameter filaments that appear similar to neurofilaments (NFs), but the precise molecular composition of LBs, including the abnormal filaments in these intracytoplasmic neuronal inclusions, remains to be clarified. Indeed, the biological significance of LBs, especially the role that they might play in the degeneration of neurons in LB disorders, is still enigmatic (Figure).

Journal ArticleDOI
TL;DR: This paper will review the literature suggesting that alterations in intracellular calcium with resulting changes in gene expression, activation of reactive oxygen species (ROS), activation of intrACEllular proteases (calpains), expression of neurotrophic factors, and activation of cell death genes (apoptosis) may play a role in mediating delayed cell death after trauma.
Abstract: The mechanisms underlying secondary or delayed cell death following traumatic brain injury (TBI) are poorly understood. Recent evidence from experimental models of TBI suggest that diffuse and widespread neuronal damage and loss is progressive and prolonged for months to years after the initial insult in selectively vulnerable regions of the cortex, hippocampus, thalamus, striatum, and subcortical nuclei. The development of new neuropathological and molecular techniques has generated new insights into the cellular and molecular sequelae of brain trauma. This paper will review the literature suggesting that alterations in intracellular calcium with resulting changes in gene expression, activation of reactive oxygen species (ROS), activation of intracellular proteases (calpains), expression of neurotrophic factors, and activation of cell death genes (apoptosis) may play a role in mediating delayed cell death after trauma. Recent data suggesting that TBI should be considered as both an inflammatory and/or a neurodegenerative disease is also presented. Further research concerning the complex molecular and neuropathological cascades following brain trauma should be conducted, as novel therapeutic strategies continue to be developed.

Journal ArticleDOI
TL;DR: No significant evidence of neurodegeneration or ongoing neural injury in the cerebral cortex was found in this sample of elderly persons with schizophrenia, and the behavioral and cognitive deterioration observed in late life did not correlate with age-related degenerative phenomena.
Abstract: Background The cognitive and functional deterioration that is observed in many "poor-outcome" patients with schizophrenia suggests a neurodegenerative process extending into late life Previous diagnostic studies have excluded known neurodegenerative diseases as explanations for this dementia However, we hypothesized that relatively small accumulations of age- or disease-related neurodegenerative lesions occurring in an otherwise abnormal brain could result in deterioration in schizophrenia Methods Postmortem studies were conducted using 23 prospectively accrued elderly persons with chronic schizophrenia for whom clinical ratings had been determined before death, 14 elderly control patients with no neuropsychiatric disease, and 10 control patients with Alzheimer disease Immunohistochemistry and unbiased stereological counting methods were used to quantify common neurodegenerative lesions (ie, neurofibrillary tangles, amyloid plaques, and Lewy bodies) and cellular reactions to a variety of noxious stimuli (ubiquitinated dystrophic neurites, astrocytosis, and microglial infiltrates) in the ventromedial temporal lobe and the frontal and the calcarine (primary visual) cortices Results No statistically significant differences were found between the patients with schizophrenia and the control patients without neuropsychiatric disease for the densities of any of the markers, while both groups exhibited fewer lesions than did the control group with Alzheimer disease Correlation analyses in the schizophrenia sample failed to identify significant correlations between cognitive and psychiatric ratings and densities of any of the neuropathologic markers Conclusions No significant evidence of neurodegeneration or ongoing neural injury in the cerebral cortex was found in this sample of elderly persons with schizophrenia Furthermore, the behavioral and cognitive deterioration observed in late life did not correlate with age-related degenerative phenomena

Journal Article
TL;DR: Venous hypertensive encephalopathy resulting from a DAVF should be considered a potentially reversible cause of vascular dementia in patients with progressive cognitive deficits.
Abstract: PURPOSE: Dural arteriovenous fistulas (DAVFs) are acquired arteriovenous shunts located within the dura. The highly variable natural history and symptomatology of DAVFs range from subjective bruit to intracranial hemorrhage and are related to the lesion's pattern of venous drainage and its effect on the drainage of adjacent brain. We examined the prevalence and features of DAVFs in patients with progressive dementia or encephalopathy. METHODS: The records and radiologic studies of 40 consecutive patients with DAVFs treated at our institution were reviewed. RESULTS: Five (12.5%) of 40 consecutive patients with DAVFs had encephalopathy or dementia. In each patient, high flow through the arteriovenous shunt combined with venous outflow obstruction caused impairment of cerebral venous drainage. Hemodynamically, the result was widespread venous hypertension causing diffuse ischemia and progressive dysfunction of brain parenchyma. Results of CT or MR imaging revealed abnormalities in each patient, reflecting the impaired parenchymal venous drainage. Pathologic findings in one patient confirmed the mechanism of cerebral dysfunction as venous hypertension. The hemodynamic mechanism and resulting abnormality appeared identical to that seen in progressive chronic myelopathy resulting from a spinal DAVF (Foix-Alajouanine syndrome). Remission of cognitive symptoms occurred in each patient after embolization. CONCLUSION: Venous hypertensive encephalopathy resulting from a DAVF should be considered a potentially reversible cause of vascular dementia in patients with progressive cognitive deficits.

Journal ArticleDOI
TL;DR: Data suggest a mechanistic link between brain trauma and Abeta levels and the death of neurons and the appearance of Alzheimer's disease-like beta-amyloid plaques in transgenic mice that overexpress mutant human amyloid precursor protein.
Abstract: Although brain trauma is a risk factor for Alzheimer's disease, no experimental model has been generated to explore this relationship. We developed a model of brain trauma in transgenic mice that overexpress mutant human amyloid precursor protein (PDAPP) leading to the appearance of Alzheimer's disease-like beta-amyloid (Abeta) plaques beginning at 6 months of age. We induced cortical impact brain injury in the PDAPP animals and their wild-type littermates at 4 months of age, ie, before Abeta plaque formation, and evaluated changes in posttraumatic memory function, histopathology, and regional tissue levels of the Abeta peptides Abeta1-40 and Abeta1-42. We found that noninjured PDAPP mice had impaired memory function compared to noninjured wild-type littermates (P < 0.01) and that brain-injured PDAPP mice had more profound memory dysfunction than brain-injured wild-type littermates (P < 0.001). Although no augmentation of Abeta plaque formation was observed in brain-injured PDAPP mice, a substantial exacerbation of neuron death was found in the hippocampus (P < 0.001) in association with an acute threefold increase in Abeta1-40 and sevenfold increase in Abeta1-42 levels selectively in the hippocampus (P < 0.01). These data suggest a mechanistic link between brain trauma and Abeta levels and the death of neurons.

Journal ArticleDOI
TL;DR: It is concluded that pallido-ponto-nigral degeneration is a hereditary neurodegenerative disorder characterized by neuronal and glial tau-rich inclusions formed from aggregated filaments and hyperphosphorylated tau proteins and can be subcategorized into the tauopathy group of chromosome 17-linked neurodegenersative disorders.
Abstract: A group of similar autosomal dominant hereditary neurodegenerative disorders have been linked to chromosome 17 in thirteen kindreds One of these disorders, known as pallido-ponto-nigral degeneration (PPND), is characterized by extensive degeneration of the globus pallidus and substantia nigra as well as accumulation of abnormally phosphorylated tau proteins The authors now present comprehensive data on the cellular and molecular pathology of PPND, allowing its classification among chromosome 17-linked neurodegenerative disorders as well as its classification among sporadic and other familial tauopathies First, we showed that PPND is characterized by abundant ballooned neurons in neocortical and subcortical regions as well as by tau-rich inclusions in the cytoplasm of neurons and oligodendroglia morphologically similar to those seen in corticobasal degeneration (CBD), but in a distribution pattern resembling progressive supranuclear palsy (PSP) Second, we demonstrated that antibodies to phosphorylation-independent (Alz50, 133, 304, Tau-2, T-46) as well as phosphorylation-dependent (AT8, PHF-6, 12E8, PHF-1, T3P, pS422) epitopes in human tau proteins stain these glial and neuronal inclusions as intensely as they stain CBD or PSP inclusions Third, we probed PPND brain by Western blots using some of the same anti-tau antibodies to reveal 2 tau immunobands with molecular weights of 69 kD and 64 kD in gray and white matter extracts, as reported for both PSP and CBD Finally, electron microscopy showed that these abnormal tau proteins formed flat twisted ribbons with a maximum diameter of 20 nanometers (nm) and a periodicity of about 200 nm, resembling those reported in CBD Based on this, we conclude that PPND is a hereditary neurodegenerative disorder characterized by neuronal and glial tau-rich inclusions formed from aggregated filaments and hyperphosphorylated tau proteins and, hence, can be subcategorized into the tauopathy group of chromosome 17-linked neurodegenerative disorders Further, since the morphologic and biochemical lesions of PPND overlap with those seen in sporadic CBD and PSP, we speculate that these disorders share common pathogenetic mechanisms

Journal ArticleDOI
TL;DR: Observations demonstrate the selective localization of RNA species to distinct pathological lesions of neurodegenerative disease brains.
Abstract: Cytoplasmic RNA species have been identified recently within neurofibrillary tangles and senile plaques of Alzheimer's disease brain. To determine whether RNA sequestration is a common feature of other lesions found in progressive neurodegenerative disorders, acridine orange histofluorescence was employed, alone or in combination with immunohistochemistry and thioflavine-S staining to identify RNA species in paraffin-embedded brain tissue sections. Postmortem samples came from 39 subjects with the following diagnoses: Alzheimer's disease, amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam, corticobasal degeneration, diffuse Lewy body disease, nor- mal controls, multiple system atrophy, Parkinson's disease, Pick's disease, progressive supranuclear palsy, and Shy- Drager syndrome. RNAs were detected in neurofibrillary tangles and neuritic senile plaques as well as in Pick bod- ies. However, Lewy bodies, Hirano bodies, and cytoplas- mic glial inclusions did not contain abundant cytoplasmic RNA species. These observations demonstrate the selective localization of RNA species to distinct pathological lesions of neurodegenerative disease brains.

Journal ArticleDOI
TL;DR: It is reported here that ischemia-induced behavioral dysfunctions were ameliorated by the neural grafts as early as 1 month post-transplantation, and the logistical and ethical concerns about the use of fetal striatal cells for transplantation therapy can be eliminated by exploiting cell line-derived human neurons as alternative graft sources.
Abstract: Stroke mortality has declined over recent decades, prompting a demand for the development of effective rehabilitative therapies for stroke survivors. This effort has been facilitated by significant progress in replicating the behavioral and neuropathological changes of authentic human cerebral ischemia using relevant animal models. Since the rodent model of middle cerebral artery occlusion mimics several motor abnormalities seen in clinical cerebral ischemia, we have utilized this model to investigate treatment strategies for stroke. The present study explored the potential benefits of neural transplantation of fetal rat striatal cells or human neurons derived from a clonal embryonal carcinoma cell line to correct the abnormalities associated with cerebral ischemia. We report here that ischemia-induced behavioral dysfunctions were ameliorated by the neural grafts as early as 1 month post-transplantation. Of note, transplantation of human neurons induced a significantly more robust recovery than fetal rat striatal grafts. Thus, the logistical and ethical concerns about the use of fetal striatal cells for transplantation therapy can be eliminated by exploiting cell line-derived human neurons as alternative graft sources. Transplantation of human neurons has a therapeutic potential for treatment of behavioral deficits associated with cerebral ischemia.

Journal ArticleDOI
TL;DR: The data show that the APP‐YAC mice do not develop AD‐like neuropathology following traumatic brain injury, and this injury does not induce elevated levels of the more amyloidogenic forms of human Aβ in these mice.
Abstract: By using transgenic mice that overexpress human beta-amyloid precursor proteins (APPs) at levels twofold higher than endogenous APPs, following introduction of the human APP gene in a yeast artificial chromosome (YAC), we examined the effects of controlled cortical impact (CCI) brain injury on neuromotor/cognitive dysfunction and the development of Alzheimer's disease (AD)-like neuropathology. Neuropathological analyses included Nissl-staining and immunohistochemistry to detect APPs, beta-amyloid (Abeta), neurofilament proteins, and glial fibrillary acidic protein, whereas Abeta levels were measured in brain homogenates from mice subjected to CCI and control mice by using a sensitive sandwich enzyme-linked immunosorbent assay. Twenty APP-YAC transgenic mice and 17 wild type (WT) littermate controls were anesthetized and subjected to CCI (velocity, 5 m/second; deformation depth, 1 mm). Sham (anesthetized but uninjured) controls (n = 10 APP-YAC; n = 8 WT) also were studied. Motor function was evaluated by using rotarod, inclined-plane, and forelimb/hindlimb flexion tests. The Morris water maze was used to assess memory. Although CCI induced significant motor dysfunction and cognitive deficits, no differences were observed between brain-injured APP-YAC mice and WT mice at 24 hours and 1 week postinjury. By 1 week postinjury, both cortical and hippocampal CA3 neuron loss as well as extensive astrogliosis were observed in all injured animals, suggesting that overexpression of human APPs exhibited no neuroprotective effects. Although AD-like pathology (including amyloid plaques) was not observed in either sham or brain-inj ured animals, a significant decrease in brain concentrations of only Abeta terminating at amino acid 40 (Abeta x-40) was observed following brain injury in APP-YAC mice (P < 0.05 compared with sham control levels). Our data show that the APP-YAC mice do not develop AD-like neuropathology following traumatic brain injury. This may be because this injury does not induce elevated levels of the more amyloidogenic forms of human Abeta (i.e., Abeta x-42/43) in these mice.

Journal ArticleDOI
01 Jan 1998-Apmis
TL;DR: This article examined a series of markers including a cell proliferation marker, neurofilament proteins, and glial fibrillary acidic protein (GFAP) in teratomas at 5, 6, 7, 9, and 12 weeks after rhesus ES cell transplantation into muscles of immunodeficient mice.
Abstract: Primate embryonic stem (ES) cells are capable of indefinite, undifferentiated proliferation and maintain the potential to differentiate to trophoblast and derivatives of embryonic endoderm, mesoderm, and ectoderm. We previously reported that neural differentiation by rhesus ES cells in teratomas includes tissue with a remarkable resemblance to neural tube (Thomson et al. 1995). Here we examine a series of markers including a cell proliferation marker, neurofilament proteins, and glial fibrillary acidic protein (GFAP) in teratomas at 5, 6, 7, 9, and 12 weeks after rhesus ES cell transplantation into muscles of immunodeficient mice. All teratomas examined contained derivatives of all three embryonic germ layers. Neural differentiation included tissues resembling neural tube and embryonic ganglia, as well as individual dispersed neurons, and brain-like gray matter. Tumours of all ages contained neurons and proliferating cells, indicated by staining for neurofilament subunits and Ki67 antigens. Younger tumours contained no or few astrocytes indicated by the absence of GFAP staining, but as these tumours developed, there was an increase in astrocyte differentiation. The results indicate that normal neural differentiation is recapitulated, in part, by the differentiation of rhesus ES cells in teratomas. The differentiation of rhesus ES cells provides an important new model for understanding human neural differentiation.

Journal ArticleDOI
TL;DR: The abundance of the distinct forms of A β reported here in formic acid extracts of AD and DS frontal cortex suggests that these Aβ species could play important roles in the deposition of Aβ inAD and DS brains.
Abstract: To gain insights into the different forms of modified amyloid beta peptides (A beta) in the Alzheimer disease (AD) and Down syndrome (DS) brain, we used two-site ELISAs with antibodies specific for isomerized (ie A beta with L-isoaspartate at positions 1 and 7) and pyroglutamate-modified (ie A beta beginning with pyroglutamate at position 3) forms of A beta to quantitate the levels of these different A beta peptides in formic acid extracts of AD and DS frontal cortex Despite variations in the proportions of distinct forms of A beta in AD and DS frontal cortex, the major species of A beta in these samples were A betaN3(pyroGlu)-42 as well as A beta x-42 (where x is a residue at position 2 or less in A beta), whereas isomerized A beta was a minor species Further, the levels of isomerized and pyroglutamate-modified forms of A beta terminating at amino acid 42 were higher than those ending at amino acid 40 The abundance of the distinct forms of A beta reported here in formic acid extracts of AD and DS frontal cortex suggests that these A beta species could play important roles in the deposition of A beta in AD and DS brains

Journal ArticleDOI
TL;DR: Both the Olfactory epithelium and central olfactory pathways represent model systems in which to study the neurobiology of these disorders, which ultimately may yield clues with diagnostic and therapeutic utility.
Abstract: Specific deficits in odor detection threshold, identification, and memory have been recognized in a variety of disorders including the neurodegenerative disorder, Alzheimer's disease (AD), and the psychiatric illness, schizophrenia, which is likely due to abnormalities in neurodevelopment. Neuropathological abnormalities in peripheral and central olfactory systems have been described in both disorder. In the olfactory, epithelium, dystrophic neurites that are immunoreactive for tau, neurofilaments and other polypeptides, as well as deposits of beta-amyloid have been observed, and these findings have been thought to contribute to the olfactory dysfunction of these disorders. However, similar findings also occur in the olfactory epithelium of many normal individuals and those with various other neurodegenerative diseases. In contrast, neuropathological studies have reported selective vulnerability of central olfactory pathways for the accumulation of neurofibrillary pathology in AD, and for cytoarchitectural, neuronal morphometric, and cytoskeletal protein abnormalities suggestive of abnormal neurodevelopment in schizophrenia. Thus, it is likely that the olfactory impairments associated with these diseases are due to damage within central olfactory pathways, and that they are further amplified by the less specific impairments associated with age-related sensory neuroepithelial abnormalities. Finally, both the olfactory epithelium and central olfactory pathways represent model systems in which to study the neurobiology of these disorders, which ultimately may yield clues with diagnostic and therapeutic utility.

Journal ArticleDOI
TL;DR: Results provide additional support to the concept that an elaborate network of cutaneous axons may play a functional role in regulation of skin inflammation and immunity.
Abstract: The present study was undertaken to characterize further the structure and function of cutaneous nerves which we have previously shown to associate with skin immune cells (Hosoi et al., Nature 1993: 363:159). Ultrastructurally, axons were prominent within the superficial dermis and epidermis in neonatal murine skin, but they were inconspicuous in adult murine and primate skin, Immunohistochemical and immunoultrastructural evaluation of normal adult human and simian skin for neural cell adhesion molecule (N-CAM), however, defined a plexus of axons surrounding superficial dermal mast cells and extending as delicate, vertical branches into the overlying epidermal la) er. Antibodies to neuropeptides substance P, calcitonin gene-related peptide, and to nerve cell-specific clathrin (LCb subunit) also reacted with this neural plexus. Double labeling disclosed intimate associations of N-CAM-positive axons with dermal chymase-positive mast cells as well as with epidermal CD1a-positive Langerhans' cells by confocal scanning laser microscopy. Functionally, capsaicin applied to forearm skin revealed by 6 h discharge of mast cell chymase and induction of E-selectin in adjacent microvascular endothelium, events consistent with release of substance P from axons and subsequent stimulation of cytokine-mediated mast cell-endothelial interaction. Identical application of capsaicin to human skin xenografted to immunodeficient mice, and thus experimentally lacking in unmyelinated axons, failed to show similar findings. These results provide additional support to the concept that an elaborate network of cutaneous axons may play a functional role in regulation of skin inflammation and immunity.

Journal ArticleDOI
TL;DR: Identifying the underlying genetic mutation will resolve the issue of genetic heterogeneity within this phenotype, and provide further insight into the mechanism of neurodegeneration in this disorder.

Journal ArticleDOI
TL;DR: The hypothesis that a distinct variety of hyperphosphorylated tau in Pick's disease compromises the long‐term viability of selectively vulnerable populations of neurons in frontal cortices that contribute to sentence processing is supported.
Abstract: We conducted cognitive, imaging, and neuropathological studies on a patient with Pick's disease. The patient was impaired at interpreting sentences with complex grammatical constructions, differing significantly from control subjects and patients with Alzheimer's disease (AD). Evaluation of regional brain functioning at rest, with positron emission tomography, revealed reduced left frontal activity compared with control subjects and AD patients. Autopsy demonstrated the classic pathology of Pick's disease, including massive neuron loss and gliosis in the frontal and cingulate cortex as well as numerous tau-positive hippocampal Pick bodies. The abnormal tau proteins were phosphorylated at the same amino acid residues as AD paired helical filament tau (PHFtau), but they exhibited a unique migration profile on western blot. Our observations support the hypothesis that a distinct variety of hyperphosphorylated tau in Pick's disease compromises the long-term viability of selectively vulnerable populations of neurons in frontal cortices that contribute to sentence processing.

Journal ArticleDOI
TL;DR: It is demonstrated that 1716 replicates in specific cell types of BALB/c mice, using immunohistochemical, immunofluorescence, in situ hybridization and virus titration studies, showing that although ICP34.5-deficient viruses are neuroattenuated, they do retain the ability to replicate in and destroy the ependyma of the murine CNS.
Abstract: Herpes simplex virus type 1 (HSV-1) variant 1716 is deleted in the gene encoding ICP34.5 and is neuroattenuated after intracranial inoculation of mice. Although the mechanism of attenuation is unclear, this property has been exploited to eliminate experimental brain tumours. Previously, it was shown that infectious 1716 was recoverable for up to 3 days after intracranial inoculation suggesting that there may be limited replication in the central nervous system (CNS). Here it is demonstrated that 1716 replicates in specific cell types (predominantly CNS ependymal cells) of BALB/c mice, using immunohistochemical, immunofluorescence, in situ hybridization and virus titration studies. While 1716-infected mice exhibited no overt signs of encephalitis, histological analysis showed a persistent loss of the ependymal lining. Thus, although ICP34.5-deficient viruses are neuroattenuated, they do retain the ability to replicate in and destroy the ependyma of the murine CNS. A detailed understanding of the mechanism(s) of neuroattenuation and limited replication could lead to the rational design of safe HSV vectors for cancer and gene therapy in the CNS.

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TL;DR: Dopamine receptor changes are not similar in PD, AD, and AD/Park, and the elevation in D1 receptors in PD may contribute to the unwanted side effects of L-dopa treatment.

Journal ArticleDOI
TL;DR: It is suggested that the paucity of PHFtau-positive neurites in the ALS/PDC plaques suggests that they reflect pathological aging rather than AD.
Abstract: The Guamanian amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is characterized by abundant neurofibrillary pathology and neuron loss. In contrast to Alzheimer’s disease (AD), where extensive neurofibrillary lesions always occur with deposits of Aβ in numerous amyloid plaques, Aβ-rich amyloid plaques are absent or rare in most ALS/PDC patients. To characterize the amyloid plaques in the latter patients, we probed plaque-rich sections of their brains by immunohistochemistry using well-characterized antibodies to specific epitopes in the N and C termini of Aβ as well as to defined epitopes in hyperphosphorylated tau (PHFtau). The results indicate that the species of Aβ in the amyloid plaques of ALS/PDC patients resemble those detected in the amyloid plaques of cognitively intact subjects with pathological aging as well as patients with AD. However, the paucity of PHFtau-positive neurites in the ALS/PDC plaques suggests that they reflect pathological aging rather than AD.