Cotton wool plaques (CWP) are large, ball-like plaques lacking dense amyloid cores that displace adjacent structures. They were first described in a Finnish kindred with early-onset Alzheimer disease (AD) with spastic paraparesis due to a presenilin-1 Δ9 mutation. We describe a case of sporadic late-onset AD with numerous neocortical CWP as well as severe amyloid angiopathy and marked leukoencephalopathy, compared with 16 cases of late-onset AD with similar degrees of amyloid angiopathy and leukoencephalopathy. The cases were studied with histologic methods and with single and double immunostaining for beta-amyloid (Aβ), paired helical filaments-tau (PHF-tau), neurofilament (NF), glial fibrillary acidic protein (GFAP), HLA-DR, and amyloid precursor protein (APP). We found that CWP were well-circumscribed amyloid deposits infiltrated by ramified microglia and surrounded by dystrophic neurites that were immunopositive for APP, but only weakly for NF and PHF-tau. Aβ1–12 was diffuse throughout the CWP, while Aβ37–42 was peripherally located and Aβ20–40 more centrally located. Two of the 16 late-onset AD cases also had CWP, but they were also admixed with diffuse plaques and plaques with dense amyloid cores. Pyramidal tract degeneration was not a consistent finding or a prominent feature in any case. The results suggest that CWP are not specific for early-onset familial AD with spastic paraparesis.
{"title":"Cotton Wool Plaques in Non‐Familial Late‐Onset Alzheimer Disease","authors":"T. Le, R. Crook, J. Hardy, D. Dickson","doi":"10.1093/JNEN/60.11.1051","DOIUrl":"https://doi.org/10.1093/JNEN/60.11.1051","url":null,"abstract":"Cotton wool plaques (CWP) are large, ball-like plaques lacking dense amyloid cores that displace adjacent structures. They were first described in a Finnish kindred with early-onset Alzheimer disease (AD) with spastic paraparesis due to a presenilin-1 Δ9 mutation. We describe a case of sporadic late-onset AD with numerous neocortical CWP as well as severe amyloid angiopathy and marked leukoencephalopathy, compared with 16 cases of late-onset AD with similar degrees of amyloid angiopathy and leukoencephalopathy. The cases were studied with histologic methods and with single and double immunostaining for beta-amyloid (Aβ), paired helical filaments-tau (PHF-tau), neurofilament (NF), glial fibrillary acidic protein (GFAP), HLA-DR, and amyloid precursor protein (APP). We found that CWP were well-circumscribed amyloid deposits infiltrated by ramified microglia and surrounded by dystrophic neurites that were immunopositive for APP, but only weakly for NF and PHF-tau. Aβ1–12 was diffuse throughout the CWP, while Aβ37–42 was peripherally located and Aβ20–40 more centrally located. Two of the 16 late-onset AD cases also had CWP, but they were also admixed with diffuse plaques and plaques with dense amyloid cores. Pyramidal tract degeneration was not a consistent finding or a prominent feature in any case. The results suggest that CWP are not specific for early-onset familial AD with spastic paraparesis.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"44 1","pages":"1051–1061"},"PeriodicalIF":0.0,"publicationDate":"2001-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88397573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
P. Burger, D. Pearl, K. Aldape, A. Yates, B. Scheithauer, S. Passe, R. Jenkins, C. James
Although there is much written about the molecular definitions of “primary” glioblastomas (GBM), there is little known about the histological features of this predominant subtype. We hypothesized that the “small cell architecture” would represent a histological feature of most primary GBMs. This was tested by comparing the presence of the small cell phenotype with the presence or absence of amplification of the epidermal growth factor receptor (EGFR), a common event in primary GBMs. After a pilot study that found a correlation between this small cell phenotype and EGFR amplification, we selected 9 pure small cell GBMs (SCGBM) and 12 non-SCGBMs to be studied for EGFR amplification by fluorescence in situ hybridization (FISH). In this set of 21 cases, 8 of 9 SCGBMs and 5 of 12 non-SCGBMs were amplified for EGFR. We then correlated the EGFR status of 79 GBMs unselected for their histological features from a set that had been previously characterized in regard to EGFR amplification. Fourteen of 21 (67%) exclusively small cell neoplasms, 8 of 25 (32%) GBMs with both small cell and non-small cell areas, and 3 of 33 (9%) non-small cell GBMs were amplified for EGFR (p = 0.0004 with an exact test). We conclude that EGFR amplification is associated with a small cell phenotype in GBMs and that SCGBMs are an important component of “primary” GBMs.
{"title":"Small Cell Architecture—A Histological Equivalent of EGFR Amplification in Glioblastoma Multiforme?","authors":"P. Burger, D. Pearl, K. Aldape, A. Yates, B. Scheithauer, S. Passe, R. Jenkins, C. James","doi":"10.1093/JNEN/60.11.1099","DOIUrl":"https://doi.org/10.1093/JNEN/60.11.1099","url":null,"abstract":"Although there is much written about the molecular definitions of “primary” glioblastomas (GBM), there is little known about the histological features of this predominant subtype. We hypothesized that the “small cell architecture” would represent a histological feature of most primary GBMs. This was tested by comparing the presence of the small cell phenotype with the presence or absence of amplification of the epidermal growth factor receptor (EGFR), a common event in primary GBMs. After a pilot study that found a correlation between this small cell phenotype and EGFR amplification, we selected 9 pure small cell GBMs (SCGBM) and 12 non-SCGBMs to be studied for EGFR amplification by fluorescence in situ hybridization (FISH). In this set of 21 cases, 8 of 9 SCGBMs and 5 of 12 non-SCGBMs were amplified for EGFR. We then correlated the EGFR status of 79 GBMs unselected for their histological features from a set that had been previously characterized in regard to EGFR amplification. Fourteen of 21 (67%) exclusively small cell neoplasms, 8 of 25 (32%) GBMs with both small cell and non-small cell areas, and 3 of 33 (9%) non-small cell GBMs were amplified for EGFR (p = 0.0004 with an exact test). We conclude that EGFR amplification is associated with a small cell phenotype in GBMs and that SCGBMs are an important component of “primary” GBMs.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"293 1","pages":"1099–1104"},"PeriodicalIF":0.0,"publicationDate":"2001-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76484731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Perry, C. Giannini, R. Raghavan, B. Scheithauer, Ruma Banerjee, L. Margraf, D. Bowers, R. Lytle, I. Newsham, D. Gutmann
Pediatric and NF2-associated meningiomas are uncommon and poorly characterized in comparison to sporadic adult cases. In order to elucidate their molecular features, we analyzed MIB-1, progesterone receptor (PR), NF2, merlin, DAL-1, DAL-1 protein, and chromosomal arms 1p and 14q in 53 meningiomas from 40 pediatric/NF2 patients using immunohistochemistry and dual-color fluorescence in situ hybridization (FISH). Fourteen pediatric (42%) patients, including 5 previously undiagnosed patients, had NF2. The remaining 19 (58%) did not qualify. All 7 of the adult patients had NF2. Meningioma grading revealed 21 benign (40%), 26 atypical (49%), and 6 anaplastic (11%) examples. Other aggressive findings included high mitotic index (32%), high MIB-1 LI (37%), aggressive variant histology (e.g. papillary, clear cell) (25%), brain invasion (17%), recurrence (39%), and patient death (17%). FISH analysis demonstrated deletions of NF2 in 82%, DAL-1 in 82%, 1p in 60%, and 14q in 66%. NF2-associated meningiomas did not differ from sporadic pediatric tumors except for a higher frequency of merlin loss in the former (p = 0.020) and a higher frequency of brain invasion in the latter (p = 0.007). Thus, although pediatric and NF2-associated meningiomas share the common molecular alterations of their adult, sporadic counterparts, a higher fraction are genotypically and phenotypically aggressive. Given the high frequency of undiagnosed NF2 in the pediatric cases, a careful search for other features of this disease is warranted in any child presenting with a meningioma.
{"title":"Aggressive Phenotypic and Genotypic Features in Pediatric and NF2‐Associated Meningiomas: A Clinicopathologic Study of 53 Cases","authors":"A. Perry, C. Giannini, R. Raghavan, B. Scheithauer, Ruma Banerjee, L. Margraf, D. Bowers, R. Lytle, I. Newsham, D. Gutmann","doi":"10.1093/JNEN/60.10.994","DOIUrl":"https://doi.org/10.1093/JNEN/60.10.994","url":null,"abstract":"Pediatric and NF2-associated meningiomas are uncommon and poorly characterized in comparison to sporadic adult cases. In order to elucidate their molecular features, we analyzed MIB-1, progesterone receptor (PR), NF2, merlin, DAL-1, DAL-1 protein, and chromosomal arms 1p and 14q in 53 meningiomas from 40 pediatric/NF2 patients using immunohistochemistry and dual-color fluorescence in situ hybridization (FISH). Fourteen pediatric (42%) patients, including 5 previously undiagnosed patients, had NF2. The remaining 19 (58%) did not qualify. All 7 of the adult patients had NF2. Meningioma grading revealed 21 benign (40%), 26 atypical (49%), and 6 anaplastic (11%) examples. Other aggressive findings included high mitotic index (32%), high MIB-1 LI (37%), aggressive variant histology (e.g. papillary, clear cell) (25%), brain invasion (17%), recurrence (39%), and patient death (17%). FISH analysis demonstrated deletions of NF2 in 82%, DAL-1 in 82%, 1p in 60%, and 14q in 66%. NF2-associated meningiomas did not differ from sporadic pediatric tumors except for a higher frequency of merlin loss in the former (p = 0.020) and a higher frequency of brain invasion in the latter (p = 0.007). Thus, although pediatric and NF2-associated meningiomas share the common molecular alterations of their adult, sporadic counterparts, a higher fraction are genotypically and phenotypically aggressive. Given the high frequency of undiagnosed NF2 in the pediatric cases, a careful search for other features of this disease is warranted in any child presenting with a meningioma.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"38 1","pages":"994–1003"},"PeriodicalIF":0.0,"publicationDate":"2001-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80137548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Zaidi, Jacquie S. Mcdonough, B. Klocke, C. B. Latham, S. Korsmeyer, R. Flavell, R. Schmidt, K. Roth
Chloroquine is a lysosomotropic agent that causes marked changes in intracellular protein processing and trafficking and extensive autophagic vacuole formation. Chloroquine may be cytotoxic and has been used as a model of lysosomal-dependent cell death. Recent studies indicate that autophagic cell death may involve Bcl-2 family members and share some features with caspase-dependent apoptotic death. To determine the molecular pathway of chloroquine-induced neuronal cell death, we examined the effects of chloroquine on primary telencephalic neuronal cultures derived from mice with targeted gene disruptions in p53, and various caspase and bcl-2 family members. In wild-type neurons, chloroquine produced concentration- and time-dependent accumulation of autophagosomes, caspase-3 activation, and cell death. Cell death was inhibited by 3-methyladenine, an inhibitor of autophagic vacuole formation, but not by Boc-Asp-FMK (BAF), a broad caspase inhibitor. Targeted gene disruptions of p53 and bax inhibited and bcl-x potentiated chloroquine-induced neuron death. Caspase-9- and caspase-3-deficient neurons were not protected from chloroquine cytotoxicity. These studies indicate that chloroquine activates a regulated cell death pathway that partially overlaps with the apoptotic cascade.
{"title":"Chloroquine‐Induced Neuronal Cell Death Is p53 and Bcl‐2 Family‐Dependent But Caspase‐Independent","authors":"A. Zaidi, Jacquie S. Mcdonough, B. Klocke, C. B. Latham, S. Korsmeyer, R. Flavell, R. Schmidt, K. Roth","doi":"10.1093/JNEN/60.10.937","DOIUrl":"https://doi.org/10.1093/JNEN/60.10.937","url":null,"abstract":"Chloroquine is a lysosomotropic agent that causes marked changes in intracellular protein processing and trafficking and extensive autophagic vacuole formation. Chloroquine may be cytotoxic and has been used as a model of lysosomal-dependent cell death. Recent studies indicate that autophagic cell death may involve Bcl-2 family members and share some features with caspase-dependent apoptotic death. To determine the molecular pathway of chloroquine-induced neuronal cell death, we examined the effects of chloroquine on primary telencephalic neuronal cultures derived from mice with targeted gene disruptions in p53, and various caspase and bcl-2 family members. In wild-type neurons, chloroquine produced concentration- and time-dependent accumulation of autophagosomes, caspase-3 activation, and cell death. Cell death was inhibited by 3-methyladenine, an inhibitor of autophagic vacuole formation, but not by Boc-Asp-FMK (BAF), a broad caspase inhibitor. Targeted gene disruptions of p53 and bax inhibited and bcl-x potentiated chloroquine-induced neuron death. Caspase-9- and caspase-3-deficient neurons were not protected from chloroquine cytotoxicity. These studies indicate that chloroquine activates a regulated cell death pathway that partially overlaps with the apoptotic cascade.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"44 1","pages":"937–945"},"PeriodicalIF":0.0,"publicationDate":"2001-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86896189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Masumi Ito, B. Blumberg, D. Mock, A. Goodman, A. Moser, H. Moser, Kirby D. Smith, J. Powers
The 2 most common forms of X-linked adreno-leukodystrophy (ALD) are the juvenile or childhood cerebral form with inflammatory demyelination and the adult adrenomyeloneuropathy (AMN) involving spinal cord tracts without significant inflammation. Modifier genes or environmental factors may contribute to the phenotypic variability. We performed immunohistochemical, an in situ polymerase chain reaction, and TUNEL analyses to identify several viruses, lymphocyte subpopulations, apoptotic cells, and effector molecules, focusing on morphologically normal white matter, dysmyelinative and acute demyelinative lesions. No distinguishing viral antigens were detected. Most lymphocytes were CD8 cytotoxic T cells (CTLs) with the α/β TCR, and they infiltrated morphologically unaffected white matter. Only a few oligodendrocytes were immunoreactive for caspase-3. MHC class II- and TGF-β-positive microglia were present. CD44, which can mediate MHC-unrestricted target cell death, was seen on many lymphocytes and white matter elements. CD1 molecules, which play major roles in MHC-unrestricted lipid antigen presentation, were noted. Our data indicate that unconventional CD8 CTLs are operative in the early stages of dysmyelination/demyelination and that cytolysis of oligodendrocytes, rather than apoptosis, appears to be the major mode of oligodendrocytic death. The presentation of lipid antigens may be a key pathogenetic element in ALD and AMN-ALD.
{"title":"Potential Environmental and Host Participants in the Early White Matter Lesion of Adreno‐Leukodystrophy: Morphologic Evidence for CD8 Cytotoxic T Cells, Cytolysis of Oligodendrocytes, and CD1‐Mediated Lipid Antigen Presentation","authors":"Masumi Ito, B. Blumberg, D. Mock, A. Goodman, A. Moser, H. Moser, Kirby D. Smith, J. Powers","doi":"10.1093/JNEN/60.10.1004","DOIUrl":"https://doi.org/10.1093/JNEN/60.10.1004","url":null,"abstract":"The 2 most common forms of X-linked adreno-leukodystrophy (ALD) are the juvenile or childhood cerebral form with inflammatory demyelination and the adult adrenomyeloneuropathy (AMN) involving spinal cord tracts without significant inflammation. Modifier genes or environmental factors may contribute to the phenotypic variability. We performed immunohistochemical, an in situ polymerase chain reaction, and TUNEL analyses to identify several viruses, lymphocyte subpopulations, apoptotic cells, and effector molecules, focusing on morphologically normal white matter, dysmyelinative and acute demyelinative lesions. No distinguishing viral antigens were detected. Most lymphocytes were CD8 cytotoxic T cells (CTLs) with the α/β TCR, and they infiltrated morphologically unaffected white matter. Only a few oligodendrocytes were immunoreactive for caspase-3. MHC class II- and TGF-β-positive microglia were present. CD44, which can mediate MHC-unrestricted target cell death, was seen on many lymphocytes and white matter elements. CD1 molecules, which play major roles in MHC-unrestricted lipid antigen presentation, were noted. Our data indicate that unconventional CD8 CTLs are operative in the early stages of dysmyelination/demyelination and that cytolysis of oligodendrocytes, rather than apoptosis, appears to be the major mode of oligodendrocytic death. The presentation of lipid antigens may be a key pathogenetic element in ALD and AMN-ALD.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"3 1","pages":"1004–1019"},"PeriodicalIF":0.0,"publicationDate":"2001-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88545689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ingmar Blümcke, Albert J. Becker, S. Normann, V. Hans, Beat M. Riederer, Stanislaw Krajewski, Otmar D. Wiestler, Guido Reifenberger, Guido Reifenberger
Microtubule-associated protein 2 (MAP2), a protein linked to the neuronal cytoskeleton in the mature central nervous system (CNS), has recently been identified in glial precursors indicating a potential role during glial development. In the present study, we systematically analyzed the expression of MAP2 in a series of 237 human neuroepithelial tumors including paraffin-embedded specimens and tumor tissue microarrays from oligodendrogliomas, mixed gliomas, astrocytomas, glioblastomas, ependymomas, as well as dysembryoplastic neuroepithelial tumors (DNT), and central neurocytomas. In addition, MAP2-immunoreactive precursor cells were studied in the developing human brain. Three monoclonal antibodies generated against MAP2A-B or MAP2A-D isoforms were used. Variable immunoreactivity for MAP2 could be observed in all gliomas with the exception of ependymomas. Oligodendrogliomas exhibited a consistently strong and distinct pattern of expression characterized by perinuclear cytoplasmic staining without significant process labeling. Tumor cells with immunoreactive bi- or multi-polar processes were mostly encountered in astroglial neoplasms, whereas the small cell component in neurocytomas and DNT was not labeled. These features render MAP2 immunoreactivity a helpful diagnostic tool for the distinction of oligodendrogliomas and other neuroepithelial neoplasms. RT-PCR, Western blot analysis, and in situ hybridization confirmed the expression of MAP2A-C (including the novel MAP2+13 transcript) in both oligodendrogliomas and astrocytomas. Double fluorescent laser scanning microscopy showed that GFAP and MAP2 labeled different tumor cell populations. In embryonic human brains, MAP2-immunoreactive glial precursor cells were identified within the subventricular or intermediate zones. These precursors exhibit morphology closely resembling the immunolabeled neoplastic cells observed in glial tumors. Our findings demonstrate MAP2 expression in astrocytic and oligodendroglial neoplasms. The distinct pattern of immunoreactivity in oligodendrogliomas may be useful as a diagnostic tool. Since MAP2 expression occurs transiently in migrating immature glial cells, our findings are in line with an assumed origin of diffuse gliomas from glial precursors.
{"title":"Distinct Expression Pattern of Microtubule‐Associated Protein‐2 in Human Oligodendrogliomas and Glial Precursor Cells","authors":"Ingmar Blümcke, Albert J. Becker, S. Normann, V. Hans, Beat M. Riederer, Stanislaw Krajewski, Otmar D. Wiestler, Guido Reifenberger, Guido Reifenberger","doi":"10.1093/JNEN/60.10.984","DOIUrl":"https://doi.org/10.1093/JNEN/60.10.984","url":null,"abstract":"Microtubule-associated protein 2 (MAP2), a protein linked to the neuronal cytoskeleton in the mature central nervous system (CNS), has recently been identified in glial precursors indicating a potential role during glial development. In the present study, we systematically analyzed the expression of MAP2 in a series of 237 human neuroepithelial tumors including paraffin-embedded specimens and tumor tissue microarrays from oligodendrogliomas, mixed gliomas, astrocytomas, glioblastomas, ependymomas, as well as dysembryoplastic neuroepithelial tumors (DNT), and central neurocytomas. In addition, MAP2-immunoreactive precursor cells were studied in the developing human brain. Three monoclonal antibodies generated against MAP2A-B or MAP2A-D isoforms were used. Variable immunoreactivity for MAP2 could be observed in all gliomas with the exception of ependymomas. Oligodendrogliomas exhibited a consistently strong and distinct pattern of expression characterized by perinuclear cytoplasmic staining without significant process labeling. Tumor cells with immunoreactive bi- or multi-polar processes were mostly encountered in astroglial neoplasms, whereas the small cell component in neurocytomas and DNT was not labeled. These features render MAP2 immunoreactivity a helpful diagnostic tool for the distinction of oligodendrogliomas and other neuroepithelial neoplasms. RT-PCR, Western blot analysis, and in situ hybridization confirmed the expression of MAP2A-C (including the novel MAP2+13 transcript) in both oligodendrogliomas and astrocytomas. Double fluorescent laser scanning microscopy showed that GFAP and MAP2 labeled different tumor cell populations. In embryonic human brains, MAP2-immunoreactive glial precursor cells were identified within the subventricular or intermediate zones. These precursors exhibit morphology closely resembling the immunolabeled neoplastic cells observed in glial tumors. Our findings demonstrate MAP2 expression in astrocytic and oligodendroglial neoplasms. The distinct pattern of immunoreactivity in oligodendrogliomas may be useful as a diagnostic tool. Since MAP2 expression occurs transiently in migrating immature glial cells, our findings are in line with an assumed origin of diffuse gliomas from glial precursors.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"45 1","pages":"984–993"},"PeriodicalIF":0.0,"publicationDate":"2001-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85774599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Minger, W. Honer, M. Esiri, J. Keene, J. Nicoll, J. Carter, T. Hope, P. Francis
Synaptic pathology is proposed to be integral to the clinical expression of Alzheimer disease (AD). Most studies have assessed only the vesicle protein synaptophysin as a measure of synaptic integrity. The interrelationships of synaptophysin, other presynaptic proteins, the cholinergic system, and severity of dementia in AD remain unclear. We studied the presynaptic proteins synaptophysin, syntaxin and SNAP-25, along with choline acetyltransferase (ChAT) activity in prefrontal cortex (BA 46) samples from 18 subjects with AD and 16 controls. Mean values of presynaptic protein immunoreactivities were significantly reduced, by 21%–28%, and ChAT activity was reduced by 41% in the AD groups. Synaptic protein immunoreactivity and ChAT activity were correlated with Mini-Mental State Examination scores obtained 1 yr prior to death. When AD cases were subgrouped into mild/moderate and severe illness at time of death, all differences in presynaptic proteins and ChAT activity were significant between controls and severe cases. However, no significant differences were detected in BA 46 between controls and mild/moderate cases. Considerable synaptic reserve or plasticity remains in BA 46 until the late stages of AD. Synaptophysin and ChAT appear to be more vulnerable in severe AD than are syntaxin or SNAP-25.
{"title":"Synaptic Pathology in Prefrontal Cortex is Present Only with Severe Dementia in Alzheimer Disease","authors":"S. Minger, W. Honer, M. Esiri, J. Keene, J. Nicoll, J. Carter, T. Hope, P. Francis","doi":"10.1093/JNEN/60.10.929","DOIUrl":"https://doi.org/10.1093/JNEN/60.10.929","url":null,"abstract":"Synaptic pathology is proposed to be integral to the clinical expression of Alzheimer disease (AD). Most studies have assessed only the vesicle protein synaptophysin as a measure of synaptic integrity. The interrelationships of synaptophysin, other presynaptic proteins, the cholinergic system, and severity of dementia in AD remain unclear. We studied the presynaptic proteins synaptophysin, syntaxin and SNAP-25, along with choline acetyltransferase (ChAT) activity in prefrontal cortex (BA 46) samples from 18 subjects with AD and 16 controls. Mean values of presynaptic protein immunoreactivities were significantly reduced, by 21%–28%, and ChAT activity was reduced by 41% in the AD groups. Synaptic protein immunoreactivity and ChAT activity were correlated with Mini-Mental State Examination scores obtained 1 yr prior to death. When AD cases were subgrouped into mild/moderate and severe illness at time of death, all differences in presynaptic proteins and ChAT activity were significant between controls and severe cases. However, no significant differences were detected in BA 46 between controls and mild/moderate cases. Considerable synaptic reserve or plasticity remains in BA 46 until the late stages of AD. Synaptophysin and ChAT appear to be more vulnerable in severe AD than are syntaxin or SNAP-25.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"113 1","pages":"929–936"},"PeriodicalIF":0.0,"publicationDate":"2001-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86766141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To study the role that immediate early gene responses may play in impaired nerve fiber regeneration in diabetes, diabetic male BB/Wor rats were subjected to sciatic nerve crush at 6 wk of diabetes. Sciatic nerve mRNA expression of IGF-I, IGF-1-receptor, NGF, and p75 (low affinity NGF receptor), as well as protein expression of C-FOS, were examined at various time points following crush injury and compared with age- and sex-matched nondiabetic BB/Wor rats. Diabetic rats showed a delay in the early peak expression of IGF-1, C-FOS, NGF, and p75. The earliest immediate gene responses were those of IGF-I and IGF-1-receptor, which peaked at 0.5 h post-crush in control rats. In diabetic rats, IGF-1 peaked at 24 h whereas IGF-1-receptor mRNA revealed no early peak. The early NGF mRNA expression showed a maximum response at 6 h and of p75 at 4 days post-crush in control rats, whereas in diabetic rats they occurred at 2 days and 6 days, respectively. C-FOS protein expression showed a maximum at 6 h in control rats and in diabetic animals an attenuated peak was present at 2 days. These data provide the first evidence that immediate early gene responses are delayed in diabetes following sciatic nerve crush injury. The delayed IGF-1 expression may affect C-FOS induction and may be responsible for the delay in the NGF response in diabetic rats. The delayed immediate early gene responses precede the previously described perturbed macrophage recruitment and delayed Wallerian degeneration in this type 1 model and provide a possible explanation for impaired nerve regeneration in diabetes.
{"title":"Altered Immediate Early Gene Expression in Injured Diabetic Nerve: Implications in Regeneration","authors":"Gang Xu, A. Sima","doi":"10.1093/JNEN/60.10.972","DOIUrl":"https://doi.org/10.1093/JNEN/60.10.972","url":null,"abstract":"To study the role that immediate early gene responses may play in impaired nerve fiber regeneration in diabetes, diabetic male BB/Wor rats were subjected to sciatic nerve crush at 6 wk of diabetes. Sciatic nerve mRNA expression of IGF-I, IGF-1-receptor, NGF, and p75 (low affinity NGF receptor), as well as protein expression of C-FOS, were examined at various time points following crush injury and compared with age- and sex-matched nondiabetic BB/Wor rats. Diabetic rats showed a delay in the early peak expression of IGF-1, C-FOS, NGF, and p75. The earliest immediate gene responses were those of IGF-I and IGF-1-receptor, which peaked at 0.5 h post-crush in control rats. In diabetic rats, IGF-1 peaked at 24 h whereas IGF-1-receptor mRNA revealed no early peak. The early NGF mRNA expression showed a maximum response at 6 h and of p75 at 4 days post-crush in control rats, whereas in diabetic rats they occurred at 2 days and 6 days, respectively. C-FOS protein expression showed a maximum at 6 h in control rats and in diabetic animals an attenuated peak was present at 2 days. These data provide the first evidence that immediate early gene responses are delayed in diabetes following sciatic nerve crush injury. The delayed IGF-1 expression may affect C-FOS induction and may be responsible for the delay in the NGF response in diabetic rats. The delayed immediate early gene responses precede the previously described perturbed macrophage recruitment and delayed Wallerian degeneration in this type 1 model and provide a possible explanation for impaired nerve regeneration in diabetes.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"45 1","pages":"972–983"},"PeriodicalIF":0.0,"publicationDate":"2001-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91529890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Recently, TX14(A), a prosaposin-derived neurotrophic peptide, was shown to prevent both large and small fiber deficits in streptozotocin diabetes. Here, the efficacy of TX14(A) in reversing established nerve conduction disorders in streptozotocin diabetes, a model of insulin deficiency, and preventing them in galactose feeding, an insulin-replete model of polyol pathway flux, was investigated. Following streptozotocin injection (50 mg/kg ip), TX14(A) treatment (1 mg/kg ip thrice weekly) was initiated in half of the animals. After 8 wk, treatment was begun in half of the untreated animals and discontinued in half of the treated animals, and the experiment continued for 6 wk. TX14(A) reversed established motor and sensory nerve conduction deficits in streptozotocin-diabetic rats and the impact of previous treatment was still evident 3 wk after withdrawal. With the onset of 40% galactose feeding, the same dose of TX14(A) was given to half of the control and half of the galactose-fed animals for 16 wk. TX14(A) was without effect in control animals but it attenuated motor and sensory nerve conduction deficits in galactose-fed rats, an effect associated with amelioration of axonal dwindling in the sciatic nerve. These observations extend the therapeutic utility of TX14(A) and highlight its potential in treating established diabetic neuropathy.
{"title":"TX14(A), a Prosaposin‐Derived Peptide, Reverses Established Nerve Disorders in Streptozotocin‐Diabetic Rats and Prevents Them in Galactose‐Fed Rats","authors":"A. Mizisin, R. Steinhardt, J. O'Brien, N. Calcutt","doi":"10.1093/JNEN/60.10.953","DOIUrl":"https://doi.org/10.1093/JNEN/60.10.953","url":null,"abstract":"Recently, TX14(A), a prosaposin-derived neurotrophic peptide, was shown to prevent both large and small fiber deficits in streptozotocin diabetes. Here, the efficacy of TX14(A) in reversing established nerve conduction disorders in streptozotocin diabetes, a model of insulin deficiency, and preventing them in galactose feeding, an insulin-replete model of polyol pathway flux, was investigated. Following streptozotocin injection (50 mg/kg ip), TX14(A) treatment (1 mg/kg ip thrice weekly) was initiated in half of the animals. After 8 wk, treatment was begun in half of the untreated animals and discontinued in half of the treated animals, and the experiment continued for 6 wk. TX14(A) reversed established motor and sensory nerve conduction deficits in streptozotocin-diabetic rats and the impact of previous treatment was still evident 3 wk after withdrawal. With the onset of 40% galactose feeding, the same dose of TX14(A) was given to half of the control and half of the galactose-fed animals for 16 wk. TX14(A) was without effect in control animals but it attenuated motor and sensory nerve conduction deficits in galactose-fed rats, an effect associated with amelioration of axonal dwindling in the sciatic nerve. These observations extend the therapeutic utility of TX14(A) and highlight its potential in treating established diabetic neuropathy.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"3 1","pages":"953–960"},"PeriodicalIF":0.0,"publicationDate":"2001-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90859499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alzheimer disease (AD) is characterized pathologically by cholinergic deficits, amyloid plaques, neurofibrillary tangles, gliosis, and neuronal and synaptic loss. The primary therapeutic approach that has arisen from the pathological analysis of AD brain has been cholinergic augmentation by cholinesterase inhibitors, which modestly improve cognitive function. Research on the underlying pathophysiological dysfunction have focussed on AD-specific processes such as amyloid precursor protein, tau, and cerebral apolipoprotein E metabolism, and more general neurodegenerative processes such as inflammation, oxidation, excitotoxicity, and apoptosis. Rational neuroprotective approaches have led to recent trials of estrogen, antioxidant and anti-inflammatory medications in AD, and to the development of anti-amyloid strategies for delaying progression or preventing development of AD.
{"title":"Alzheimer Disease Therapeutics","authors":"M. Irizarry, B. Hyman","doi":"10.1093/JNEN/60.10.923","DOIUrl":"https://doi.org/10.1093/JNEN/60.10.923","url":null,"abstract":"Alzheimer disease (AD) is characterized pathologically by cholinergic deficits, amyloid plaques, neurofibrillary tangles, gliosis, and neuronal and synaptic loss. The primary therapeutic approach that has arisen from the pathological analysis of AD brain has been cholinergic augmentation by cholinesterase inhibitors, which modestly improve cognitive function. Research on the underlying pathophysiological dysfunction have focussed on AD-specific processes such as amyloid precursor protein, tau, and cerebral apolipoprotein E metabolism, and more general neurodegenerative processes such as inflammation, oxidation, excitotoxicity, and apoptosis. Rational neuroprotective approaches have led to recent trials of estrogen, antioxidant and anti-inflammatory medications in AD, and to the development of anti-amyloid strategies for delaying progression or preventing development of AD.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"96 1","pages":"923–928"},"PeriodicalIF":0.0,"publicationDate":"2001-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84279680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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