Biomedical subjects

E G McGeer

Publications and source records attributed to E G McGeer.

At least 19 recordsLinked to original sources

PubMed1992

Apparent anterograde transport of basic fibroblast growth factor in the rat nigrostriatal dopamine system.

Five hours after the stereotaxic injection of approximately 1 ng of [125I]basic fibroblast growth factor (bFGF) into rat substantia nigra (SN), small but consistent amounts of radioactivity were found in the ipsilateral striatum (CP). None was found in the ipsilateral thalamus or contralateral CP, SN or thalamus. The amount found in the ipsilateral CP was very markedly reduced in rats injected 5-7 days after 6-hydroxydopamine-induced lesions of the nigrostriatal dopaminergic tract but was unaffected by prior kainic acid lesion of the CP. No radioactivity was found in the ipsilateral SN 5 h after injections of similar amounts of radioactive bFGF into the CP. These results are consistent with anterograde transport of bFGF in the dopaminergic nigrostriatal tract.

Animals↗

PubMed1992

High molecular weight basic fibroblast growth factor-like protein is localized to a subpopulation of mesencephalic dopaminergic neurons in the rat brain.

A rabbit antiserum (R917) was raised to a purified fraction of bovine brain basic fibroblast growth factor (bFGF). On Western blots of rat midbrain extract, the antiserum did not recognize low molecular weight forms of bFGF. Instead, it recognized a single band of 27-28 kDa. Immunohistochemically, the antiserum preferentially stained a subpopulation of calbindin-negative mesencephalic dopaminergic neurons. The positive somata were mainly packed in a ventral portion of the tegmentum including the A10 region, the ventral tegmental area and the pars compacta of the medial substantia nigra, but were also scattered in both the pars compacta and reticulata portions of the lateral substantia nigra. Processes of dendrites and axons were clearly visible. Terminal fields were located in striosomes, the dorsolateral rim of the neostriatum, the anterodorsal aspect of the nucleus accumbens shell, the infralimbic cortex, and the medial prefrontal cortex. These results suggest that trophic specialization in subpopulations may occur in all three of these dopaminergic projection systems, i.e. the nigrostriatal, mesolimbic and mesocortical pathways.

Animals↗

PubMed1992

Localization of amyloid precursor protein in selective postsynaptic densities of rat cortical neurons.

One of the hallmarks of Alzheimer pathology is extracellular deposition of beta-amyloid protein (BAP) which is derived from a larger glycoprotein called amyloid precursor protein (APP). Although APP has often been described as a surface membrane protein, such a localization has not previously been demonstrated at the light or electron microscopic level. We now report the results of immunoelectron microscopy using three specific antibodies against different synthetic fragments of APP. All three antibodies demonstrated a major localization to organelles such as the Golgi apparatus, endoplasmic reticulum and vesicular-like structures. A minor proportion of staining with all three was on selective postsynaptic membranes of asymmetrical synapses, whereas staining of presynaptic membranes was not observed. The morphological evidence suggests that one role of APP may be in association with the function of selective synapses.

Amyloid beta-Protein Precursor↗

PubMed1992

Cholinergic fiber loss occurs in the absence of synaptophysin depletion in Alzheimer's disease primary visual cortex.

The significance of cholinergic degeneration in Alzheimer's disease (AD) depends, in part, on whether it is an early event, possibly integral to the progression of the disease, or a late event, occurring only as a secondary effect of cortical degeneration. We have been studying the primary visual cortex in AD cases, on the assumption that the disease process may be retarded in this relatively-spared area, thus providing a 'window' on early AD. In this work, we have quantified acetylcholinesterase fiber density and the density of an immunohistochemical reaction for synaptophysin as measures of cholinergic and total synaptic loss, respectively, in the primary visual cortex of AD and control cases. Cholinergic fibers were depleted to 15% of control values, while synaptophysin density was not significantly altered. Cholinergic degeneration thus appears to occur in the absence of generalized synaptic loss in this area.

Acetylcholinesterase↗

PubMed1992

Appearance of paired nucleated, Tau-positive glia in patients with progressive supranuclear palsy brain tissue.

Many Tau-positive glia with paired nuclei and astrocyte type morphology were identified in three brains from patients with progressive supranuclear palsy (PSP). They were positive by Bielschowsky's and Bodian's silver staining as well as by immunostaining with Tau-2, Alz-50, anti-GFAP and anti-paired helical filament antibodies, but not with anti-ubiquitin antibody. They were predominantly localized in the striatum, thalamus and frontal cortex but were not seen in white matter and were not plentiful in areas of heavy neuronal degeneration. Electron microscopy clearly showed the nuclear pairing and localized the Tau protein to bundles suggestive of microtubules in the cytoplasm and proximal processes. Such glial cells were rarely seen in cases of other neurodegenerative diseases or neurologically normal controls. These data suggest that there is an unusual gliotic reaction in PSP in brain areas which show relatively little neuronal loss.

Aged↗

PubMed1992

Reactive microglia/macrophages phagocytose amyloid precursor protein produced by neurons following neural damage.

Kainic acid lesions of rat striatum caused an elevation of amyloid precursor protein (APP) immunoreactivity in neurons and neurites, some of which were then phagocytosed by reactive microglia/macrophages. Immunoexpression of APP was observed in neurites and neurons 1 day after the kainic injection. Four days after lesioning, immunoreactivity was still concentrated in thick and distorted neurites, but it began to appear in microglia/macrophages and in the tissue matrix. The cells were identified as microglia/macrophages by the phenotypic markers Ia (OX6), leukocyte common antigen (OX1), C3bi receptor (OX42), and macrophage marker (ED1). They were negative for the astrocytic marker glial fibrillary acidic protein (GFAP). APP immunoreactivity in these phagocytic cells was most prominent between 1 week and 1 month postlesioning. No extracellular amyloid fibrils were detectable. These results suggest that APP production is rapidly upregulated in damaged neurons and accumulates in degenerating axons. However, phagocytosis of APP by reactive microglia/macrophages in this rat model does not result in production of Alzheimer type amyloid deposits.

Amino Acid Sequence↗

PubMed1992

Senile plaques, amyloid beta-protein, and acetylcholinesterase fibres: laminar distributions in Alzheimer's disease striate cortex.

The laminar distributions of senile plaques and amyloid beta-protein (A beta P) within the striate cortex of patients with Alzheimer's disease (AD) were studied with enhanced Bielschowsky (roughly equivalent to the Campbell technique) and immunohistochemical methods. The laminar distribution of acetylcholinesterase (AChE) fibres within the striate cortex of both AD patients and control patients was studied with an enzyme histochemical method. Quantification of Bielschowsky-stained plaque numbers along intersect lines drawn parallel to laminar boundaries revealed a significant aggregation of plaques at the interface of layers IVc and V. Lines drawn through layer VI intersected significantly fewer plaques than lines through other laminae. Immunoperoxidase staining for A beta P revealed a similar distribution of senile plaques, and addition, prominent, diffuse deposits of A beta P within layers I and IVc. AChE fibres were markedly depleted in the striate cortex of AD cases. In control cases, AChE fibres were, like A beta P immunoreactivity, concentrated within layer I and IVc. The results indicate that enhanced silver methods may not reveal the complete distribution of A beta P. The codistribution of A beta P-immunoreactive diffuse amyloid deposits and AChE fibres to the same cortical laminae is consistent with the possibility that these deposits may be formed from degenerating cholinergic elements. The formation of a line of senile plaques at the interface of two cortical laminae within the striate cortex, in an anatomically analogous situation to a similar line of plaques within the dentate gyrus, suggests that formation of well-defined plaques may be accelerated by the interaction of specific neuronal systems.

Acetylcholinesterase↗

PubMed1992

Lewy bodies in Parkinson's disease are recognized by antibodies to complement proteins.

The substantia nigra (SN) in 11 Parkinson's disease (PD) patients and 5 neurologically normal controls was examined immunohistochemically using antibodies to various proteins of the complement system. In PD, but not in control SN, intra- and extraneuronal Lewy bodies and dendritic spheroid bodies were stained with anti-human C3d, C4d, C7 and C9 antibodies, but not with antibodies to C1q, fraction Bb of factor B or properdin. Axonal spheroid bodies in the nigrostriatal tract were not stained by any of the complement antibodies. However, complement-activated oligodendroglia were revealed by anti-C3d and anti-C4d antibodies in the PD substantia nigral area. These data indicate that some pathological structures in PD activate the classical complement pathway.

Aged↗

PubMed1992

Identification and characterization of a large human brain gene whose expression is increased in Alzheimer disease.

A cDNA clone that was isolated from a human substantia innominata cDNA library is described. By Northern hybridization analysis, a 15.5 kilobase (kb) transcript was identified by this clone in RNA samples from several brain regions, but not in RNA samples from white matter, liver or placenta. Hybridization to human genomic DNA revealed a pattern indicative of a single copy gene. DNA sequence analysis showed 3.0 kb of 3' untranslated region with no significant open reading frame. An additional cDNA clone, representing a section of an alternate form of this transcript, was isolated that contained an additional 1.5 kb at the 3' end. Using a nuclease protection assay, the expression of this gene was found to be increased by 30% in Alzheimer disease temporal cortex RNA samples compared to temporal cortex RNA samples from normal controls, but to be at equivalent levels in Alzheimer disease, as compared to normal control, substantia innominata RNA samples. This assay also showed that this gene was expressed at 3.5-fold higher levels in normal substantia innominata than in normal cerebellum. In situ hybridization analysis showed that the transcript could be detected in cerebellar neurons.

Aged↗

PubMed1992

Decreased prostaglandin synthesis in postmortem cerebral cortex from patients with Alzheimer's disease.

The syntheses of prostaglandin (PG) F2 alpha, E2 and D2, and thromboxane (TX) B2 from [14C]arachidonic acid were studied in frontal cortex of human control and Alzheimer's disease (AD) brains using the microsomal fractions. Under the assay conditions employed, it was found that the major metabolite of [14C]arachidonic acid was PGE2 accounting for 63% of total prostanoid production; PGF2 alpha accounted for 21.5%, TXB2 for 9%, and PGD2 for 6.5%. When AD samples were compared to control samples, microsomal PG synthesis was significantly decreased, with reduced production of PGE2, PGF2 alpha and PGD2. Such decreases in AD brain seem unrelated to age, sex, postmortem delay and, as far as could be determined, antemortem state. In both control and Alzheimer groups, a history of anti-inflammatory therapy seemed to correlate with increased PG synthesis.

Aged↗

PubMed1991

Cytomegalovirus infection of the developing brain alters catecholamine and indoleamine metabolism.

Tissue concentrations of noradrenaline (NA), serotonin (5-HT), dopamine (DA) and selected metabolites were measured in the spinal cord, cerebellum, cerebral cortex and caudate-putamen of developing mice following intraventricular inoculation with murine cytomegalovirus (MCMV) on postnatal day 10. MCMV-infected animals exhibited transient signs of neurological impairment, including apparent hypertonicity of hindlimb extensors and abnormal gait, beginning on days 14-16 and continuing for 3-5 days. At the onset of neurological impairment, tissue concentrations of NA were significantly reduced in the spinal cord (20%), cerebellum (32%) and cerebral cortex (40%) of infected animals. Levels of 5-HT were significantly increased in the caudate-putamen (50%), while 5-hydroxyindoleacetic acid (5-HIAA) was increased in both the spinal cord (94%) and caudate-putamen (65%). The ratio of 5-HIAA/5-HT, which is frequently used as an estimate of turnover of 5-HT, was significantly increased in the spinal cord (90%) at the onset of neurological impairment. In the caudate-putamen of MCMV-infected animals, there were significant increases in the tissue levels of DA (37%), homovanillic acid (HVA, 41%) and 3,4-dihydroxyphenylacetic acid (DOPAC, 34%). All neurochemical parameters were normal in the MCMV-infected animals by postnatal day 70, approximately 50 days after the resolution of neurological signs. These results indicate transient alterations in monoamine metabolism in the developing nervous system during the pathogenesis of cytomegalovirus-induced movement and postural disorders.

Animals↗

PubMed1991

Detection of the membrane inhibitor of reactive lysis (CD59) in diseased neurons of Alzheimer brain.

The membrane inhibitor of reactive lysis (MIRL) protects host cells from complement-mediated lysis. It was detected immunohistochemically in tangled neurons and dystrophic neurites of Alzheimer disease (AD) tissue in a pattern highly similar to that observed for the membrane attack complex of complement, C5b-9. MIRL was also detected in cultured IMR-32 neuroblastoma cells. The mRNA for MIRL was detected in RNA extracts of both AD and normal brain. These data provide the first evidence of brain neuronal expression of MIRL and its upregulation in neurons exposed to complement attack. They are consistent with the previously advanced hypothesis that complement-mediated neuronal injury may play a role in AD.

Alzheimer Disease↗

PubMed1991

Reactions of the immune system in chronic degenerative neurological diseases.

Elements consistent with a cell mediated immune response were identified immunohistochemically in amyotrophic lateral sclerosis (ALS) spinal cord and Alzheimer disease (AD) hippocampus. T helper/inducer and cytotoxic/suppressor lymphocytes were detected in affected tissues in both diseases. In addition, abundant reactive microglia were found expressing the major histocompatibility glycoproteins HLA-A,B,C and HLA-DR, as well as receptors for the Fc chain (Fc gamma R1), for complement 3 and 4, and for vitronectin. In AD, the complement proteins C1q, C4d, C3d and C5b-9 were found on dystrophic neurites, neuropile threads and some neurofibrillary tangles. In ALS, the only complement proteins identified were C4d and C3d. The integrin ligands vitronectin and ICAM-1 were also identified in affected tissues in both diseases.

Alzheimer Disease↗

PubMed1991

Parallel distributed processing and neural networks: origins, methodology and cognitive functions.

Parallel Distributed Processing (PDP), a computational methodology with origins in Associationism, is used to provide empirical information regarding neurobiological systems. Recently, supercomputers have enabled neuroscientists to model brain behavior-relationships. An overview of supercomputer architecture demonstrates the advantages of parallel over serial processing. Histological data provide physical evidence of the parallel distributed nature of certain aspects of the human brain, as do corresponding computer simulations. Whereas sensory networks follow more sequential neural network pathways, in vivo brain imaging studies of attention and rudimentary language tasks appear to involve multiple cortical and subcortical areas. Controversy remains as to whether associative models or Artificial Intelligence symbolic models better reflect neural networks of cognitive functions; however, considerable interest has shifted towards associative models.

Artificial Intelligence↗

PubMed1990

Relative sparing in Parkinson's disease of substantia nigra dopamine neurons containing calbindin-D28K.

The distribution of calbindin-D28K (CaBP)-positive neurons was investigated by immunohistochemistry in 4 controls, 5 cases of Parkinson's disease and a single case of strionigral degeneration. CaBP-positive neurons were preferentially localized to the mediodorsal portion of the substantia nigra pars compacta (SNC) in the beta layer, while CaBP-negative, melanin-positive neurons were concentrated in the ventrolateral SNC in the alpha layer. In Parkinson's disease and the case of strionigral degeneration, there was a relative sparing of the CaBP-positive neurons compared with CaBP-negative, pigmented neurons. These data imply that CaBP may confer some protection to SNC dopaminergic neurons against the pathological process which is responsible for Parkinson's disease and strionigral degeneration.

Aged↗

PubMed1990

Lamotrigine protects against kainate but not ibotenate lesions in rat striatum.

Pretreatment of rats with 8-16 mg/kg of lamotrigine 1 h before intrastriatal injections of 2 nm of kainic acid significantly attenuated the neurotoxicity as evidenced by measurements of striatal choline acetyltransferase and glutamate decarboxylase activities. No significant effect was seen on the toxicity of intrastriatal injections of quinolinic acid or ibotenic acid. These differential effects are further evidence that these neurotoxins act at different excitatory amino acid receptors and that the neurotoxicity of kainate is uniquely dependent on neuronally released glutamate.

Animals↗

PubMed1990

Correlations of regional postmortem enzyme activities with premortem local glucose metabolic rates in Alzheimer's disease.

Correlations were sought between local cerebral metabolic rates (LCMRs) for glucose in various regions of the cortex, determined in premortem PET scans, with the regional activities of choline acetyltransferase (ChAT), acetylcholinesterase (AChE), beta-glucuronidase (Gluc, a probable index of reactive gliosis), and phosphate-activated glutaminase (PAG, a possible indice of the large pyramidal neurons) measured on postmortem tissue. Significant negative correlations between LCMRs and Gluc activities were found in 6 PET-scanned cases of Alzheimer disease (AD), and positive correlations of LCMRs with PAG were found in 5. By contrast, a positive correlation with ChAT and AChE was found in only 1. The results are consistent with the metabolic deficits in AD being primarily a reflection of local neuronal loss and gliosis. Similar data on two cases of Huntington's disease showed no significant correlations, while 1 patient with Parkinson dementia showed a significant (negative) correlation only with Gluc.

Aged↗

PubMed1990

gamma-Glutamyltransferase activity is unchanged in acutely quinolinate-lesioned rat neostriatum but is elevated in Huntington's disease caudate.

gamma-Glutamyltransferase (GGT; gamma-glutamyl transpeptidase) was measured in the neostriata of rats 5-7 days after local injections of 0-150 nmol of quinolinic acid. In contrast to the high levels seen in studies on the caudate in a few Huntington's disease cases, GGT activity showed no significant relation to the amount of quinolinic acid injected or to the extent of neuronal loss, as indicated by assays of choline acetyltransferase and glutamate decarboxylase on the same striatal homogenates. The chronicity of the degenerative disease, contrasted with the acuteness of the lesion, may explain the difference.

Animals↗