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C W Cotman

Publications and source records attributed to C W Cotman.

At least 163 records · Page 9Linked to original sources
PubMed1994

Selective increase of NMDA-sensitive glutamate binding in the striatum of Parkinson's disease, Alzheimer's disease, and mixed Parkinson's disease/Alzheimer's disease patients: an autoradiographic study.

Parkinson's disease (PD) and Alzheimer's disease (AD) may share certain abnormalities since a subset of PD patients suffer from dementia, and some AD individuals show extrapyramidal symptoms. In vitro quantitative autoradiography was used to examine different subtypes of excitatory amino acid (EAA) receptors (NMDA, KA, and AMPA) and dopamine transporter sites in the striatum (caudate, putamen) and nucleus accumbens (NAc) from idiopathic PD, pure AD, and mixed PD/AD patients. PD and AD groups, and to a lesser extent the PD/AD groups, showed substantially increased binding to NMDA receptors in the striatum and NAc. No statistically significant changes in binding to KA and AMPA receptors were found in any patient group. 3H-mazindol binding to dopamine transporter sites was significantly decreased in the striatum and NAc of PD and PD/AD patients, but only in the putamen and NAc of AD patients. The data indicate that (1) the majority of striatal EAA receptors are not located on dopaminergic nigrostriatal nerve terminals, and (2) elevated binding to striatal NMDA receptors correlates with binding to dopamine transporter sites in PD patients, but not in AD and PD/AD individuals. Thus, the mechanisms of NMDA receptor changes in the striatum of AD and PD patients may be different. However, it is postulated that increased binding to NMDA receptors in Parkinson and Alzheimer striatum occurs in response to an insult(s) within the striatothalamocortical circuits and that this may contribute to the clinical similarities described for subsets of PD and AD patients.

Aged↗
PubMed1993

Surface determinants of neuronal survival and growth on self-assembled monolayers in culture.

We have studied the modulation of hippocampal neuron morphological development in vitro using surfaces derivatized with aminosilane self-assembled monolayers (SAMs). The efficacies of model SAMs, alone, or in combination with adsorbed heparan sulfate glycosaminoglycan (HS), are related to the physical and chemical properties of the surfaces. These properties are determined using X-ray photoelectron spectroscopy (XPS), optical ellipsometry, and wettability measurements. The ability of surfaces to promote somal adhesion and the maintenance of discrete neurites appears to be sensitive to the density and accessibility of positively charged amine or amide groups, and has less of an apparent relationship to the surface density of uncharged amines. Aromatic ring-containing aminosilanes are ineffective in promoting neuron growth, while adsorbed HS augments the neurite-promoting capacity of one marginally adhesive SAM. These results are relevant to an improved understanding of the 'non-specific' contributions of the substrate in affecting neuronal development and the rational design of model surface coatings for neuronal culture.

Animals↗
PubMed1993

Co-distribution of protease nexin-1 and protease nexin-2 in brains of non-human primates.

The protease nexins are protease inhibitors which regulate key blood coagulation proteases and which appear to be involved in certain physiological and pathological processes in the brain. Protease nexin-1 (PN-1), a potent inhibitor of thrombin, can regulate processes on cultured neurons and astrocytes. Protease nexin-2 (PN-2), a potent inhibitor of coagulation factor XIa, is identical to the secreted form of the Alzheimer's amyloid beta-protein precursor. In the present studies, PN-1 and PN-2 were analyzed in different tissues of monkey using monoclonal antibodies for either quantitative immunoblotting or specific [125I]protease-binding assays. PN-1 was detected only in brain. PN-2 was most abundant in brain, followed by testis and to a lesser extent kidney. Other tissues examined including spinal cord, heart, pancreas, spleen, liver, lung and muscle were essentially devoid of both PN-1 and PN-2. Within the brain, the levels of PN-1 and PN-2 were highest in the parietal cortex and lowest in the cerebellum and brainstem. The thalamus and striatum contained intermediate amounts of both proteins. Aged Cebus monkey cerebral cortical tissue contained slightly lower levels of PN-1 than did the middle-aged or young monkey tissue. The co-distribution of PN-1 and PN-2 in brain, their relative abundance in brain cortex, and previous studies on their functions suggest that in the brain they may participate in the regulation of blood coagulation and cell growth and differentiation.

Amyloid beta-Protein Precursor↗
PubMed1993

Identification and distribution of axonal dystrophic neurites in Alzheimer's disease.

Dystrophic neurites (DNs) are one of the neuropathological characteristics of Alzheimer's disease (AD). Previously, it has been suggested that tau-immunoreactive DNs are of dendritic origin and that axonal and dendritic dystrophic neurites are morphologically indistinguishable. In the present study, two monoclonal antibodies, tau-1 and PHF-1, were used to examine sections of the hippocampal formation from AD and normal aged brains. Both antibodies stained dendritic DNs as well as axonal DNs. Axonal DNs were clearly seen in axonal fiber tracts, white matter and hippocampal terminal regions. Axonal DNs arising from neurofibrillary tangles were easily detected in CA3 and CA1. The morphological appearance of axonal DNs varied with the neuron type from which it originated. The most distinctive feature of tau-1 or PHF-1 immunostained axonal DNs was their uneven contour, alternating swollen and shrunken segments and short rod or cone shaped fragments. In contrast, dendritic dystrophic neurites are thicker and more tortuous. It appears that while DNs are both dendritic and axonal in origin, axonal DNs are more prevalent and widespread in the AD brain than previously realized and may represent one of the main pathological lesions in AD.

Aged↗
PubMed1993

beta-Amyloid peptides induce degeneration of cultured rat microglia.

Microglia are often associated with senile plaques, a primary pathological hallmark of Alzheimer's disease (AD) that consists largely of insoluble deposits of beta-amyloid (A beta) protein. Synthetic A beta peptides have been shown to induce neurite dystrophy and neuronal death in vitro when the peptides are assembled into aggregates. We now report that assembled A beta peptides induce morphological evidence of degeneration in process-bearing microglia in vitro, as well as metabolic dysfunction in microglial cultures, but a non-assembling scrambled sequence A beta peptide does not.

Amyloid beta-Peptides↗
PubMed1993

Carbachol increases intracellular free calcium in cultured rat microglia.

Microglia are resident macrophages in the CNS and have been shown to exhibit immune system responses common to other macrophages, including phagocytosis, secretion of superoxide anions, and secretion of regulatory and trophic factors such as interleukin-1. Phagocytosis and oxidative burst by macrophages are often reported to be preceded by an increase in cytosolic free calcium. In addition, a variety of compounds, including neuroactive peptides, have been shown to elicit such calcium responses in various macrophage preparations. The results presented demonstrate that cultured rat microglia respond to exposure to carbachol with an increase in intracellular free calcium which is atropine-sensitive and the result of the release of calcium from intracellular stores. Norepinephrine also induced increases in free calcium, whereas the metabotropic glutamate agonist 1S,3R-ACPD, serotonin, adenosine and ATP did not. These results suggest that microglia can respond to select neurotransmitters, and that there may exist a signaling loop between neurons and microglia. Furthermore, since cholinergic fibers have been shown to infiltrate neuritic plaques in Alzheimer's disease (AD) and microglia have been reported to be activated in plaques, these results suggest that interactions between select neurotransmitters and microglia may play a key role in neurodegenerative diseases.

Animals↗
PubMed1993

Apoptosis is induced by beta-amyloid in cultured central nervous system neurons.

The molecular mechanism responsible for the neurodegeneration in Alzheimer disease is not known; however, accumulating evidence suggests that beta-amyloid peptide (A beta P) contributes to this degeneration. We now report that synthetic A beta Ps trigger the degeneration of cultured neurons through activation of an apoptotic pathway. Neurons treated with A beta Ps exhibit morphological and biochemical characteristics of apoptosis, including membrane blebbing, compaction of nuclear chromatin, and internucleosomal DNA fragmentation. Aurintricarboxylic acid, an inhibitor of nucleases, prevents DNA fragmentation and delays cell death. Our in vitro results suggest that apoptosis may play a role in the neuronal loss associated with Alzheimer disease.

Amyloid beta-Peptides↗
PubMed1993

Stimulation of phosphoinositide hydrolysis by trans-(+/-)-ACPD is greatly enhanced when astrocytes are cultured in a serum-free defined medium.

Recent studies have demonstrated that astrocytes have much greater abilities to produce and respond to signalling molecules in the CNS than had been previously estimated. We now report a dramatic enhancement in the ability of a glutamate metabotropic receptor agonist, 1-aminocyclopentane-trans-(+/-)-1,3-dicarboxylic acid (trans-(+/-)-ACPD, to stimulate phosphoinositide hydrolysis in astrocytes cultured in a serum-free defined medium compared with astrocytes cultured in conventional serum-containing medium (43.2 +/- 3.6 vs. 3.2 +/- 0.48-fold of basal, respectively). This enhancement was selective to trans-(+/-)-ACPD as little or no difference in the response to carbachol or norepinephrine was seen between the two culture conditions. These results indicate a great potential for the phosphoinositide pathway in astrocyte glutamatergic signal transduction.

Animals↗
PubMed1993

Increased sensitivity to adenosine in the rat dentate gyrus molecular layer two weeks after partial entorhinal lesions.

The molecular layer of the dentate gyrus exhibits extensive circuit and receptor reorganization after entorhinal lesions and in Alzheimer's disease, including decreased adenosine (A1) receptor binding in the terminal zone of damaged perforant path fibers. We examined the adenosine-sensitivity of evoked synaptic activity recorded from the rat dentate gyrus molecular layer in hippocampal slices prepared after electrolytic lesions were placed in approximately the middle third of the entorhinal cortex. Extracellular field potentials (EFPs) recorded in slices prepared from animals two days post-lesion were small, upward-going, and exhibited paired-pulse potentiation, but by two weeks post-lesion EFPs had recovered to large, downward-going responses that exhibited paired-pulsed depression. EFPs recorded from two week post-lesion slices were about 2-fold more sensitive (P < or = 0.05) to exposure to adenosine when compared to EFPs recorded from slices from unlesioned animals. Adenosine-induced reduction of paired-pulse depression was similar between unlesioned and post-lesion slices. AChE histochemistry performed after recording revealed dense staining in the dentate gyrus molecular layer of post-lesion slices as compared to slices from unlesioned animals, confirming that sprouting of cholinergic fibers occurred as expected from previous entorhinal lesion studies. Autoradiography performed on adjacent slices showed a decrease in binding to A1-adenosine receptors in the dentate gyrus molecular layer in post-lesion slices as compared to slices from unlesioned animals, indicating that there was a loss of presynaptically located A1-adenosine receptors on damaged perforant pathway terminals. These results indicate that, in addition to the recovery of the major excitatory signal to the hippocampus after entorhinal cell loss, this signal is more sensitive to modulation by adenosine, suggesting an increase in A1-adenosine receptor efficacy in the reinnervated region.

Acetylcholinesterase↗
PubMed1993

Distribution of fibroblast growth factor 5 mRNA in the rat brain: an in situ hybridization study.

Fibroblast growth factors (FGFs) are potent growth factors with roles in the brain ranging from development to adult plasticity. FGF-5 is a newly described member of the fibroblast growth factor family. In order to evaluate a possible role of FGF-5, we have examined the locus of synthesis of FGF-5 in the rat brain. We have used in situ hybridization of 35S-labelled RNA probe complementary to FGF-5 mRNA. FGF-5 mRNA was present in neurons in select regions of the rat brain. FGF-5 mRNA expression was particularly intense in the olfactory bulb within periglomerular elements and the mitral cell layer. The primary olfactory cortex also showed a robust expression of FGF-5 mRNA mostly within layer II. In the hippocampal formation, the greatest labelling of FGF-5 mRNA occurred in hippocampal pyramidal cells within subfields CA3 and secondarily within subfields CA1, CA2 and CA4. The dentate gyrus granule cells displayed a modest hybridization signal. The cerebral cortex (neocortex) showed a light labelling throughout its rostro-caudal extent mostly within external layers. The entorhinal cortex showed a higher FGF-5 mRNA expression as compared to the neocortex and signal appeared more intense in layer II. In general, FGF-5 mRNA was shown to be localized mostly in limbic structures, suggesting that FGF-5 may play a role in limbic system function or dysfunction.

Animals↗
PubMed1993

Effects of aging on NMDA and MK801 binding sites in mice.

[3H]MK801 binding was significantly reduced in three cortical and two subcortical regions in 30-month-old C57Bl mice, as compared to 3-month-olds. NMDA binding sites showed significant reductions with aging in sixteen of nineteen brain regions. These results suggest that, in a majority of cortical and hippocampal regions, decreases in binding to NMDA sites with aging may be due to factors other than cell loss.

Aging↗
PubMed1993

Trophic effects of interleukin-4, -7 and -8 on hippocampal neuronal cultures: potential involvement of glial-derived factors.

The main purpose of the present study was to determine whether specific lymphokines may be neurotrophic, by testing their effects on the survival of hippocampal neuronal cultures. Previous studies have shown that a variety of interleukins may be neurotrophic or neurotoxic, depending upon the culture conditions, as well as the concentration and time of exposure to the interleukins. The present results indicate that interleukins-4, -5, -7 and -8 significantly enhance neuronal survival of hippocampal cultures. These effects were concentration-dependent and reached maximal levels with concentrations of the lymphokines ranging from 500 to 1,000 ng/ml. With increased exposure to the lymphokines, the increase in neuronal survival compared to control untreated cultures persisted. Moreover, with IL-7, and particularly IL-8, this increased survival was more pronounced in the longer-term cultures. Thus, in the 7-day-old cultures, the magnitude of the increase in survival in the IL-8-treated cultures ranged from 93 to 123% compared to 56-68% in the 3-day-old cultures. In contrast, other lymphokines tested, interleukin-3 and -6, did not affect the survival of 1-day-old cultures and caused significant reductions in the longer-term cultures. Although the mechanism(s) of the neurotrophic effects of interleukins-4, -7 and -8 are not clear, an indirect effect mediated by proliferating glia in the treated cultures may be possible. Clearly, exposure to interleukins-4, -7 and -8 resulted in a marked increase in the number of astroglia and microglia compared to the control cultures, an effect that was amplified with increased time in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Perineuronal satellitosis in the human hippocampal formation.

A previously unreported example of perineuronal satellitosis in the medial CA1 and adjacent subiculum in the human hippocampal formation is described. This phenomenon is characterized by a clustering of glial cells in relation to the perikarya of a subpopulation of neurons in the deep pyramidal layer and around most neurons scattered in the stratum oriens and subcortical white matter. Most of the perineuronal satellite glia were identified as oligodendrocytes based on their nuclear chromatin patterns and antigenic properties. Satellite oligodendrocytes were mostly of the medium dense variety. A type of satellite glia with nuclear features of the dark oligodendrocyte could not be identified unequivocally using the antigenic criteria employed in this study.

Adult↗
PubMed1993

Neuritic involvement within bFGF immunopositive plaques of Alzheimer's disease.

As early as 1928, Cajal suggested that plaques contain a trophic substance which attracts neurites. Recently, basic fibroblast growth factor (bFGF) levels were shown to be elevated in Alzheimer's disease (AD) and localized to plaques and neurofibrillary tangles. We sought to clarify the subtype of plaques which contain bFGF and provide more detail on bFGFs neuronal and vascular localization in normal aged brain, AD brain, and Down's syndrome (DS) brain. We combined double-labeling immunocytochemistry for bFGF with heparan sulfate glycosaminoglycans, beta-amyloid, and thioflavine fluorescence. In addition, the neuritic markers tau-1 and PHF-1 were combined with bFGF staining. Eleven AD, five nondemented controls, and four DS cases were examined. Most bFGF immunopositive plaques contained numerous dystrophic fibers, indicating they were of the neuritic subtype. We also detected a variety of bFGF-positive cells, including hilar, dentate granule, pyramidal, and stellate neurons, as well as astrocytes. The basement membrane of large and small arterioles also contained bFGF. bFGF immunoreactivity within neurons, astrocytes and the vasculature was increased in AD cases relative to controls. Immunoreactivity within the DS cases was intermediate. These results suggest that bFGF is up-regulated in AD and support the hypothesis that bFGF may attract neurites into plaques. Alternatively, an injured neurite may induce bFGF production by responding glia, resulting in further neuritic attraction.

Aged↗
PubMed1993

Adenosine, L-AP4, and baclofen modulation of paired-pulse potentiation in the dentate gyrus: interstimulus interval-dependent pharmacology.

Paired-pulse potentiation of the glutamate-mediated excitatory postsynaptic potential (EPSP) recorded in the dentate gyrus molecular layer is thought to be mediated presynaptically. It is known that the activation of adenosine (A1) and GABAB receptors results in the reduction of glutamate release in the dentate molecular layer via presynaptic mechanisms. To examine possible modulatory roles of these receptors on paired-pulse potentiation, we examined the effects of adenosine and baclofen (a GABAB agonist) on paired-pulse potentiation using extracellular recording from the lateral perforant path in rat hippocampal slices maintained in vitro. We compared these effects with those of L-alpha-amino-4-phosphonobutyric acid (L-AP4) over a wide range of interstimulus intervals (ISIs). L-AP4 enhanced paired-pulse potentiation over the full range of ISIs tested (40-800 ms), whereas adenosine enhanced paired-pulse potentiation only at ISIs of 40-100 ms. In contrast, baclofen reduced paired-pulse potentiation only at ISIs of 400-800 ms. Furthermore, baclofen increased the amplitude of lateral perforant path field potentials, previously reported to be baclofen-insensitive. These results suggest that paired-pulse potentiation can be modulated through the activation of adenosine and baclofen receptors, indicate that this modulation is dependent on ISI, and show that there are at least two pharmacologically separable components of paired-pulse potentiation in the dentate gyrus.

Adenosine↗
PubMed1993

Cultured GABA-immunoreactive neurons are resistant to toxicity induced by beta-amyloid.

Neurodegeneration in Alzheimer's disease is characterized by a selective loss of particular cell populations. Several recent lines of evidence suggest that beta-amyloid protein directly contributes to the disease's progression and is likely responsible for the observed pattern of neuronal death. We have previously demonstrated that aggregated beta-amyloid peptides are neurotoxic to cultured neurons. We now report that a neuronal population exhibiting GABA-immunoreactivity is resistant to beta-amyloid-induced toxicity in vitro, a finding consistent with observations in the Alzheimer brain. Determination of the intrinsic neuronal characteristics responsible for resistance to beta-amyloid may prove beneficial in both understanding the mechanism(s) of beta-amyloid neurotoxicity and halting the disease's progressive neuronal degeneration.

Alzheimer Disease↗
PubMed1993

Reduced density of adenosine A1 receptors and preserved coupling of adenosine A1 receptors to G proteins in Alzheimer hippocampus: a quantitative autoradiographic study.

Binding to adenosine A1 receptors and the status of their coupling to G proteins were studied in the hippocampus and parahippocampal gyrus of Alzheimer individuals and age-matched controls. The binding to A1 receptors was compared with binding to the N-methyl-D-aspartate receptor complex channel-associated sites (labeled with (+)-[3H]5-methyl-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5,10-imine maleate). In vitro quantitative autoradiography demonstrated a similar anatomical distribution of A1 receptors labeled either with an agonist ((-)-[3H]phenylisopropyladenosine) or antagonist ([3H]8-cyclopentyl-1,3-dipropylxanthine) in the brains of elderly controls. In Alzheimer patients, significant decreases in the density of both agonist and antagonist binding sites were found in the molecular layer of the dentate gyrus. Decreased A1 agonist binding was also observed in the CA1 stratum oriens and outer layers of the parahippocampal gyrus, while reduced antagonist binding was found in the subiculum and CA3 region. Reduced density of the N-methyl-D-aspartate receptor channel sites was found in the CA1 region and parahippocampal gyrus. The reductions in binding to adenosine A1 and N-methyl-D-aspartate receptors were due to a decrease in the density of binding sites (Bmax), and not changes in receptor affinity (KD). In both elderly control and Alzheimer subjects, GTP substantially reduced the density of A1 agonist binding sites with a concomitant increase in the KD values, whereas antagonist binding was unaffected by GTP. The results suggest that adenosine A1 receptor agonists and antagonists recognize overlapping populations of binding sites. Reduced density of A1 receptors in the molecular layer of the dentate gyrus most probably reflects damage of the perforant path input in Alzheimer's disease, while altered binding in the CA1 and CA3 regions is probably due to loss of intrinsic neurons. Similar effects of GTP on binding to A1 receptors in control and Alzheimer individuals suggest lack of alterations in coupling of A1 receptors to G proteins in Alzheimer's disease, thus supporting the notion of normal receptor coupling to their effector systems in Alzheimer's disease.

Adenosine↗