The current status of the cortical cholinergic system in Alzheimer's disease and Parkinson's disease.
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Acetylcholinesterase↗
Biomedical subjects
J A Edwardson
Publications and source records attributed to J A Edwardson.
Cholinergic receptors in cognitive disorders.
Cholinergic receptors (muscarinic subtypes M1 and M2, and putative nicotinic binding) have been examined in the hippocampus obtained at autopsy from a variety of patients with cognitive disorders (Alzheimer's, Parkinson's, and Huntington's diseases, Down's Syndrome and alcoholic dementia) and compared with neurologically normal controls and cases of Motor Neuron disease. In all of the disorders associated with a pre-synaptic cortical cholinergic deficit reflected by an extensive loss of choline acetyltransferase (Alzheimer's disease, Parkinson's disease and Down's Syndrome) there was a substantial reduction in the binding of (3H) nicotine to the nicotinic receptor. By contrast reductions in both muscarinic subtypes (M1 and M2) were apparent to only a moderate extent in Alzheimer's disease, whereas in Parkinson's disease binding was significantly increased (apparently not in relation to anti-cholinergic drug treatment) in the non-demented but not demented cases. A further abnormality detected in Alzheimer's disease but not the other disorders investigated was a decrease in an endogenous inhibitor of nicotinic binding, the identity of which is as yet unknown but which may be a candidate for a possible endogenous modulator of the nicotinic receptor. These observations suggest that in Alzheimer's disease not only muscarinic but also nicotinic receptor function should be considered in relation both to future therapeutic strategies and, in the search for a clinical marker which might be of diagnostic value, to potential probes of the cortical cholinergic system.
Cognition Disorders↗
Neuropeptides in gliomas: identification of somatostatin 14 in a medulloblastoma.
Forty nine gliomas were analysed for the following neuropeptides: somatostatin (SS), substance P (SP), neurotensin (NT) and vasoactive intestinal polypeptide (VIP) and the pituitary peptide, adrenocorticotrophin (ACTH). A significant amount of authentic SS was found in a medulloblastoma, and low concentrations of SP and NT immunoreactivity in an ependymoma and cerebellar astrocytoma respectively. The majority of the other gliomas did not contain detectable levels of these five neuropeptides. Low levels of neuropeptides were found in some specimens probably due to contamination with cerebral cortex.
Astrocytoma↗
Evidence for the early prenatal development of cortical cholinergic afferents from the nucleus of Meynert in the human foetus.
A combined histochemical and biochemical approach has shown that the cholinergic system in the nucleus of Meynert region of the substantia innominata is well defined both histochemically and neurochemically within the first 3 months of gestation in the human foetus. Thus, at between 12 and 22 weeks of development the most intense acetylcholinesterase (AChE) histochemical reactivity was observed in the neuropil, cell bodies and processes in the nucleus of Meynert. AChE-stained fibres were observed which coursed from the nucleus of Meynert towards the cortical mantle and within the mantle AChE-stained fibres were also present. Micropunch samples from within the nucleus of Meynert contained higher levels of choline acetyltransferase (ChAT) activity than any other area examined including the striatum, while in the cortical mantle the level of ChAT activity was comparable to that found in the adult cerebral cortex. These observations suggest that the cholinergic innervation from the nucleus of Meynert--considered to be the major source of cholinergic afferents in the adult cerebral cortex--may play a key role in the early development of the human neocortex.
Acetylcholinesterase↗
Abnormal behavioural changes associated with vasopressin-induced barrel rotations.
Arginine-8-vasopressin (AVP) was injected into the cerebral ventricles of rats in order to characterize the dose-response relations of the convulsant actions of AVP and to obtain a detailed description of other acute behavioural effects. The incidence of barrel rotations, a violent and apparently uncontrolled motor activity during which rats rotate about their long axis, was found to be dose dependent, with a threshold of between 1 and 10 ng per rat. Other behavioural effects of AVP including immobility, titubation, ataxia, backward walking, and inhibition of exploratory activities and of grooming were seen at doses as low as 100 pg. These behavioural effects occurred within 9 min after injection, and thus have the same time course as barrel rotations. These acute actions of AVP may be significant in interpreting the effects of AVP on cognitive processes and memory and should also be taken into consideration in the clinical use of AVP as an anti-amnestic.
Animals↗
Agonal status affects the metabolic activity of nerve endings isolated from postmortem human brain.
Isolated nerve endings (synaptosomes) that show high rates of metabolic activity have been prepared up to 24 h postmortem from the brains of patients who have died suddenly. In contrast, similar preparations from brains of patients dying after a prolonged terminal illness showed little or no respiration. These data suggest that the agonal state of the patient is of major importance when investigating specific defects in neurotransmitter function in cerebral disorders and effects of neuroactive drugs on human tissue.
Adult↗
Somatostatin immunoreactivity in cortical and some subcortical regions in Alzheimer's disease.
Reverse phase HPLC analysis of somatostatin immunoreactivity in the cerebral cortex in elderly normal individuals revealed that the majority of the immunoreactivity co-eluted with synthetic somatostatin-14. While an immunoreactive peak corresponding to somatostatin-28 was not detected there was a peak of immunoreactivity which eluted after somatostatin-14. In cases of senile dementia of Alzheimer type (SDAT), where abundant neurofibrillary tangles and senile plaques (density greater than 30 per 1.3-mm2 field) were present in the cerebral cortex, somatostatin immunoreactivity was found to be significantly decreased in either the frontal or temporal cortex. Chromatographic analysis, however, revealed that both the major immunoreactive peaks detected in the normal group were reduced in SDAT in the temporal and frontal cortex. Using a punch microdissection technique somatostatin immunoreactivity has been assessed in the nucleus of Meynert and amygdala of SDAT and elderly normal cases. While there was no change in somatostatin immunoreactivity in the nucleus of Meynert in the SDAT group, tissue punches taken from the amygdala revealed a selective decrease in somatostatin immunoreactivity in the basal nucleus, in the SDAT cases.
Aged↗
Metabolism of neuropeptides at brain and pituitary sites.
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Animals↗
N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) affects locomotor activity without producing a nigrostriatal lesion in the rat.
Drug addicts abusing heroin substitutes contaminated with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and perhaps those who work with this substance, may develop symptoms similar to those seen in Parkinson's disease [7, 12, 13]. We describe the results of a study in which rats were given daily injections of MPTP for two weeks. A progressive suppression of activity was seen, but the subjects rapidly recovered when treatment ceased. The animals were then injected with D-amphetamine or apomorphine; the former drug enhanced activity, to levels seen in control (non-MPTP treated) subjects. Apomorphine had no effect, either on control or MPTP-treated subjects. The effects of acute (0, 2.5, 5.0 and 10.0 mg per rat) administration of MPTP were also studied. The two lower doses significantly decreased activity, but the highest dose did not. Histological examination showed that 2 weeks' treatment with MPTP did not produce neuronal degeneration in the pars compacta of the substantia nigra (SN). In these animals, there were no changes in levels of dopamine, 5-hydroxytryptamine, or their metabolites in either the SN or the caudate nucleus. MPTP had no effect on the levels of neurotensin, somatostatin and substance P in several brain areas. It is concluded that MPTP has reliable effects on locomotor activity in rats without producing measurable histological or neurochemical changes in the nigrostriatal dopaminergic system.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Amino acid transport by synaptosomes isolated from post mortem human brain.
Synaptosomes isolated from post mortem human brain release the transmitter amino acids upon depolarisation. Active preparations can be isolated for up to 24 hours post mortem. The amount of depolarisation-induced release of the transmitter amino acids is correlated with the rate of oxygen uptake. Only when this correlation is taken into consideration would it be possible to detect disease-related changes in presynaptic amino-acid transport systems.
Alanine↗
Chromatographic characterization of neuropeptides in post mortem human brain.
Reverse phase high performance liquid chromatography was used to establish the immunoreactive species of five neuropeptides (thyrotropin-releasing hormone, luteinising hormone-releasing hormone, neurotensin, substance-P and somatostatin) in three areas of post mortem human brain--the hypothalamus, amygdala and cortex. In the majority of cases the major immunoreactive peak corresponded to the authentic peptide, although other peaks of immunoreactivity were observed in several instances. It was established that somatostatin-14 was present as the major immunoreactive form and that somatostatin-28 did not occur in any of the three brain areas, although other somatostatin-immunoreactive peaks of unknown structure were detected. In addition to authentic neurotensin in the cortex, a substantial peak of immunoreactivity corresponding to the elution time of neurotensin (1-11) was observed. LH-RH was not detected in the amygdala, but was present in the cortex as a minor component of overall immunoreactivity. The major peak of substance-P immunoreactivity in all three brain areas corresponded to authentic substance-P; in addition immunoreactive material eluting in the region of [Met-O] substance-P, substance-P (5-11) and substance-P (6-11) were detected. TRH occurred as the major peak in all three areas, although minor peaks of immunoreactivity were seen in the amygdala.
Adult↗
Release of aspartate and glutamate caused by chloride reduction in synaptosomal incubation media.
Release of the amino acid neurotransmitter candidates aspartate and glutamate from synaptosomes can be stimulated by reduction of [Cl-] in the incubation medium by replacement with the impermeant anions propionate and isethionate. Replacement by the permeant anion Br- is without effect on amino acid release. This release offers a biochemical method of studying the Cl-ion channel in CNS membrane.
Animals↗
Intralaminar neurochemical distributions in human midtemporal cortex: comparison between Alzheimer's disease and the normal.
The intralaminar distributions of transmitter and nontransmitter enzyme activities and amino acid levels were determined in the midtemporal cortices from normal individuals and established cases of Alzheimer's disease. In the normal, choline acetyltransferase (CAT) and acetylcholinesterase (AChE) activities were relatively high in the outer cortical layers, particularly, for CAT, in the two granular layers (II and IV). Both activities were reduced in Alzheimer's disease at all, although generally most extensively in the outer and middle layers of the grey matter whereas activities were near normal in the white matter. Further, the enzyme distribution patterns of these cholinergic activities were also disrupted in Alzheimer's disease and the activity of CAT throughout the cortex was generally reduced to that found in the white matter. No such differences in distribution were found for two other enzymes, pseudocholinesterase and lactate dehydrogenase. Assessment of the gamma-aminobutyric acid (GABA) system in the normal revealed a much more extensive intralaminar variation in the enzyme, glutamate decarboxylase, compared with the level of GABA itself. In contrast with the cholinergic enzymes, neither the levels nor intralaminar patterns of GABA were altered in Alzheimer's disease. From an analysis of free amino acids at the different cortical levels, the cortical pattern of glutamic acid in the normal was different from that for GABA, aspartic acid, or nontransmitter amino acids such as alanine. Neither of the putative amino acids, glutamate or aspartate, was altered in Alzheimer's disease. These findings demonstrate the relatively selective nature of microchemical changes occurring in the cortex in Alzheimer's disease and suggest that a functional abnormality in cholinergic input to the outer neocortical layers (I-IV) with predominantly receptive and associative functions may be an important feature of the disease.
Acetylcholinesterase↗
Corticotrophin releasing factor is more potent than some corticotrophin-related peptides in affecting passive avoidance behaviour in rats.
The peptides corticotrophin releasing factor (CRF), ACTH4-10 and alpha-MSH have previously been shown to be behaviourally and neurochemically active. Using a passive avoidance task, we studied the effects of intra-ventricular administration of these peptides (0, 10 or 100 ng/rat) given either immediately following the learning trial, or 1 h prior to retention (24 h post-learning) test. We found that they affected behaviour; in some cases improving and in others disrupting performance. Statistical examination of the data suggests that these substances probably act on arousal mechanisms, in a manner reminiscent of the effects of vasopressin [13, 15].
Adrenocorticotropic Hormone↗
Post mortem levels of thyrotropin-releasing hormone and neurotensin in the amygdala in Alzheimer's disease, schizophrenia and depression.
The levels of neurotensin and thyrotropin-releasing hormone (TRH) in normal post mortem human amygdala have been compared with those in cases of schizophrenia, Alzheimer's disease and depression. Amongst various factors which can influence post mortem human brain biochemistry (including age, sex, post mortem delay, time of death, disease status and severity), sex difference appeared to be responsible for the most extensive variation. The levels of both peptides were nearly doubled in males compared with females and this increase was significant in the case of neurotensin. There was also a positive correlation between neurotensin and TRH levels. Although levels of neurotensin and TRH tended to be lower in the disease groups these trends did not reach significance.
Aged↗
Studies on the characterisation of alpha-MSH-like immunoreactivity in rat hypothalamus.
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Animals↗
Metabolically active synaptosomes can be prepared from frozen rat and human brain.
Nerve ending particles (synaptosomes) were prepared from pieces of rat and human brain and from brain homogenate that had been frozen and thawed under a variety of conditions. Their purity, as judged by electron microscopy, and performance in terms of a number of metabolic and functional parameters [accumulation of tissue potassium, respiration, release of transmitter amino acids, and the responses on these indices to depolarisation by veratrine (VX)] were compared with those of fresh tissue-derived synaptosomes. It was found that rapid freezing and/or slow thawing severely impaired the subsequent performance of incubated synaptosomes. In contrast, synaptosomes from tissue frozen slowly and thawed rapidly showed relatively good retention of morphology and metabolic performance. It was better to use whole (1-5 g) pieces of tissue than tissue homogenate: the synaptosome fraction from frozen tissue pieces contained 80% of the proportion of identified synaptosomes found in the fresh tissue synaptosome fraction, its respiratory rate was 65%, and its tissue potassium content 70% of that of fresh controls. Moreover, it responded to VX or potassium stimulation by showing increased respiratory rate, decreased tissue potassium, and increased release of neurotransmitter amino acids, to an extent that was comparable to that of fresh tissue fractions. Thus, preparations from frozen rat and human brain were shown to be metabolically and functionally active, and can be used for a variety of neurotransmitter-related studies.
Animals↗
Use of post-mortem human synaptosomes for studies of metabolism and transmitter amino acid release.
Synaptosomes have been prepared from human brain obtained at autopsies carried out up to 24 h postmortem (p.m.). They showed generally good retention of morphology, as well as accumulation of tissue potassium and linear rates of oxygen uptake. In response to veratrine depolarization they showed increased respiration rate, decreased tissue potassium content and the specific release of transmitter amino acids. Regression analysis indicated that metabolically and functionally active preparations may be obtained up to ca. 25 h p.m. Preparations obtained from patients dying with brain injury were inactive.
Adult↗