Amorphous aluminosilicates promote nucleation of amyloid beta protein and tachykinins.
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Aluminum Silicates↗
Biomedical subjects
A E Oakley
Publications and source records attributed to A E Oakley.
Aluminium accumulation, beta-amyloid deposition and neurofibrillary changes in the central nervous system.
Deposition of beta-amyloid and the formation of neurofibrillary tangles (NFTs) are central to the aetiopathogenesis of Alzheimer's disease (AD). The possible effects of aluminium on these processes have been investigated in patients with renal failure who are exposed chronically to high blood levels of aluminium. Focal accumulation of aluminium was observed in neurons with high densities of transferrin receptors, indicating transferrin-mediated uptake, in regions such as cortex and hippocampus which are selectively vulnerable in AD. Increased staining for the beta-amyloid precursor protein (APP) in cortical pyramidal neurons was evident in the majority of renal patients and immature senile plaques were present in 30% of cases, suggesting that aluminium may induce or accelerate beta-amyloid deposition. The absence of neurofibrillary changes in this group of renal patients indicates that aluminium does not directly cause the formation of NFTs. The brain aluminium content was not raised in neuropathologically assessed cases of AD and we have been unable to confirm claims of defective transferrin binding in this disorder. If aluminium contributes to the development of sporadic AD, it must do so indirectly, perhaps via effects on the synthesis or metabolism of APP, or by contributing generally to the age-related attrition of neurons and thus reducing the threshold for deficits produced by more specific disease-related processes.
Aluminum↗
Aluminium accumulation in relation to senile plaque and neurofibrillary tangle formation in the brains of patients with renal failure.
The effects of long-term exposure to aluminium on the development of Alzheimer-type neuropathological changes have been studied post-mortem in patients with chronic renal failure who did not have dialysis encephalopathy. Administration of aluminium-containing phosphate binding compounds appears to be a major factor in the accumulation of aluminium in the brain of dialysis patients. The mean serum aluminium concentrations determined during life and brain aluminium concentrations determined post-mortem correlated with both the duration and total amount of aluminium hydroxide administered to these patients. No correlation was found between the presence of bone aluminium and either the mean serum or brain aluminium concentration. Longitudinal monitoring of serum aluminium concentrations may provide a more reliable index than bone biopsy of brain aluminium concentrations in dialysis patients. Dynamic secondary ion mass spectrometry revealed focal accumulations of aluminium associated with cortical pyramidal neurones. The majority of patients also showed immunostaining in pyramidal neurones with an antibody to the N-terminal region of the beta/A4 amyloid precursor protein, while staining was absent in age-matched control cases. One-third of the patients exhibited beta/A4-positive amorphous senile plaques in the cerebral cortex. However, there was no clear correlation between either the presence and intensity of beta/A4 amyloid precursor immunostaining or the presence of senile plaques and the concentration of aluminium in the cerebral cortex. Cortical neurofibrillary tangles were not observed in any of the dialysis patients. These data suggest that it is unlikely that aluminium plays any major role in neurofibrillary tangle formation and that its putative role in senile plaque formation is likely to be only part of a complex cascade of changes.
Aluminum↗
The imaging and quantification of aluminium in the human brain using dynamic secondary ion mass spectrometry (SIMS).
Dynamic secondary ion mass spectrometry (SIMS) has been utilised to study the post-mortem distribution of aluminium in air-dried frozen sections from unfixed, unstained human brain in order to minimise contamination of the tissue and avoid redistribution and extraction of endogenous tissue aluminium. Substrates, sputter-coated with silver, were found to be free of focal aluminum surface contamination and thus minimised substrate induced artefacts in the tissue aluminium ion image. SIMS imaging of aluminium secondary ions at a mass resolution that eliminated the major molecular interferences, combined with a photomontage technique provided a unique strategy for studying aluminium distribution in tissue unrivalled by other spatially resolved microanalytical techniques such as laser microprobe mass spectrometry or X-ray microanalysis. Using this strategy, high densities of focal aluminium accumulations have been demonstrated in the cerebral cortex of the majority of chronic renal dialysis patients studied. In contrast, such aluminium accumulations were absent in control patients. SIMS imaging of aluminium appeared to provide much better discrimination between the dialysis patient group and the control group than one of the most widely used techniques for measuring aluminium in bulk samples, graphite furnace atomic absorption spectrometry. Preliminary studies have shown the feasibility of quantifying focal aluminium SIMS images obtained from brain tissue using aluminium-loaded brain homogenates as reference standards.
Adult↗
Histochemical distribution of non-haem iron in the human brain.
The detailed anatomical distribution of iron in the post-mortem human brain has been studied using Perl's and Turnbull's methods with the diaminobenzidine intensification procedure for the demonstration of non-haem Fe3+ and Fe2+, respectively. Attention to methodological procedures has revealed that even brief immersion of tissue in routinely used fixatives causes a reduction of staining intensity in areas of high iron content and, often, loss of staining in areas of low iron content. Optimal staining is obtained using frozen section briefly fixed for 5 min in 4% formalin and Perl's stain (Fe3+) with diaminobenzidine intensification. Highest levels of stainable iron were found in the extrapyramidal system with the globus pallidus, substantia nigra zona reticulata, red nucleus and myelinated fibres of the putamen showing highest staining reactivity. Moderate staining intensity with Perl's technique was found in the majority of forebrain, midbrain and cerebellar structures with the striatum, thalamus, cortex and deep white matter, substantia nigra zona compacta, and cerebellar cortex showing consistent staining patterns with intensification of Perl's stain. The brain-stem and spinal cord generally only showed staining with the intensification procedure and even this was of low intensity. Microscopically the non-heam iron appears to be found predominantly in glial cells as fine cytoplasmic granules which in heavily stained areas coalesce to fill the entire cell. Iron-positive granules appear to be free in the neuropil and also around blood vessels in the globus pallidus, striatum and substantia nigra. The neuropil shows a fibrous impregnation when stained for iron which is, in part, derived from glial processes, myelinated fibres and fibre bundles. Neurones, in general, show only very low reactivity for iron, and this is difficult to discern due, often, to the higher reactivity of the surrounding neuropil. In the globus pallidus and substantia nigra zona reticulata, neurones with highly stainable iron content are found with granular cytoplasmic iron reactivity similar to that seen in the local glial cells. Our results are comparable with those of early workers, but with the use of intensification extend the distribution of non-haem iron to areas previously reported as negative. No apparent correlation of iron staining with known neurotransmitter systems is seen and the predilection for the extrapyramidal system is not easily explained, though the non-haem iron in the brain appears to be as a storage form in the iron storage protein ferritin. The localization of iron in the brain provides a foundation for the study of iron in certain neurodegenerative diseases such as Parkinson's disease, where iron has been implicated in the pathogenesis.
Aged↗
Multicatalytic, high-Mr endopeptidase from postmortem human brain.
The main high molecular weight (650K) multicatalytic endopeptidase has been purified from postmortem human cerebral cortex. As in other tissues and species, this enzyme is composed of several subunits of 24-31K and has three distinct catalytic activities, as shown by the hydrolysis of the fluorogenic tripeptide substrates glutaryl-Gly-Gly-Phe-7-amido-4-methylcoumarin, benzyloxycarboxyl-Gly-Gly-Arg-7-amido-4-methylcoumarin, and benzyloxycarboxyl-Leu-Leu-Glu-2-naphthylamide with hydrophobic (Phe), basic (Arg), and acidic (Glu) residues in the P1 position, respectively. These activities are distinguishable by their differential sensitivity to peptidase inhibitors. The enzyme hydrolysed neuropeptides at pH 7.4 at multiple sites with widely differing rates, ranging from 113 nmol/min/mg for substance-P, down to 2 nmol/min/mg for bradykinin. The enzyme also had proteinase activity as shown by the hydrolysis of casein. For the hydrolysis of the Tyr5-Gly6 bond in luteinizing hormone-releasing hormone, the Km was 0.95 mM and the specificity constant (kcat/Km) was 4.7 X 10(3) M-1 s-1. The bond specificity of the enzyme at neutral pH was determined by identifying the degradation products of 15 naturally occurring peptide sequences. The bonds most susceptible to hydrolysis had a hydrophobic residue at P1 and either a small (e.g., -Gly or -NH2) or hydrophobic residue at P'1. Hydrolysis of -Glu-X bonds (most notably in neuropeptide Y) and the Arg6-Arg7 bond in dynorphin peptides was also seen. Thus the three activities identified with fluorogenic substrates appear to be expressed against oligopeptides.
Brain↗
Role for aluminum and silicon in the pathogenesis of senile plaques: studies in chronic renal dialysis.
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Adult↗
Comparison of the regional distribution of transferrin receptors and aluminium in the forebrain of chronic renal dialysis patients.
Recent studies have emphasised the potential neurotoxicity of aluminium in dialysis encephalopathy and it has also been suggested that this element may have a role in the pathogenesis of Alzheimer's disease. Aluminium is known to be transported by the iron transport protein transferrin. In this study using receptor autoradiography we have demonstrated the presence of transferrin binding sites in the human forebrain and shown a pattern similar to that found in other species. Imaging secondary ion mass spectrometry has demonstrated the distribution of aluminium-containing cell-like profiles in the brains of chronic renal dialysis patients who have raised levels of brain aluminium (greater than 4 micrograms/g dry weight) and even in dialysis patients where the gross level of aluminium was within the normal range. The density of these profiles corresponded to the regions of high transferrin receptor density. In contrast, the distribution of iron in the brain showed an inverse correlation with transferrin receptor density with highest iron levels present in the globus pallidus, an area of low transferrin receptor density. These results suggest that the regional distribution of neuropathological changes seen in dialysis encephalopathy patients and also Alzheimer's disease may reflect the distribution of transferrin receptors. The discrepancy between iron distribution and transferrin receptor distribution suggests that further, as yet uncharacterized mechanisms, govern the distribution of brain iron.
Adult↗
Autoradiographic visualization of binding sites for [3H]somatostatin in the rat brain.
[4-3H][Phe6]somatostatin-14 was used to localize somatostatin binding sites in the rat brain by tritium-film autoradiography. The distribution of binding sites using 0.7 nM [3H]somatostatin confirmed that previously described for iodinated tyrosyl analogues of somatostatin, with highest densities of sites in the cerebral cortex (particularly in laminae III-V), amygdala, lateral septal nucleus, hippocampus and claustrum. Investigation of the pharmacological specificity of the binding sites showed that somatostatin-28, but not its N-terminal dodecapeptide, somatostatin-28 (1-12) or des-Ala1[Gly2,Lys4,Asn5,Thr12,Ser13]somatostatin displaced [3H]somatostatin. Further examination of the binding inhibition characteristics, using a homogenate assay, suggested the presence of two classes of binding sites in the cerebral cortex, hippocampus, midbrain and striatum. The existence of sub-populations of somatostatin binding sites in the rat brain has implications for future studies on the physiological and pharmacological significance of somatostatin receptors in the central nervous system.
Animals↗
Aluminosilicates and senile plaque formation in Alzheimer's disease.
Aluminium and silicon were found to be colocalised in the central region of senile plaque cores in studies with energy dispersive X-ray microanalysis. The distribution of these elements was similar in cores isolated from the cerebral cortex of patients with senile dementia of the Alzheimer type and in cores studied in situ from tissue sections from the cerebral cortex of presenile and senile patients with Alzheimer's disease, and elderly, mentally normal patients. High-resolution solid-state nuclear magnetic resonance techniques showed aluminium and silicon to be present as aluminosilicates. The presence of aluminosilicates at the centre of senile plaque cores contrasts with the distribution of other inorganic constituents and suggests that they may be involved in the initiation or early stages of senile plaque formation.
Aged↗
Aluminosilicates and the ageing brain: implications for the pathogenesis of Alzheimer's disease.
Senile plaques are a neuropathological feature of the ageing brain and consist of abnormal neuritic and glial processes surrounding an extracellular core of material with fibrillary ultrastructure. Present at low densities in the cerebral cortex of most aged individuals, they occur in large numbers in Alzheimer's disease, the major form of senile dementia. Energy-dispersive X-ray microprobe analysis of isolated cores and plaques in situ from patients with Alzheimer's disease or Down's syndrome and from normal controls has shown co-localization of high concentrations of aluminium (4-19%) and silicon (6-24%) at the centre of the core. The presence of these elements as aluminosilicates has been confirmed using solid-state 27Al nuclear magnetic resonance. These findings provide a link with the other major neuropathological feature of Alzheimer's disease, the neurofibrillary tangle-bearing neurons, where high intracellular levels of Al and Si have also been reported. The focal deposition of these elements may be an early and essential factor in the pathogenesis of Alzheimer-type changes, reflecting an increased exposure to aluminium.
Aged↗
The current status of the cortical cholinergic system in Alzheimer's disease and Parkinson's disease.
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Acetylcholinesterase↗
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↗
Human cerebellar cortex possesses high affinity binding sites for [3H]somatostatin.
Somatostatin binding sites have been identified in the human brain using [4-3H-(Phe6)]-somatostatin-14. In contrast to that of the rat, the human cerebellar cortex possesses a high density of somatostatin binding sites, comparable to that found in either the rat or human cerebral cortex. Autoradiographic localisation of somatostatin binding sites in the human cerebellum reveals that the highest density is associated with the granule cell layer.
Aged↗
Neuropeptide localisation in the substantia innominata and adjacent regions of the human brain.
A dense peptidergic innervation has been demonstrated in the substantia innominata region in postmortem specimens of human brain using immunocytochemical techniques. A peptidergic innervation of the nucleus of Meynert - the prominent nucleus of this area containing the cholinergic cell bodies which innervate the cerebral cortex - has been demonstrated by immunostaining with antisera against the following eight neuropeptides: somatostatin, substance P, cholecystokinin octapeptide, vasoactive intestinal polypeptide, met-enkephalin, ACTH, alpha-MSH and oxytocin. Other immunocytochemical features of the substantia innominata region include a dense band of peptide immunoreactivity beneath the medial aspect of the anterior commissure and islands of somatostatin and substance P terminal immunoreactivity in the rostral part of the substantia innominata. Somatostatin immunostained cell bodies have been located in a discrete area of the bed nucleus of the stria terminalis and in the rostral portion of the substantia innominata, nucleus accumbens and the ventral part of the putamen. The dense band of peptide immunoreactivity beneath the medial aspect of the anterior commissure consists of ribbon-like processes stained with antisera against somatostatin, substance P, cholecystokinin octapeptide, vasoactive intestinal polypeptide and met-enkephalin. Less intense immunostaining of ribbon-like elements is also present in the globus pallidus. The presence of a peptidergic innervation to the nucleus of Meynert suggests a possible important modulatory role in cortical cholinergic function.
Adrenocorticotropic Hormone↗
The substantia innominata and adjacent regions in the human brain: histochemical and biochemical observations.
The substantia innominata was investigated in the adult human brain with particular reference to the cholinergic nature of the nucleus of Meynert. Based on histochemical observations of acetylcholinesterase activity and biochemical estimations of choline acetyltransferase the relations of the Meynert nucleus to adjacent structures in the substantia innominata region were identified precisely. A new dissection procedure is described which permits combined histochemical and histological examination of anatomically complex regions of the human brain, such as the substantia innominata, to be carried out in conjunction with accurate tissue dissection for neurochemical analysis. Using this technique, various acetylcholinesterase-positive and choline acetyltransferase-containing structures are apparent in coronal sections removed from the rostrocaudal length of the substantia innominata. These include, in addition to the prominently stained, putative cholinergic neurons, acetylcholinesterase-positive tracts which contain putative cholinergic projections to the neocortex, and 'islands' of acetylcholinesterase-positive neuropil which presumably reflect a collateral or intrinsic cholinergic innervation in the area. This anatomical complexity of cholinergic structures in the substantia innominata suggests that neurochemical analysis should be conducted on microdissected as opposed to macrodissected tissue samples. Neuropathologically, the present report provides a further basis for optimising quantification of putative cholinergic perikarya. Continued systematic analysis of the nucleus of Meynert at the morphological and biochemical level should thus establish the role of this nucleus in normal brain function and in disease.
Acetylcholinesterase↗
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↗