Pathological correlates of dementia in Alzheimer's disease.
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Biomedical subjects
D M Mann
Publications and source records attributed to D M Mann.
High-level expression and secretion of a lysine-containing analog of Escherichia coli heat-stable enterotoxin.
The mechanism of action of the heat-stable enterotoxin STa secreted from enterotoxigenic forms of Escherichia coli has remained elusive, in part due to a tedious, low-yield purification procedure. We report here a method for obtaining large amounts of a biologically active lysine-containing analog of STa. Initial attempts to express the toxin using an expression vector that did not encode a signal sequence resulted in no biologically active material being recovered either from lysed cells or as a secretory product. However, use of the secretion vector pJAL36, which contains the STII enterotoxin signal sequence, allowed large amounts of an STa derivative containing the additional sequence Ser-Thr-Lys at the amino terminus of the mature enterotoxin to be readily purified from culture supernatants. This enterotoxin analog, known as KSTa-1, was equal in biological and receptor binding activity to the native toxin STa. The lysine residue present in KSTa-1 promises to be useful as a reactive amino acid that is readily derivatized to allow coupling of the enterotoxin to supports for affinity chromatography and antigenic conjugates. Additionally, the insertion of the lysine residue carboxy terminal to the Ser-Thr sequence adds a reversible "handle" to the toxin sequence in that the Ser-Thr-Lys segment can be removed by treatment with trypsin, releasing the native form of STa.
Amino Acid Sequence↗
Monoamine metabolism in Down syndrome.
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Adult↗
The topography of nerve cell loss from the locus caeruleus in elderly persons.
A topographical analysis of nerve cell loss from the locus caeruleus in "mentally normal" old people shows cell loss to be uniformly diffuse throughout the whole nucleus with no preferential involvement of any one particular area. Such findings contrast with those of ours on Alzheimer's disease and suggest differing mechanisms underlying the cell loss of old age and Alzheimer's disease. Cell loss in Alzheimer's disease is thought to relate to primary pathogenetic events in terminal fields of cerebral cortex. In "normal" old age, cell loss may be determined by changes occurring at perikaryal level possibly in respect of the cytotoxic effects of noradrenaline degradation and neuromelanin accumulation.
Adolescent↗
A commentary on the diagnostic criteria for the neuropathological assessment of Alzheimer's disease.
Apart from providing a potential framework for a universally acceptable protocol for the pathological diagnosis of Alzheimer's disease, the Working Party has dispelled one of the major myths of so-called normal aging, namely that minor degrees of Alzheimer-type change (i.e., plaques and tangles) are not the product of growing older alone but should always be regarded as pathological, as they probably represent the tissue substrate of incipient Alzheimer's disease. Establishment of the pathological criteria for such preclinical disease will be of equal importance as that associated with clinical change.
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Photoaffinity heterobifunctional cross-linking reagents based on N-(azidobenzoyl)tyrosines.
New heterobifunctional cross-linking reagents that possessed a photoactive terminus, an electrophilic terminus, and a linking arm between the two termini that had a radiolabeled, enzymatically cleavable bond were synthesized. In a model study, succinimidyl N-[N'-(4-azidobenzoyl)tyrosyl]-beta-alanate (16A) was coupled to n-butylamine (a Lys surrogate), iodinated, and cleaved with chymotrypsin in the presence of tyrosylamide to afford the desired adduct (N-(N'-(4-azidobenzoyl)-3-iodotyrosyl)tyrosinamide, thereby demonstrating the feasibility of the enzymatic cleavage. In a biochemical study, succinimidyl N-[N'-(3-azido-5-nitrobenzoyl)tyrosyl]-beta-alanate (16C) was coupled to Lys-75 of calmodulin (CaM), and the radioiodinated monoadduct was successfully photo-cross-linked, in a calcium-dependent manner, to the human erythrocyte plasma membrane Ca2+,Mg2(+)-ATPase and to a synthetic fragment (M13) containing the CaM-binding region of myosin light-chain kinase. In the latter case, densitometry readings indicated 20% cross-linking efficiency.
Affinity Labels↗
Neuromelanin and RNA in cells of substantia nigra.
We have found that with accumulation of neuromelanin granules within cell bodies of neurones of the human substantia nigra there is a reduction in cytoplasmic RNA and a decrease in nucleolar volume. These observations imply a gradual decrease in the functional capacity of the cell such that eventually, the cell is unable to produce sufficient protein to maintain its metabolic economy with atrophy and death ensuing. This reduction in protein synthesis may result from the mechanical displacement and disruption of the endoplasmic reticulum by the accumulated pigment granules.
Brain Chemistry↗
The quantitative assessment of lipofuscin pigment, cytoplasmic RNA and nucleolar volume in senile dementia.
Treatment of patients suffering from senile dementia with meclofenoxate has been reported to result in an improvement in mental performance. Furthermore meclofenoxate reduces the amount of lipofuscin pigment in nerve cells. We have shown that, although nerve cells in a group of demented patients have decreased amounts of cytoplasmic RNA and reduced nucleolar volume, they contain no more pigment than do cells of a control group. It seems, therefore, unlikely that removal of lipofuscin, per se, has any bearing on this reported improvement in intellectual capability, nor is it implicated in the aetiology of senile dementia.
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A quantitative study of the glia of the Purkinje cell layer of the cerebellum in mammals.
The cerebella of fourteen mammals have been examined and the number of each DNA class of glial cell, within the Purkinje cell layer, counted. Diploid glial cells were present in all species and related in number to the surface area of the Purkinje cell. It is likely that they assist in the maintenance of the physiology of this latter cell type. Tetraploid glial cells, however, occur in significant numbers only in the human and chimpanzee and possibly play a part in the establishment of certain learned patterns of co-ordinated movement peculiar to these species.
Animals↗
Nuclear inclusions in Alzheimer's disease.
Biopsy samples of parietal cortex from seven patients undergoing atrio-ventricular shunt operations have been examined electron microscopically. Five were suffering from Alzheimer's disease, while two were subjects with normotensive hydrocephalus following previous head injuries. Intranuclear neuronal, inclusions of three types were found. Most frequent was the intranuclear rodlet, which was commonly observed in four of the patients with Alzheimer's disease, but in one block only from one of the hydrocephalus cases. The other two types, namely the spherical inclusion body and the vermicellar-like inclusion, were found less commonly and in only two cases. No inclusions were seen in glial nuclei.
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A histoquantitative study of the striate cortex and lateral geniculate body in normal, blind and demented subjects.
The amount of myelin in the outer band of Baillarger in the human visual cortex stained by Luxol Fast Blue MBS, has been measured in normal individuals of wide age range, in a group of blind and severely visually impaired but otherwise normal individuals and in a series of demented patients of the Alzheimer and multi-infarct type who were apparently visually normal. The amount of myelin is found to be significantly reduced in the blind and demented groups. Examination of the lateral geniculate body in the blind cases demonstrated slight reduction in neuron numbers and marked reduction in mean neuron diameter. Neuronal cytoplasmic ribonucleic acid, nucleolar volume and numbers of tetraploid glial nuclei in the blind or visually impaired cases were significantly reduced when compared with controls, indicating reduced function in these neurons. Similar results were obtained on examining this nucleus in Alzheimer and multi-infarct cases, suggesting that the visual pathways may be involved in these conditions. It is concluded that loss of myelin from the outer band of Baillarger occurs in association with reduced function of neurons in the lateral geniculate body.
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Neurofibrillary pathology and protein synthetic capability in nerve cells in Alzheimer's disease.
Nucleolar volume was measured in nerve cells of the temporal cortex in cases of Alzheimer's disease, obtained at both biopsy and autopsy. Measurements were made on those nerve cells containing neurofibrillary tangles and also on ones free of such changes. Results showed that nucleolar volume is significantly reduced, by at least 40%, in both tangle and non-tangle bearing cells, in both biopsy and autopsy cases, when compared with corresponding values from appropriate control cases. Furthermore, in the autopsy cases, nerve cell nucleolar volume was reduced by a further 30% in tangle bearing cells compared to non-tangle bearing neighbours. No such difference was noted in these cells in the biopsy cases. These findings imply that alterations in protein synthetic capability occur in nerve cells early in the course of Alzheimer's disease, and that this change is not, at least in these initial stages, related to accumulation of neurofibrillary material within the cell body, although later on such accumulation may result in added disruption of cell metabolism.
Adult↗
Immunohistochemical staining of senile plaques.
Immunohistochemical staining of serum proteins, including immunoglobulins, was carried out on formalin-fixed cerebral tissue from 24 autopsy cases (twenty dements, four controls) and fifteen biopsy cases (ten dements, five controls). Sixteen of the autopsy cases showed focal regions where there was staining of globulins and other serum proteins within senile plaque 'cores', nerve cell perikarya and astrocytes. This pattern of staining, generally, occurred either in relation to areas of cerebral infarction or in the neighbourhood of small arteries displaying arteriosclerotic changes. In tissue areas, distant from these vascular alterations, no staining occurred. Furthermore, none of the biopsy cases showed any such areas of staining. These findings indicate that the positive immunohistochemical reactions demonstrated within senile plaques (and other tissue components) are more likely to result from leakage of serum proteins, including immunoglobulins out of damaged vessels and into the brain parenchyma, rather than being indicative of the involvement of immunological mechanisms in the aetiology of plaques, as has been suggested by other workers.
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Nerve cell protein metabolism and degenerative disease.
The mechanisms and organelles through which control of protein synthesis within healthy nerve cells is governed are discussed, and the ways in which expression of these biochemical pathways can be related to cell morphology are described. The volumes of the nucleus and nucleolus, and the amount of RNA within the cell body, are all interrelated and seem to be set at genetically predetermined levels which normally match the neurones basal needs for replacement proteins in respect of the size of its' projection field. However, in situations of (induced) hyperactivity or cell damage, or in others where disease may lower nerve cell activity, the protein requirements change, and it is noted that these morphological features also alter in a direction appropriate to the need for greater or lesser amounts of protein. How these alterations in protein synthesis can provide information as to both the basic pathology, or even the pathogenesis, of degenerative disease of the nervous system is illustrated by reference to Alzheimer's disease and motor neurone disease.
Alzheimer Disease↗
Pathological basis for neurotransmitter changes in Parkinson's disease.
In eight patients with idiopathic Parkinson's disease, loss of nerve cells from the locus caeruleus, together with reductions in capacity for function in those of the dorsal motor vagus nucleus, the supraoptic and paraventricular nuclei of the hypothalamus and the nucleus basalis of Meynert in the substantia innominata are reported. These changes were more severe in three of these eight patients where mental impairment was present, though in none of these three was the number of senile plaques and neurofibrillary tangles or extent of granulovacuolar degeneration greater in the hippocampus and other cerebral cortical areas than would be expected for the age of the patient. Although these same three patients had received long term L-dopa, it seems that their pathology was related to the disease process and was not drug induced. It is possible therefore, that the dementia seen in some patients with Parkinson's disease is related to degeneration and failing function of noradrenergic and cholinergic neurotransmitter systems and not always associated with the coincidental acquisition of Alzheimer type lesions (Alzheimer's disease).
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Alzheimer's presenile dementia, senile dementia of Alzheimer type and Down's syndrome in middle age form an age related continuum of pathological changes.
A loss of nerve cells from the nucleus basalis of Meynert and the locus caeruleus together with a reduction in nucleolar volume in surviving cells was measured in twenty-two patients with Alzheimer's disease who ranged in age from 48-92 years, and in six patients over 50 years of age with Down's syndrome who also showed extensive formation of senile plaques and neurofibrillary tangles within their cerebral cortex. When compared with age matched controls the severity of these changes was greatest in the younger patients with Alzheimer's disease, but this fell with age such that by 90 years the level of change in Alzheimer's disease approached that in old age alone. There were only slight differences in the extent of these pathological changes in those patients with Down's syndrome when compared with others of similar age with Alzheimer's disease. It is concluded that the presenile dementia of Alzheimer's disease, the senile dementia of Alzheimer type and Down's syndrome in middle age all form an age-related continuum of pathological change.
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The topography of plaques and tangles in Down's syndrome patients of different ages.
The topographical distribution of senile plaques and neurofibrillary tangles has been investigated in 12 patients with Down's syndrome ranging from 31 to 65 years of age. No plaques or tangles whatsoever were seen in the brain of the 31-year-old patient. The nine patients over 53 years of age, showed a similar pathological picture in which there were numerous mature plaques in all areas of cerebral cortex, hippocampus and amygdala and numerous tangles in these areas and in subcortical structures such as nucleus basalis, locus caeruleus, dorsal raphe, ventral tegmental area, substantia nigra, olfactory bulb and tracts. In the other two patients aged 37 and 51 years, an intermediate pathological picture was seen in which primitive plaques predominated within the cortex, with numerous mature plaques in hippocampus and amygdala. In the 37-year-old patient, tangles were numerous in the entorhinal cortex, but much less common in hippocampus and amygdala, rare in cerebral cortex and absent in the subcortical areas, olfactory bulbs and tracts. A similar pattern was seen in the 51-year-old patient though here some cells in the subcortex were also affected. These observations suggest that the primary focus of plaque and tangle formation in Down's syndrome may be in amygdala, entorhinal cortex and hippocampus, with a 'spreading out' to subsequently involve all areas of cortex, certain subcortical regions and the olfactory bulbs and tracts. It appears unlikely that the olfactory bulbs and tracts provide a portal of entry for any pathogenic agent that may be responsible for inducing plaque and tangle formation within the rest of the brain.
Adult↗
An ultrastructural analysis of the effects of accumulation of neurofibrillary tangle in pyramidal neurons of the cerebral cortex in Alzheimer's disease.
Quantitative morphometric (stereological) methods have been used to assess the effects of accumulation of neurofibrillary material on the fine structure of pyramidal cells in biopsy specimens of temporal cortex from nine patients with Alzheimer's disease. When compared with non-tangled cells from the same patients, tangled cells show an increase in total area of cytoplasm due to the accumulation of tangle and a reduction in the area of the nucleus; the area proportion of the cell body occupied by total cytoplasm, therefore, increases whereas that of the nucleus decreases. Within the total cytoplasm, nucleolar and mitochondrial areas are maintained, but that of lipofuscin is increased, though all are increased when expressed as a proportion of the useful cytoplasm alone (i.e. total cytoplasmic area minus area occupied by tangle). Measures of the amount of rough endoplasmic reticulum and ribosomes are decreased overall in tangled cells, though when related to useful cytoplasm alone such measures approach non-tangled cell values. Measures of smooth endoplasmic reticulum are unaltered throughout. When related to the amount of tangle within cells it was found that the most heavily tangled cells retain 28% of useful cytoplasm, 72% of the nuclear area, 50% of the rough endoplasmic reticulum and 27% of ribosomes present within least tangled and non-tangled cells. By contrast, mitochondrial area is maintained and that of lipofuscin increased. The capacity for protein synthesis in tangled cells appears, therefore, to be progressively decreased with accumulation of tangle, whereas that for oxidative metabolism is maintained and lysosomal activity, perhaps, increased. Neurofibrillary tangle formation and accumulation may, therefore, lead to the eventual death of neurons and be the major cause of nerve cell loss in Alzheimer's disease.
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