Cellular and molecular pathology in Alzheimer's disease.
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Alzheimer Disease↗
Biomedical subjects
T G Ohm
Publications and source records attributed to T G Ohm.
A subpopulation of hippocampal glial cells specific for the zinc-containing mossy fibre zone in man.
The projection of the zinc-containing axons of granule cells of the fascia dentata, e.g. the mossy fibres, is restricted to the hilar region and sector CA3 of the hippocampus. Serial sections of human hippocampi were stained for zinc-containing fibres with a non-perfusion Timm method, while adjacent ones were stained with Darrow red and aldehydefuchsin. GFAP, glutamine synthetase immunocytochemistry and a specific silver stain were employed to label other subtypes of astrocytes. The distribution of Timm-stained areas correlates only with the distribution of aldehydefuchsin-positive glial cells, most probably astrocytes. Since glial cells regulate axonal outgrowth in a region-specific manner, it is temptative to speculate that the aldehydefuchsin-positive glial cell is a candidate for a specific neuron-glia interaction which is somehow involved in the control of outgrowth of mossy fibres.
Hippocampus↗
Dose-dependent stimulation of adenylate cyclase in rat hippocampal tissue by isoprenaline, Gpp(NH)p and forskolin: lack of circadian phase-dependency.
In rat hippocampal tissue the basal as well as drug-stimulated adenylate cyclase (AC) activity was studied after sacrificing the animals at 9 different circadian times (01.00, 04.00, 07.00, 10.00, 13.00, 16.00, 19.00, 22.00, 01.00 h). The AC was stimulated in vitro either via the beta-adrenoceptor by isoprenaline (IPN, 0.01-100 mumol/l plus GTP 0.005-50 mumol/l, via the GTP-binding protein by Gpp(NH)p (0.03-100 mumol/l) or via the catalytic unit of the AC by forskolin (0.1-600 mumol/l). For each drug dose-response curves could be constituted in single hippocampal tissues at each of the time points of sacrifice. Whereas maximal stimulation by forskolin was not achieved with the highest dose used (600 mumol/l, EC50-, Emax-values and Hill-coefficients could be calculated for both IPN and Gpp(NH)p, respectively. Thus, the rank order of drug stimulated AC activity was forskolin > Gpp(NH)p > IPN. However, no circadian phase-dependency in basal as well as drug-stimulated AC activity was found.
Adenylyl Cyclases↗
Reduced basal and stimulated (isoprenaline, Gpp(NH)p, forskolin) adenylate cyclase activity in Alzheimer's disease correlated with histopathological changes.
Cyclic adenosine monophosphate (cAMP) is an adenylate cyclase borne second messenger involved in basic metabolic events. The beta-adrenoceptor sensitive adenylate cyclase was studied in post-mortem hippocampi of controls and Alzheimer patients. Virtually identical subsets of each hippocampus homogenate were stimulated by 100 mumol isoprenaline, Gpp(NH)p and forskolin, respectively, in presence of an ATP-regenerating system. The determination of cAMP formed was carried out by means of a radioassay. The observed significant 50% reduction in basal as well as in stimulated adenylate cyclase activity in Alzheimer's disease is negatively correlated with semiquantitative evaluations of amyloid plaques (P less than 0.05) but not with neuritic plaques, neurofibrillary tangles or neuropil threads. This reduction in enzyme activity is obviously not due to simple cell loss alone. It is likely that the crucial point of the observed functional disturbance is at the level of the catalytic unit of the adenylate cyclase, since the same degree of reduction is maintained at all steps of the signal cascade.
Adenylyl Cyclases↗
Calbindin-D-28k-like immunoreactive structures in the olfactory bulb and anterior olfactory nucleus of the human adult: distribution and cell typology--partial complementarity with parvalbumin.
Calbindin-D-28k and parvalbumin are calcium-binding proteins. The laminar distribution and morphological features of calbindin-D-28k-like immunoreactive structures were studied in 60-microns-thick sections of the human olfactory bulb. Except for the olfactory nerve layer, immunoreactive neurons were present in all layers of the olfactory bulb. They reached highest densities in the external plexiform layer and internal granule cell layer. Considerable numbers of calbindin-like nerve cells were also found in the olfactory tract and in distal portions of the anterior olfactory nucleus. When comparing the distribution of calbindin-positive structures to that of parvalbumin-positive ones a partially complementary distribution pattern was found. Calbindin-like immunoreactive portions of the anterior olfactory nucleus and olfactory tract were mirrored by immunonegative areas in adjacent sections stained for parvalbumin. Using the combined pigment-Nissl procedure we observed the presence of lipofuscin deposits in nearly 80% of all the calbindin-immunoreactive neurons analysed. Moreover, analysis of their lipofuscin deposits rendered the further differentiation of morphologically similar neuronal subpopulations possible. In contrast, all parvalbumin-like immunoreactive neurons remained free of lipofuscin granules.
Adult↗
Vasopressinergic neurons in the magnocellular nuclei of the human basal forebrain.
Vasopressinergic structures were examined within the magnocellular nuclei of the human basal forebrain. Vasopressinergic neurons were found in all parts of the diagonal band nucleus, and less frequently in the anteromedial subnucleus of the basal nucleus (Meynert). They belong to the group of large multipolar neurons, previously defined as type I neurons, characterized by fine lipofuscin granules widely spread within the soma. Species differences exist in the topographic arrangement of vasopressinergic structures.
Adult↗
Glutamic-acid-decarboxylase-and parvalbumin-like-immunoreactive structures in the olfactory bulb of the human adult.
This study examines the distribution and morphological characteristics of glutamic-acid-decarboxylase-like (GAD)- and parvalbumin-like (PA)-immunoreactive structures in the olfactory bulb of the human adult. GAD-immunoreactive somata occurred in the glomerular layer, the external granule cell layer, the more superficial portion of the external plexiform layer, and the internal granule cell layer. The cells were small- to medium-sized. Demonstration of lipofuscin pigment revealed the presence of unpigmented as well as pigmented neurons, thus suggesting the existence of two subpopulations of GAD-positive neurons. GAD-immunoreactive puncta and/or fibers were mainly seen in the periglomerular region and the internal granule cell layer. All other layers of the bulb, as well as the intrabulbar portion of the anterior olfactory nucleus, displayed considerably less of these puncta and/or fibers. The olfactory nerve layer remained practically clear of immunoreactive material. PA-immunoreactive somata occurred in the glomerular layer and both the external and internal granule cell layer. Only a small number of immunoreactive nerve cells were encountered within the white matter or the olfactory tract. Most PA-positive neurons displayed characteristics of short axon cells whereas a few others resembled van Gehuchten cells. All of the PA-immunoreactive neurons were devoid of lipofuscin pigment. Immunoreactive puncta and fibers were present in all layers though predominating in the periglomerular region, the olfactory nerve layer, and the internal granule cell layer. The intrabulbar portions of the anterior olfactory nucleus did not show any immunoreactive structures.
Adult↗
Auditory brainstem nuclei in Alzheimer's disease.
Serial sections of 7 Alzheimer brainstems were examined. The histopathological hallmarks were demonstrated by means of Kongo red- and silver-stained preparations. A subsequent counterstaining with a Nissl dye, allowing the cytoarchitectonical interpretation, revealed a considerable plaque formation in the central nucleus and the dorsomedial nucleus of the inferior colliculus. To a lesser degree plaques were also present in the deep layers of the dorsal cortex of the inferior colliculus. All other auditory brainstem nuclei were devoid of neuritic plaques. Neurofibrillary tangles were rarely seen. They occur in the dorsal cochlear nucleus, the periolivary region, the ventral nucleus of the lateral lemniscus, and in the central nucleus of the inferior colliculus.
Alzheimer Disease↗
The human oral raphe system. Architectonics and neuronal types in pigment-Nissl preparations.
Serial sections (15 microns, 120 microns, and 400 microns) of nine brain stems treated with a combined lipofuscin pigment-Nissl stain were examined in order to delineate the three-dimensional conformation and subdivisions as well as the neuronal types of the human oral raphe system. Characteristic lipofuscin deposits within the somata of various cell types facilitated the demarcation of the oral raphe nuclei from surrounding structures. The dorsal, central, and linear raphe nuclei, e.g. the major subdivisions of the oral raphe system, share common traits as far as neuronal composition and pigmentation is concerned. The interfascicular subnucleus, the dorsofascicular subnucleus, and the intercalate subnucleus are minor subdivisions of the dorsal raphe nucleus. The intercalate one cannot be differentiated from surrounding areas in preparations solely stained for Nissl-material, while it can facilely be identified in combined pigment-Nissl preparations by virtue of differences in the pigmentation pattern. Our architectonical concept of the oral raphe system is in good accordance with the one derived from immunocytochemical investigations of serotonin-containing neurons in the human brain stem. Furthermore, five main neuronal types are described which constitute the oral raphe nuclei. They have been differentiated according to their characteristics as seen in combined pigment-Nissl preparations. I) Large ovoid to polygonal neurons with densely packed and intensely stained pigment granules. II) Similarly featured cells displaying dust-fine and faintly stained pigment granules. III) Medium-sized, ovoid to polygonal neurons with loosely distributed, small pigment granules. IV) Small ovoid neurons devoid of pigment or with only few, intensely stained granules. V) Small spindle-shaped nerve cells with various amounts of intensely stained pigment granules.(ABSTRACT TRUNCATED AT 250 WORDS)
Autopsy↗
Reduced cAMP-signal transduction in postmortem hippocampus of demented old people.
The basal as well as the stimulated activity of the adenylate cyclase was determined in postmortem hippocampi. The tissue probes were obtained from 12 demented individuals (10 Alzheimer-type dementia; 1 Down's syndrome; 1 argyrophilic grains syndrome) and from 15 age-matched controls. The diagnoses were done in accordance with histopathological criteria. Adenylate cyclase was stimulated by isoprenaline, Gpp(NH)p, or forskolin. The amount of cAMP formed was determined by the protein binding method using a radioimmuno assay. In tissues of controls as well as of demented patients adenylate cyclase was stimulated in the rank order of isoprenaline less than Gpp (NH) p less than forskolin. In hippocampal tissues of demented individuals a significant reduction (50%, p less than 0.01) in basal as well as stimulated adenylate cyclase activity was found. This reduction in cAMP signal transduction is not caused by simple cell loss.
Adenylyl Cyclases↗
Neuropeptide Y-like immunoreactive neurons in the human olfactory bulb.
Neuropeptide Y-like (NPY) immunoreactivity was localized in the adult human olfactory bulb by the unlabeled antibody enzyme (peroxidase anti-peroxidase; PAP) technique in vibratome sections. The majority of NPY-immunoreactive somata was localized in the white matter surrounding the anterior olfactory nucleus. Immunoreactive neurons were less numerous within the anterior olfactory nucleus and within the olfactory bulb layers. NPY-immunoreactive fibres were present in the white matter, the anterior olfactory nucleus, and in the olfactory bulb layers. Fibres within the white matter were generally aligned in a straight path parallel to the long axis of the olfactory bulb and tract. Fibres within the anterior olfactory nucleus showed no clear orientation and displayed numerous branching points. Coiled plexus of NPY-immunoreactive fibres were present in the glomerular layer of the olfactory bulb. Additional characteristics of the NPY-immunoreactive neurons were studied after decolouring the chromogen and restaining the sections with aldehydefuchsin to demonstrate the presence of lipofuscin granules and also with gallocyanin chrome alum to stain the Nissl substance. This analysis showed that the neurons belong to the class of non-pigmented nerve cells.
Aged↗
Somatostatin-14-like immunoreactive neurons and fibres in the human olfactory bulb.
This study describes the morphological features and the distribution pattern of neurons in the human olfactory bulb which are immunoreactive for an antiserum against the neuropeptide somatostatin-14. Immunoreactive nerve cell bodies were mainly found in the white matter surrounding the cell clusters of the anterior olfactory nucleus. Some immunoreactive neurons were also found scattered throughout the anterior olfactory nucleus and the deeper parts of the inner granule cell layer. Only a few immunoreactive neurons were localized in the glomerular layer and the outer granule cell layer. Immunoreactive fibres were found in all layers of the olfactory bulb. In addition, an impressive number of coiled and kinked immunoreactive fibres were localized within the anterior olfactory nucleus forming a dense plexus. Accumulations of twisted and coiled branches of immunoreactive fibres were rarely found either surrounding or within the olfactory glomerula. The characteristics of somatostatin-14 immunoreactive neurons as seen in the combined pigment-Nissl preparation were studied after decolourizing the chromogen and restaining the preparations with aldehydefuchsin in order to demonstrate the lipofuscin pigment and gallocyanin chrome alum for Nissl material. About 90% of the immunoreactive neurons studied in this manner turned out to be devoid of lipofuscin granules. The remaining 10% displayed different patterns of pigmentation. These findings suggest the presence of different types of somatostatin-14-like immunoreactive neurons in the olfactory bulb of the human adult.
Adult↗
The pigmented subpeduncular nucleus: a neuromelanin-containing nucleus in the human pontine tegmentum. Morphology and changes in Alzheimer's disease.
A nuclear gray is found in the human pontine tegmentum close to the lower circumference of the superior cerebellar peduncle and is located within the pedunculo-lemniscal trigone. It is mainly characterized by the presence of medium-sized neuro-melanin-containing neurons and, therefore, referred to as the pigmented subpeduncular nucleus. Three basic neuronal types occur within the boundaries of the nucleus. Scattered among the neuromelanin-containing type I nerve cells are type II cells with lipofuscin deposits and type III neurons devoid of any pigmentation. In cases of Alzheimer-type dementia, the pigmented subpeduncular nucleus shows severe changes. Neurofibrillary tangles can frequently be found within the somata of both the melanin-laden and the lipofuscin-containing neurons. In contrast, the non-pigmented nerve cells remain devoid of such pathological filaments. Furthermore, large numbers of neuropil threads are scattered throughout the nuclear gray.
Alzheimer Disease↗
Olfactory bulb changes in Alzheimer's disease.
Olfactory bulbs in cases of Alzheimer's disease and age-matched controls have been examined by means of combining silver staining of pathological filaments with pigment-Nissl staining of the cell bodies. Neuritic plaques were found in the anterior olfactory nucleus. Neurofibrillary tangles and neuropil threads occurred in the anterior olfactory nucleus and in all layers of the olfactory bulb except the outer fibrous layer. The tangle-bearing neurons of the olfactory bulb were identified as tufted cells, outer granule cells, and two different types of nerve cells forming the rostral part of the anterior olfactory nucleus.
Alzheimer Disease↗
Unbiased estimation of neuronal numbers in the human nucleus coeruleus during aging.
The total number of the neuromelanin-containing neurons of the nucleus coeruleus was determined by means of a newly developed unbiased stereological counting scheme and a low-cost apparative set-up. The individuals (n = 20, age from 49-98 years) included in this study were carefully examined for absence of neurological or psychiatric disorders. However, minor Alzheimer's disease-related neurofibrillary changes occurred in some of the individuals of higher age and these changes were staged. The mean number of neurons per side of the nucleus coeruleus was 15,731 +/- 3,408 SD with a range from 11,737 to 25,319. In three individuals, we compared the left and right nuclei and did not observe significant side differences between the numbers of neurons. There was no correlation between the age of the individuals and the cell number. Also, no correlation was detected between the cell number and the staged occurrence of minor neurofibrillary changes of the Alzheimer type. Due to the novel counting method, the determination of the total cell number took less than 2 h per case.
Age Factors↗
Spatial, temporal and numeric analysis of Alzheimer changes in the nucleus coeruleus.
The distribution of neurofibrillary tangles in the nucleus coeruleus was topographically and quantitatively analyzed. The topographical analysis showed statistically significant differences with regard to the distribution of neurofibrillary tangles in the dorsal-ventral and medial-lateral axes. More neurofibrillary tangles were found to be located in the dorsal and medial regions than in ventral and lateral areas. No significant difference in neurofibrillary tangle content was found between the rostral and the caudal areas of the nucleus coeruleus. Neurofibrillary tangle formation begins in the central parts of the nucleus coeruleus. The total number of neuromelanized neurons in the nucleus coeruleus was determined using a modern, unbiased sampling scheme and related to the cortical stage of Alzheimer's disease-related neurofibrillary changes present. A statistically significant reduction (50%) in nucleus coeruleus neurons was evident only in cases meeting the histopathological criteria for Alzheimer's disease. The extent of reduction in the total number of neurons in the nucleus coeruleus did not correlate with the number of neurofibrillary tangles observed. Our data suggest that despite the relatively early susceptibility of the nucleus coeruleus to neurofibrillary tangle formation, significant neuronal loss appears to occur much later, with an estimated average delay time of at least 25 years. Nonetheless, comparison of the topographical pattern of neurofibrillary tangle formation and cell loss indicates that neuronal loss is tangle-related.
Age Factors↗
Decrease in adenylate cyclase activity antecedes neurofibrillary tangle formation.
In previous studies, the formation of cAMP was seen to be significantly reduced in various brain regions in Alzheimer patients. Recently, a staging system was introduced in which Alzheimer-related. histopathological changes were classified according to the pattern of alterations rather than their density. In this study, we examined the degree of correlation between these stages and the postmortem activity of the CAMP-generating enzyme adenylate cyclase. Our findings suggest that forskolin-stimulated adenylate cyclase activity is significantly decreased before major neurofibrillary changes develop. Early impairment of postreceptor signalling could have potentially important consequences for drug treatment and/or for the development of neurofibrillary changes.
Adenylyl Cyclases↗