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Results for “selective vulnerability”

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PubMed1979

Ischemic lesions of the hippocampus and their relation to Ammon's horn sclerosis. A neuropathological study of two cases and a comparison to the vascular anatomy.

Two adult brains with small ischemic lesions in the hippocampus, due to impairment of the supply from the posterior cerebral artery, are presented. The first case corresponds to what is described in the literature as "incisural sclerosis" and shows no difference in vulnerability between the Sommer and the Spielmeyer sector. In the second case the hippocampal lesion is due to an embolic occlusion of the posterior cerebral artery and consists of selective necrosis of the subiculum, the Sommer sector and part of the endfolium of the pyramidal layer, the Spielmeyer sector remaining noninfarcted. The postmortem angiograms of 12l hippocampi of adults, as well as full term born and premature infants, show that the h1 and h2 sectors and part of the h3 sector of the hippocampus are supplied by the same "sulcus" arteries. Although there is a selective vulnerability to ischemia in some sectors of the hippocampus, which is typical for Ammon's horn sclerosis, this cannot be explained by a difference of arterial supply or by compression of arteries during the process of birth.

Blood Vessels↗

PubMed1992

An immediate light microscopic response of neuronal somata, dendrites and axons to non-contusing concussive head injury in the rat.

Sixteen rats were killed by transcardial perfusion fixation 1 min after a non-contusing concussive head injury, and seven rats 1 day later. In each of the "1-min" animals Golgi-like neurons and long axonal segments scattered in various proportions among unstained neurons and axons were demonstrated by a new silver method both near to and far from the impact site in a parenchymal environment unaffected by contusion. The silver-stained neurons, dendrites and axons were considered to have been damaged by the trauma because they were consistently absent from control brains. In the "1-day" brains silver-stained dendrites and axons had a beaded appearance, indicating an advanced stage of morphopathological damage. From details of these findings the following conclusions were drawn: (1) trauma can directly induce some kind of morphopathological damage in neurons which manifests itself in shrinkage of the soma and tortuosity of appendages as well as in type III argyrophilia; (2) different vulnerability of various brain areas is likely due to the inhomogeneity of the trauma-induced pressure wave propagating through the brain; and (3) the somato-dendritic and axonal domains of the neuron are selectively vulnerable to different values of the parameters of the intracranial pressure wave.

Animals↗

PubMed2026

Single-cell transcriptomic atlas of Alzheimer's disease middle temporal gyrus reveals region, cell type, and sex specificity of gene expression with novel genetic risk for MERTK in female.

BackgroundAlzheimer's disease (AD), the most common age-related neurodegenerative disease, is closely associated with both amyloid-β plaque and neuroinflammation. Two thirds of AD patients are female, and they have a higher disease risk; women with AD have more extensive brain histological changes than men along with more severe cognitive symptoms and neurodegeneration.ObjectiveThis study aimed to determine how sex difference induces structural brain changes and molecular cell vulnerabilities in AD, with a focus on identifying sex-specific transcriptional alterations and genetic risk factors.MethodsWe performed single nucleus RNA sequencing on postmortem brains from individuals with AD and age- and sex-matched controls, focusing on the middle temporal gyrus, a cortical brain region strongly affected by the disease, and integrated single nucleus RNA sequencing results with genome-wide association study (GWAS) data using cell type-specific enrichment and generalized gene-set analysis approaches. The analysis pipeline is provided with threshold information.ResultsWe identified a selectively vulnerable subpopulation of layer 2/3 excitatory neurons that were RORB-negative and CDH9-expressing in both males and females. Disease-associated, but sex-independent, reactive astrocyte signatures were also present. In clear contrast, the microglia signatures of AD brains differed between males and females. Integrating single cell transcriptomic data with results from GWAS, we identified MERTK genetic variation as a candidate novel risk factor for AD selectively in females.ConclusionsTaken together, our single cell atlas of middle temporal gyrus revealed a unique cellular-level view of sex-specific transcriptional changes in AD, illuminating GWAS identification of sex-specific AD genes. These data serve as a rich resource for interrogation of the molecular and cellular basis of AD.

Alzheimer's disease↗

PubMed2023

Single-cell transcriptomic atlas of Alzheimer's disease middle temporal gyrus reveals region, cell type and sex specificity of gene expression with novel genetic risk for MERTK in female.

Alzheimer's disease, the most common age-related neurodegenerative disease, is closely associated with both amyloid-ß plaque and neuroinflammation. Two thirds of Alzheimer's disease patients are females and they have a higher disease risk. Moreover, women with Alzheimer's disease have more extensive brain histological changes than men along with more severe cognitive symptoms and neurodegeneration. To identify how sex difference induces structural brain changes, we performed unbiased massively parallel single nucleus RNA sequencing on Alzheimer's disease and control brains focusing on the middle temporal gyrus, a brain region strongly affected by the disease but not previously studied with these methods. We identified a subpopulation of selectively vulnerable layer 2/3 excitatory neurons that that were RORB-negative and CDH9-expressing. This vulnerability differs from that reported for other brain regions, but there was no detectable difference between male and female patterns in middle temporal gyrus samples. Disease-associated, but sex-independent, reactive astrocyte signatures were also present. In clear contrast, the microglia signatures of diseased brains differed between males and females. Combining single cell transcriptomic data with results from genome-wide association studies (GWAS), we identified MERTK genetic variation as a risk factor for Alzheimer's disease selectively in females. Taken together, our single cell dataset revealed a unique cellular-level view of sex-specific transcriptional changes in Alzheimer's disease, illuminating GWAS identification of sex-specific Alzheimer's risk genes. These data serve as a rich resource for interrogation of the molecular and cellular basis of Alzheimer's disease.

Journal Article↗

PubMed1992

Why are nigral catecholaminergic neurons more vulnerable than other cells in Parkinson's disease?

Although the cause of neuronal death in Parkinson's disease remains unknown, a hyperoxidation phenomenon has been implicated as a potential cytotoxic mechanism. Catecholaminergic neurons containing neuromelanin, an autoxidation byproduct of catecholamines, are more vulnerable in Parkinson's disease than nonmelanized catecholaminergic neurons. High levels of CuZn superoxide dismutase mRNA have been observed in the substantia nigra, suggesting that high levels of oxygen free radicals are indeed produced in the structure. Catecholaminergic neurons surrounded by a low density of glutathione peroxidase cells are more susceptible to degeneration in Parkinson's disease than those well protected against oxidative stress. The nigral content in iron, a compound that exacerbates the production of free radicals in catecholaminergic neurons, is increased in Parkinson's disease. Altogether these data suggest that hyperoxidation may participate in the selective vulnerability of catecholaminergic neurons in Parkinson's disease.

Calcium↗

PubMed2024

Heterozygous knockout of Synaptotagmin13 phenocopies ALS features and TP53 activation in human motor neurons.

Spinal motor neurons (MNs) represent a highly vulnerable cellular population, which is affected in fatal neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). In this study, we show that the heterozygous loss of SYT13 is sufficient to trigger a neurodegenerative phenotype resembling those observed in ALS and SMA. SYT13+/- hiPSC-derived MNs displayed a progressive manifestation of typical neurodegenerative hallmarks such as loss of synaptic contacts and accumulation of aberrant aggregates. Moreover, analysis of the SYT13+/- transcriptome revealed a significant impairment in biological mechanisms involved in motoneuron specification and spinal cord differentiation. This transcriptional portrait also strikingly correlated with ALS signatures, displaying a significant convergence toward the expression of pro-apoptotic and pro-inflammatory genes, which are controlled by the transcription factor TP53. Our data show for the first time that the heterozygous loss of a single member of the synaptotagmin family, SYT13, is sufficient to trigger a series of abnormal alterations leading to MN sufferance, thus revealing novel insights into the selective vulnerability of this cell population.

Humans↗

PubMed1992

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↗

PubMed1992

Differential expression of cytochrome oxidase (COX) genes in different regions of monkey brain.

A frontal pole cDNA library from monkey (Macaca mulatta) brain was screened to identify mRNAs that are expressed more in frontal pole as compared to primary visual cortex. Three cDNA clones, whose greater expression was confirmed by Northern blot analysis, were identified as cytochrome oxidase (COX) subunits I, II, and III (COX I, II, and III). Each clone showed higher levels of mRNA in the frontal pole, dorsal lateral prefrontal cortex, and hippocampus than in the primary visual or somatosensory cortices. COX histochemistry of prefrontal, visual, and somatosensory cortical regions demonstrated heterogeneous distributions, with highest activity in dendrite-rich neuropil of the cortex. A laminar distribution of COX mRNA expression also was demonstrated with in situ hybridization. mRNA was detected in cell bodies and in apical dendrites. These results indicate region specific differences in the distribution of COX activity and in the corresponding mRNA for three of its subunits within the monkey brain. Such differences may be related to differences in the distribution of neuropil as compared with cell bodies among the brain regions studied, and may be relevant to selective vulnerability in Alzheimer's disease.

Animals↗

PubMed1992

Insulin increases amino acid transport into rat soleus motor axons.

Hyperosmotic neurosecretion was used to measure basal and insulin-stimulated amino acid and myoinosital transport into rat motor nerve terminals. L-Alanine and alpha(methylamino)-isobutyric acid (a nonmetabolizable system A-specific analog) transport was rapid into motor nerve terminals innervating a fast-twitch muscle, the extensor digitorum longus, and slow into motor nerve terminals innervating the soleus, a slow-twitch muscle. A physiological concentration of insulin, 10 microU/mL, increased L-alanine and alpha(methylamino)-isobutyric acid transport into motor nerve terminals in the soleus. Large doses of insulin, 100 or 1000 microU/mL, had no effect on L-alanine or alpha(methylamino)-isobutyric acid transport into nerve terminals in the extensor digitorum longus. There was negligible basal or insulin-stimulated transport of D-alanine or myoinositol into nerve terminals of the soleus or extensor digitorum longus. These studies show that insulin regulates sterospecific amino acid transport into soleus motor axons, but has no effect on the rapid amino acid transport into extensor digitorum longus motor axons. Differences in basal and insulin-stimulated transport suggest that motor axons differ in their metabolism, and might be selectively vulnerable to disease processes.

Amino Acids↗

PubMed1992

The microglial reaction in the rat hippocampus following global ischemia: immuno-electron microscopy.

Transient arrest of the cerebral circulation leads to neuronal cell death in selectively vulnerable regions of the central nervous system. It has recently been shown at the light microscopical level that neuronal necrosis is accompanied by a rapid microglial reaction in ischemia (Gehrmann et al. (1992) J. Cereb. Blood Flow Metab. 12:257-269). In the present study we have examined the postischemic microglial reaction in the dorsal rat hippocampus at the ultrastructural level using immuno-electron microscopy. Global ischemia was produced by 30 min of four-vessel occlusion and the microglial reaction then studied after 8, 24 and 72 h. In sham-operated controls microglial cells were not phagocytic; they were randomly distributed throughout the neuropil and occasionally made contacts with other structures such as dendrites in CA1. Ultrastructural signs of activation were observed from 1 day postlesion onward. Reactive microglial cells were consistently seen to phagocytose degenerating neurons particularly in the CA1 stratum pyramidale and in the CA4 sector. They were sometimes interposed between two morphologically distinct types of CA1 neurons, i.e., "dark" (degenerating) and "pale" (surviving) types of neurons. Phagocytic microglial cells also became positive for major histocompatibility complex (MHC) class II antigens at these locations from 1 day after ischemia onward. Furthermore, activated microglial cells were frequent along degenerating dendrites in the stratum radiatum of CA1. After survival times of up to 72 h microglial cells, but not astrocytes, were occasionally observed to undergo mitosis. In addition to their random distribution across the neuropil, microglial cells were frequently observed in a perivascular position under normal conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1978

Topographic distribution of neurofibrillary tangles and granulovacuolar degeneration in hippocampal cortex of aging and demented patients. A quantitative study.

Topographic analysis was performed of the distribution of Alzheimer's neurofibrillary tangles and the granulovacuolar degeneration of Simchowicz in the hippocampal cortex of patients with Alzheimer's dementia and mentally normal aged controls. A semiautomated scanning stage microscope was linked potentiometrically to an XY pen recorder in order to plot cytoarchitectonic "scattergrams" from the sequentially screened hippocampal formations. The density of both lesions per cubic mm of pyramidal cortex was quantified by measuring the area of each of six "zones", using a digitizer and programmable calculator. In elderly normal brains as well as those of Alzheimer's disease, the statistically most representative ranking order of predilection for neurofibrillary tangles (in decreasing severity) was: entorhinal cortex greater than subiculum greater than H1 greater than end-plate greater than presubiculum greater than H2. For granulovacuolar degeneration the best rank order was: subiculum greater than H1 greater than H2 greater than end-plate greater than entorhinal cortex greater than presubiculum. The notable similarities of both such orders of predilection to the well-recognized "selective vulnerability" of certain hippocampal neurones in clinical conditions of hypoxia, ischemia and epilepsy suggest some common, focally accentuated cytotoxic mechanism may underlie all these regional predispositions.

Age Factors↗

PubMed1975

Experimental cerebral ischemia in mongolian gerbils. I. Light microscopic observations.

Light microscopic observations were carried out on Mongolian gerbils (Meriones unguiculatus) subjected to a partial cerebral ischemia by occlusion of the left common carotid artery at the neck. About 30% of gerbils developed an ischemic injury in the ipsilateral hemisphere and their brains revealed the following histopathologic features: 1. the changes were related to the intensity (duration) of the ischemic insult and to the time elapsed following release of the occlusion. The ischemic lesions appear to progress after re-establishment of the circulation and this presents one facet of a "maturation" phenomenon which seems to be a general principle applicable to various parameters of ischemic injury. The rate of "maturation" of the lesions is related to the intensity of the ischemic insult, a lesser intensity resulting in longer development of lesions. 2. The changes were either focal or diffuse in character. The former were assumed to be directly related to a vascular involvement; among the latter the topistic distribution of the hippocampal changes suggested a feature of selective vulnerability. 3. An indirect indication of neuronal recovery was surmised from observations on animals sacrificed after different periods following occlusions of the same duration. Also capable of recovery was a "reactive change" observed in the H3 neurons of the hippocampus. This change was characterized by central chromatolysis and resembled the "rimäre Reizung" of Nissl.

Animals↗

PubMed1978

Loss of pigment-laden stellate cells: a severe alteration of the isocortex in juvenile neuronal ceroid-lipofuscinosis.

Juvenile neuronal ceroid-lipofuscinosis is associated with a moderate numerical decrease of isocortical neurons. From Nissl preparations, it is not apparent, whether this neuronal rarefication occurs at random or affects specific types of cortical neurons. Lipopigment preparations facilitate the distinction between pyramidal and stellate cells. In juvenile neuronal ceroid-lipofuscinosis, they reveal an almost complete to total loss of small pigment-laden stellate cells. This type of local circuit neurons, scattered throughout the corpuscular and pyramidal layer in varying numbers and patterns of distribution, is common to all isocortical regions. Its pronounced and selective vulnerability in this lysosomal disease may be causally related to the marked functional impairment of the brain.

Adolescent↗

PubMed1978

Experimental stroke in gerbils: effect on translation and transcription.

The effect of cerebral ischemia on polypeptide synthesis with isolated microsomes and DNA-dependent RNA polymerase activity with isolated nuclei was investigated by occlusion of right common carotid artery of gerbils. There was a prompt decline of microsomal polypeptide synthesis already at 30 min after occlusion of the artery, and at 4--5 h the specific radioactivity (dpm per microgram protein) was 50% of the control value. At 24 h, when the animals were only slightly responsive to external stimuli, the specific radioactivity of ischemic brain was only 20% of the control value. DNA-dependent RNA polymerase activity was unaffected for 1 h, and clear suppression did not appear until 3 h after occlusion. However, the extent of suppression was similar between polypeptide synthesis and RNA polymerase activity beyond 3 h after occlusion. Although more selective vulnerability of polypeptide synthesis thus exists in cerebral ischemia, the difference between two biochemical processes was not as striking as seen in cerebral anoxia. Focal progression of cerebral ischemia to diffuse infarction in gerbils was suggested as a possible explanation for the disparity in comparison to the diffuse effect in cerebral anoxia along with the difference in the magnitude of acidosis and depletion of energy reserve.

Animals↗

PubMed1992

Density and distribution of excitatory amino acid receptors in the developing human fetal brain: a quantitative autoradiographic study.

The binding of [alpha-3H]amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to quisqualate receptors, [3H]kainate (KA) to KA receptors, and L-[3H]glutamate to N-methyl-D-aspartate (NMDA) receptors was determined by quantitative autoradiography in brains obtained from twelve aborted human fetuses ranging from 16.5 to 26 weeks of gestational age. Among the three receptor subtypes, specific binding to AMPA was the highest, followed by NMDA and KA, respectively, in all age groups. Receptor binding was already apparent by 16.5 weeks in the hippocampus, thalamus, and subthalamic nucleus, rose sharply by 20-21.5 weeks, and subsequently declined to their lowest levels by 24-26 weeks. Anatomically distinct binding patterns for each of the three major excitatory amino acid (EAA) receptor subtypes were well established by 20-21.5 weeks. Within the hippocampus, AMPA was localized primarily in the stratum pyramidale, NMDA in the stratum radiatum, and KA in the molecular layer of the dentate gyrus and in the stratum lucidum of the CA3 region. The cerebral cortex showed dense labeling of AMPA in the outer layers, whereas KA binding was more prominent within the inner layers. The putamen and globus pallidus also showed relatively dense receptor binding in all age groups. The sharp rise in receptor density at 20-21.5 weeks of age suggests involvement of EAA pathways in developmental plasticity, including reorganization of neuronal processes or synapses, during this period of development. Developmental changes in the density and distribution of EAA receptors, as shown in this study, may also provide insight into shifts in the localization of age-dependent selective vulnerability within the developing human fetal brain.

Autoradiography↗

PubMed1992

Lifelong ethanol consumption enhances the age-related changes in rat sympathetic neurons.

The effects of aging and chronic ethanol administration on the histochemical and morphometric features of rat superior cervical ganglion were studied in a rat strain selected for voluntary alcohol consumption. Ethanol was administered to the experimental group ad libitum (10% v/v in drinking water) from 3 months to 28 months of age, the average ethanol intake being 6.4-5.4 g/kg per day. The sympathetic neurons of the ethanol consuming rats showed several signs of enhanced degeneration, e.g. decreased neuronal packing density, increased amount of age-pigment and decreased intensity of catecholamine histofluorescence and tyrosine hydroxylase immunoreactivity. The results may indicate a selective vulnerability of peripheral sympathetic neurons rather than a universal accelerated aging due to chronic ethanol exposure.

Aging↗

PubMed1992

Ultrastructure of spared dopamine terminals in caudate-putamen nuclei of adult rats neonatally treated with intranigral 6-hydroxydopamine.

Residual dopamine terminals in the dorsal striatum, caudate-putamen nuclei (CPN), of adult rats neonatally lesioned with 6-hydroxydopamine (6-OHDA) sustain a relatively high level of dopamine release. We examined whether there were morphological differences in the spared dopamine terminals that might correlate with this increased efficacy. Postnatal male rat pups from 50 litters were pretreated with desmethylimipramine (DMI) to protect from non-specific monoamine damage, then given unilateral intranigral injections of 6-OHDA or vehicle. Coronal sections through the CPN and substantia nigra of the surviving adult animals from each litter were co-processed for immunoautoradiographic or immunoperoxidase localization of the catecholamine synthesizing enzyme, tyrosine hydroxylase (TH). Quantitative ultrastructural analysis established that in animals showing maximal (greater than 90%) depletions in immunoautoradiographic labeling for TH, the number of TH-labeled axons in the CPN ipsilateral to the 6-OHDA injections was reduced to one third of the number seen in the contralateral, unlesioned hemisphere, or the CPN from vehicle-injected animals. The ultrastructural features of residual terminals ipsilateral to 6-OHDA lesions were morphologically similar to those of the contralateral side or in vehicle-injected animals. However, in comparison with controls, these TH-labeled terminals had significantly larger mean cross-sectional diameters. When subdivided into groups according to size, there were significantly fewer small (0.0-0.1 micron 2) and more large (0.41-0.50 micron 2) TH-immunoreactive profiles in lesioned versus unlesioned CPN. The remaining TH-labeled terminals ipsilateral to the 6-OHDA lesions also appeared to be more often in direct contact with unlabeled soma and proximal dendrites as opposed to dendritic spines in the unlesioned CPN. These results suggest that the enhanced activity of dopamine neurons innervating the CPN after nigral 6-OHDA lesions may contribute to changes in size and target of their terminals. Alternatively, the observed large size of remaining dopamine terminals may reflect selective vulnerability of smaller axons to 6-OHDA toxicity.

Aging↗

PubMed1992

The neurofilament triplet is present in distinct subpopulations of neurons in the central nervous system of the guinea-pig.

It is commonly assumed that most, if not all, neurons contain the intermediate filament protein class known as the neurofilament protein-triplet. The following study investigated the distribution of neurofilament protein-triplet immunoreactivity in selected regions of the guinea-pig central nervous system using monoclonal antibodies directed against phosphorylation-independent epitopes on the three subunits under optimal tissue processing conditions. Neurofilament protein-triplet immunoreactivity was present in distinct subpopulations of neurons in the cerebellar cortex, neocortex, hippocampal formation, retina, striatum and medulla oblongata. In many of these regions, labelled neurons represented only a small proportion of the total. The selective distribution of this intermediate filament protein class was confirmed in double-labelling experiments using antibodies to the neurofilament protein-triplet in combination with antibodies to other neuronal markers. The distribution of neurofilament protein-triplet immunoreactivity also correlated with the distribution of staining observed with a silver impregnation method based on Bielschowsky. The present results in combination with previous observations have demonstrated that the neurofilament protein-triplet is found in specific subclasses of neurons in different regions of the nervous system. Content of this intermediate filament protein class does not appear to be correlated with neuronal size or length of projection. These results also suggest that the selectivity of staining between neuronal classes observed with classical silver impregnation methods may be due to the presence or absence of the neurofilament protein-triplet. The present results may also provide a new perspective on the basis of the selective vulnerability of neurons in degenerative diseases.

Animals↗