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Results for “selective vulnerability”

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PubMed1988

Activity-dependent regulation of GABA expression in the visual cortex of adult monkeys.

Levels of the inhibitory transmitter, GABA, and its synthesizing enzyme, GAD, appear to be regulated in the visual cortex of young adult monkeys in an activity-dependent manner. In monkeys subjected to monocular deprivation by eye removal, tetrodotoxin injection, or eyelide suture, the number of GABA and GAD immunoreactive neurons in deprived-eye columns of the cortex is reduced by up to 50%. This effect is unaccompanied by cell death and is reversible. After cessation of TTX injection or reopening of the eyes, the number of immunostained cells returns to normal. The effect appears after 4-5 days of eye removal or tetrodotoxin injection, but only after 7-16 weeks of eyelid suture. In the latter case, it is more severe in the younger monkeys. The reversible reduction in GABA and GAD immunostaining extends out of layer IVC into lay IVA and to neurons around but not in cytochrome oxidase periodicities of layer III. This may indicate selective vulnerability of GABA cells sensitive to high spatial frequency.

Animals↗

PubMed1993

Assessment of neurological injury due to circulatory arrest during profound hypothermia. An experimental study in vertebrates.

To investigate brain changes in induced deep core hypothermia (15 degrees C) with circulatory arrest, five groups of neonatal pigs were subjected to cardiopulmonary bypass (CPB), with circulatory arrest (CA) periods varying from 70-120 min. The parameters analysed were: 1. Histology and electron microscopy of the brain six hours post-CPB, 2. Creatinophosphokinase (CPK) from cerebrospinal fluid (CSF), 3. Vasointestinal neuropeptide (VIP) and 7B2 specific neuropeptide both in plasma and brain tissue. The earliest morphological changes were seen after 90 min CA and were highly significant after 120 min arrest. These changes involved mainly the Purkinje cells of the interior half of the cerebellum with vacuolation in their cytoplasm. A rise in CPK in CSF occurred in all piglet-groups. The differences among the various groups were highly significant at 2 and 5 h post-CPB. (P < 0.05). Statistically significant differences were not exhibited among the various groups both in serum and brain tissue total mean values of VIP and 7B2 neuropeptides. We suggest that 1. The cerebellar region is the most sensitive where ischemic lesions attain their maximal severity and extent; the frequency and pattern of selective vulnerability of the cerebellum may be related primarily to its pattern of blood supply 2. The maximum time of CA without histopathological sequelae should not exceed 70 min.

Anesthesia, General↗

PubMed2005

Hereditary optic neuropathies: from the mitochondria to the optic nerve.

PURPOSE: To review our current knowledge of inherited optic neuropathies. DESIGN: Perspective. METHODS: Literature review. RESULTS: The hereditary optic neuropathies consist of a group of disorders in which optic nerve dysfunction figures solely or prominently and direct inheritance is clinically or genetically proven. The most common of these disorders are autosomal dominant optic atrophy (Kjers' disease) and maternally-inherited Leber's hereditary optic neuropathy. Other inherited neurologic and systemic syndromic diseases will frequently manifest optic neuropathy. A selective vulnerability of the optic nerve to perturbations in mitochondrial function may underlie a final common pathway among these disorders. CONCLUSIONS: The ophthalmologist should be familiar with the clinical characteristics and diagnosis of the hereditary optic neuropathies. Recent advances in our understanding of the underlying pathophysiology of the inherited optic neuropathies may provide insight into their treatment and the treatment of acquired optic nerve disorders.

Humans↗

PubMed2004

Neurological disorders produced by Clostridium perfringens type D epsilon toxin.

Although the epsilon toxin of Clostridium perfringens type D produces disease in many species of domestic livestock, neurological disturbance is more common and better studied in sheep. High levels of circulating toxin, especially in lambs, cause cerebral microvascular endothelial damage with disruption of the blood-brain barrier leading to a severe, diffuse vasogenic oedema and an acute or peracute clinical course to death. With lower toxin levels, or in partially immune sheep, a focal, bilaterally symmetrical encephalomalacia sometimes occurs in selectively vulnerable brain regions after a more protracted clinical course, but the pathogenesis is uncertain.

Journal Article↗

PubMed2006

Functional biology of the neuronal ceroid lipofuscinoses (NCL) proteins.

Neuronal ceroid lipofucinoses (NCLs) are a group of severe neurodegenerative disorders characterized by accumulation of autofluorescent ceroid lipopigment in patients' cells. The different forms of NCL share many similar pathological features but result from mutations in different genes. The genes affected in NCLs encode both soluble and transmembrane proteins and are localized to ER or to the endosomes/lysosomes. Due to selective vulnerability of the central nervous system in the NCL disorders, the corresponding proteins are proposed to have important, tissue specific roles in the brain. The pathological similarities of the different NCLs have led not only to the grouping of these disorders but also to suggestion that the NCL proteins function in the same biological pathway. Despite extensive research, including the development of several model organisms for NCLs and establishment of high-throughput techniques, the precise biological function of many of the NCL proteins has remained elusive. The aim of this review is to summarize the current knowledge of the functions, or proposed functions, of the different NCL proteins.

Aminopeptidases↗

PubMed2006

Longitudinal study of the effects of a high-fat diet on glucose regulation, hippocampal function, and cerebral insulin sensitivity in C57BL/6 mice.

Although the increasing rate of obesity has stimulated interest in the effects of diet composition on peripheral systems, comparatively little work has been done to examine effects upon the brain. A diet high in fat is one of many factors that can promote obesity, and previous research has shown that such a diet can produce learning and memory impairment in rodents. In the present study, C57BL/6 mice were placed on either a high-fat (45% kcal fat) or regular (5% kcal fat) diet, and examined at different points during the subsequent year. The high-fat diet led to increased weight gain, significant impairment in glucoregulation, and altered insulin-mediated signaling within the hippocampus, an area of the brain believed to be important for the acquisition of memory. Following ten months on either diet, synaptic function in ex vivo hippocampal slices was examined, and neither stimulus-response curves nor electrically induced long-term potentiation were found to be different. As well, performance in the Morris water maze, a hippocampal-dependent test of spatial memory, was not influenced by diet. However, mice consuming a high-fat diet failed to perform an operant bar-pressing task, indicating a significant impairment to procedural learning and consolidation processes. Despite causing broad peripheral changes in C57BL/6 mice, consuming a large proportion of calories from saturated fat had only a limited effect upon learning and memory, which suggests that certain aspects of brain function are selectively vulnerable to the influences of diet.

Analysis of Variance↗

PubMed2005

Molecular aging in human prefrontal cortex is selective and continuous throughout adult life.

BACKGROUND: Aging leads to morphologic and functional changes in the brain and is associated with increased risk for psychiatric and neurological disorders. METHODS: To identify age-related transcriptional changes in the human brain, we profiled gene expression in two prefrontal cortex (PFC) areas in postmortem samples from 39 subjects, ranging in age from 13 to 79 years. RESULTS: Robust transcriptional age-related changes were identified for at least 540 genes. Gene expression correlates of aging were highly specific, and the large majority of the 22,000 transcripts investigated were unaffected by age. Across subjects, changes were progressive throughout adult life and accurately predicted chronological age. Age-upregulated transcripts were mostly of glial origin and related to inflammation and cellular defenses, whereas downregulated genes displayed mostly neuron-enriched transcripts relating to cellular communication and signaling. CONCLUSIONS: Continuous changes in gene expression with increasing age revealed a "molecular profile" of aging in human PFC. The restricted scope of the transcript changes suggests cellular populations or functions that are selectively vulnerable during aging. Because age-related gene expression changes begin early in adulthood and are continuous throughout life, our results suggest the possibility of identifying early cellular mechanisms that may be engaged in preventive or detrimental age-related brain functions.

Adolescent↗

PubMed2006

Hippocampal volume and mood disorders after traumatic brain injury.

BACKGROUND: Recent evidence from clinical studies and animal models of traumatic brain injury (TBI) suggest that neuronal and glial loss might progress after the initial insult in selectively vulnerable regions of the brain such as the hippocampus. There is also evidence that hippocampal dysfunction plays a role in the pathogenesis of mood disorders. We examined the relationship between hippocampal damage and mood disorders after TBI and the effect of hippocampal atrophy on the outcome of TBI patients. METHODS: The study group consisted of 37 patients with closed head injury who were evaluated at baseline and at 3, 6, and 12 months after trauma. Psychiatric diagnosis was made with a structured clinical interview and DSM-IV criteria. Quantitative magnetic resonance imaging scans were obtained at 3-months follow-up. RESULTS: Patients with moderate to severe head injury had significantly lower hippocampal volumes than patients with mild TBI. Patients who developed mood disorders had significantly lower hippocampal volumes than patients without mood disturbance. Furthermore, there was a significant interaction between mood disorders diagnosis and severity of TBI, by which patients with moderate to severe TBI who developed mood disorders had significantly smaller hippocampal volumes than patients with equivalent severe TBI who did not develop mood disturbance. Finally, reduced hippocampal volumes were associated with poor vocational outcome at 1-year follow-up. CONCLUSIONS: Our findings are consistent with a "double-hit" mechanism by which neural and glial elements already affected by trauma are further compromised by the functional changes associated with mood disorders (e.g., the neurotoxic effects of increased levels of cortisol or excitotoxic damage resulting from overactivation of glutaminergic pathways). Finally, patients with greater hippocampal damage were less likely to return to a productive life 1 year after trauma.

Adolescent↗

PubMed2003

AMPA-induced dark cell degeneration of cerebellar Purkinje neurons involves activation of caspases and apparent mitochondrial dysfunction.

Cerebellar Purkinje neurons (PNs) are selectively vulnerable to AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepriopionic acid)-induced delayed neurotoxicity known as dark cell degeneration (DCD) that is expressed as cytoplasmic and nuclear condensation, neuron shrinkage, and failure of physiology. The present study was initiated to determine whether AMPA-receptor-induced DCD in PNs is associated with Bax translocation to the mitochondria, cytochrome C release from the mitochondria, changes in mitochondrial potential, and activation of representative initiator and executor caspases that include caspase-9, caspase-3, and caspase-7. AMPA consistently and rapidly hyperpolarized mitochondria as reflected by an increase in MitoTracker Red CMS Ros fluorescence. Increases in Bax immunoreactivity were quantitatively and temporally variable and Bax failed to localize to mitochondria. Additionally, we observed a marked increase in immunoreactivity of cytochrome C although its release from mitochondria was not apparent. Mitochondrial membrane hyperpolarization and increases in cytochrome C immunoreactivity preceded caspase activation. Immunohistochemical analyses revealed the active form of caspases-3 and -9 were markedly and significantly increased in PNs following 30 microM AMPA, and caspase-9 activation preceded caspase-3. Increases in active caspase-7 immunoreactivity were less frequently encountered in PNs. Thus DCD shares some characteristics of apoptotic programmed cell death, but lacks typical mitochondrial pathophysiology associated with classic apoptosis. These findings suggest that AMPA-induced DCD is a form of active PCD that lies on a spectrum between classical apoptosis and passive necrosis.

Animals↗

PubMed2004

The role of oxidative stress, impaired glycolysis and mitochondrial respiratory redox failure in the cytotoxic effects of 6-hydroxydopamine in vitro.

The neurotoxin, 6-hydroxydopamine (6-OHDA) has been implicated in the neurodegenerative process of Parkinson's disease. The current study was designed to elucidate the toxicological effects of 6-OHDA on energy metabolism in neuroblastoma (N-2A) cells. The toxicity of 6-OHDA corresponds to the total collapse of anaerobic/aerobic cell function, unlike other mitochondrial toxins such as MPP+ that target specific loss of aerobic metabolism. The toxicity of 6-OHDA paralleled the loss of mitochondrial oxygen (O2) consumption (MOC), glycolytic activity, ATP, H+ ion gradients, membrane potential and accumulation of the autoxidative product, hydrogen peroxide (H2O2). Removing H2O2 with nonenzymatic stoichiometric scavengers, such as carboxylic acids, glutathione and catalase yielded partial protection. The rapid removal of H2O2 with pyruvate or catalase restored only anaerobic glycolysis, but did not reverse the loss of MOC, indicating mitochondrial impairment is independent of H2O2. The H2O2 generated by 6-OHDA contributed toward the loss of anaerobic glycolysis through lipid peroxidation and lactic acid dehydrogenase inhibition. The ability of 6-OHDA to maintain oxidized cytochrome c (CYT-C-OX) in its reduced form (CYT-C-RED), appears to play a role in mitohondrial impairment. The reduction of CYT-C by 6-OHDA, was extensive, occurred within minutes, preceded formation of H2O2 and was unaffected by catalase or superoxide dismutase. At similar concentrations, 6-OHDA readily altered the valence state of iron [Fe(III)] to Fe(II), which would also theoretically sustain CYT-C in its reduced form. In isolated mitochondria, 6-OHDA had negligible effects on complex I, inhibited complex II and interfered with complex III by maintaining the substrate, CYT-C in a reduced state. 6-OHDA caused a transient and potent surge in isolated cytochrome oxidase (complex IV) activity, with rapid recovery as a result of 6-OHDA recycling CYT-C-OX to CYT-C-RED. Typical mitochondrial toxins such as MPP+, azide and antimycin appeared to inhibit the catalytic activity of ETC enzymes. In contrast, 6-OHDA alters the redox of the cytochromes, resulting in loss of substrate availability and obstruction of oxidation-reduction events. Complete cytoprotection against 6-OHDA toxicity and restored MOC was achieved by combining catalase with CYT-C (horse heart). In summary, CYT-C reducing properties are unique to catecholamine neurotransmitters, and may play a significant role in selective vulnerability of dopaminergic neurons to mitochondrial insults.

Animals↗

PubMed2004

Accumulation of protein-bound 4-hydroxy-2-hexenal in spinal cords from patients with sporadic amyotrophic lateral sclerosis.

4-Hydroxy-2-hexenal (HHE) is a toxic, reactive aldehydic intermediate formed by nonenzymatic peroxidation of n-3 polyunsaturated fatty acids. The aim of this study was to determine the implication for HHE in the pathomechanism of amyotrophic lateral sclerosis (ALS) by immunohistochemical and enzyme-linked immunosorbent assay (ELISA) techniques using a mouse monoclonal IgG(1) antibody mAbHHE53 specific for protein-bound HHE. Immunohistochemical analysis on formalin-fixed, paraffin-embedded sections and frozen sections of spinal cords obtained at autopsy from 10 sporadic ALS patients and 10 age-matched control subjects demonstrated that protein-bound HHE immunoreactivity was seen and was prominent in the entire gray matter in the ALS cases and localized in the neurons, reactive astrocytes, microglial cells, and the surrounding neuropil, while the immunoreactivity was obscure or undetectable in the control cases. No significant protein-bound HHE immunoreactivity was seen in sections processed with omission of mAbHHE53 or in sections incubated with the antibody with an excess of the respective antigen. Competitive ELISA analysis on trypsin-digested protein extracts of fresh-frozen spinal cord samples disclosed a significant increase in protein-bound HHE level in the ALS cases compared with the control cases. Our results indicate that enhanced HHE formation occurs in the entire gray matter of sporadic ALS spinal cords and suggest that the selective vulnerability of motor neurons to HHE mediates the pathomechanism of this disease.

Aged↗

PubMed2006

Parvalbumin and calbindin D-28k immunoreactivity in transgenic mice with a G93A mutant SOD1 gene.

Immunohistochemical study was performed to examine if calcium-binding proteins are involved in the degeneration of motor neurons in the brain stems and the spinal cords of transgenic mice carrying a G93A mutant human SOD1 gene. Specimens from age-matched non-transgenic wild-type mice served as controls. In the spinal cord of the controls, the density of parvalbumin-immunoreactive neurons was highest in the large anterior horn neurons and lower in the posterior horn neurons in the spinal cord. On the other hand, calbindin D-28k immunoreactivity was much less apparent than that observed with parvalbumin antisera. Rexed's lamina II was densely immunostained for calbindin D-28k, whereas, in the anterior horn, calbindin-D-28k-positive small neurons were barely dispersed in a scattered pattern. In transgenic mice, parvalbumin-positive anterior horn neurons were severely reduced, even at the presymptomatic stage, whereas calbindin-positive neurons were largely preserved. At the symptomatic stage, both parvalbumin and calbindin D-28k immunoreactivity markedly diminished or disappeared in the anterior horn. Immunoblotting analysis revealed a significant reduction of immunoreactivity to parvalbumin antibody in transgenic mice compared with the controls. In the brain stem, parvalbumin-positive oculomotor and abducens neurons and the calbindin D-28k-positive sixth nucleus were well-preserved in transgenic mice as well as in the controls. Thus, the diffuse and severe loss of parvalbumin immunoreactivity of large motor neurons even at early stages in SOD1-transgenic mice and the absence of calbindin D-28k immunoreactivity of normal large motor neurons suggest that these calcium-binding proteins may contribute to selective vulnerability and an early loss of function of large motor neurons in this SOD1-transgenic mouse model.

Abducens Nerve↗

PubMed2004

Decompressive hemicraniectomy in a new cat model. Methodological description of the PET study protocol.

Positron emission tomography (PET) is increasingly used to quantify regional hemodynamic and metabolic changes in different animal models. Most of these (multitracer) studies provided important early data on already functionally altered brain tissue, indicating selective vulnerability by a large variability in the functional blood flow threshold of individual neurons. To fill the gap between experimental studies at early time points and rather late clinical studies at well-defined but singular time points, we repeatedly measured cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), oxygen extraction rate and cerebral metabolic rate of glucose (CMRglc) in three cats before and up to 28 h after decompressive hemicraniectomy on normal brain tissue. Decompressive hemicraniectomy in the cat decreased CBF, and to a lesser extent CMRO2 and CMRglc 2 h after surgical intervention in normal brain tissue that last for at least 1 day. CBF significantly decreased (p < 0.01) and oxygen extraction fraction (OEF) (p < 0.05) significantly increased. CMRO2 and CMRglc decreased only in regions with most severe CBF reduction. These effects remained for at least a day irrespective of corrective sustaining cranioplasty. The method and data analysis is decreased and discussed in detail in the presented protocol. In conclusion, serial positron emission tomography studies are best suited to repeatedly and non-invasively demonstrate circulatory and biochemical changes by surgical interventions in normal brain tissue for at least one day. The transition of normal brain tissue into misery-perfused or non-viable regions can be followed over time. Such state-of-the-art imaging modalities as sequential high-resolution positron emission tomography provide insight into the dynamic of regional pathophysiology and may thus further justify the development of rational therapeutic strategies for decompressive hemicraniectomy, especially for disease with focal disturbances in cerebral blood flow.

Animals↗

PubMed2026

Early proteomic and metabolic signatures of liver and eye in OAT-deficient mice.

Ornithine aminotransferase (OAT) deficiency causes hyperornithinemia and gyrate atrophy (GA) of the choroid and retina, a rare inherited retinal degeneration. To understand the early molecular changes that make the eye susceptible to damage, we performed quantitative proteomic and metabolomic profiling of liver, retina, and retinal pigment epithelium and choroid (RPE/Cho) from OAT-deficient (Oatrhg) mice prior to detectable vision impairment. In addition to reduced OAT expression and elevated ornithine, methylation-related metabolites such as N(6)-methyl-lysine were altered in all examined tissues of Oatrhg mice. In the liver, excess ornithine was directed into urea cycle metabolism, together with altered expression of detoxification enzymes and histone H2B proteins. In contrast, the retina showed minimal proteomic changes but pronounced alterations in amino acid pathways that support glutamate homeostasis. The RPE/Cho demonstrated the most extensive proteomic changes, particularly in mitochondrial metabolism, cytoskeleton, and extracellular matrix, along with changes in metabolites involved in lysine metabolism, energy metabolism, and antioxidant capacity. Incubation with 13C lysine demonstrated that lysine was primarily degraded in RPE/Cho but not the retina, and ornithine enhanced lysine degradation in an OAT-dependent manner. Together, these findings highlight common and tissue-specific impacts of OAT on the liver and ocular tissues and provide insight into early molecular changes that contribute to the selective vulnerability of the eye in GA. Proteomics data are available via ProteomeXchange (PXD063614) and metabolomics data via MassIVE repository (MSV000101103).

Animals↗

PubMedDate not supplied

Mechanisms of the inhibitory effects of amyloid beta-protein on synaptic plasticity.

Alzheimer's disease can be considered a protein misfolding disease. In particular, inappropriate processing of a proteolytic fragment of amyloid precursor protein, amyloid beta-protein (Abeta), in early stages of Alzheimer's disease may lead to stabilization of small oligomers that are highly mobile and have a potential to be extremely toxic assemblies. Recently, the importance of such soluble species of Abeta in triggering synaptic dysfunction, long before neuronal loss occurs, has become apparent. Animal models have revealed that plasticity of hippocampal excitatory synaptic transmission is relatively selectively vulnerable to Abeta both in vitro and in vivo. This review focuses on the mechanisms of Abeta inhibition of long-term potentiation at synapses in the rodent hippocampus from two complimentary perspectives. Firstly, we examine evidence that the synaptic activity of this peptide resides primarily in oligomeric rather than monomeric or fibrillar Abeta species. Secondly, the importance of different oxidative/nitrosative stress-linked cascades including JNK, p38 MAPK and NADPH oxidase/iNOS-generated reactive oxygen/nitrogen free radicals in mediating the inhibition of LTP by Abeta is emphasised. These mechanistic studies provide a plausible explanation for the sensitivity of hippocampus-dependent memory to impairment in the early preclinical stages of Alzheimer's disease.

Aged↗

PubMed2005

Elevation of hippocampal MMP-3 expression and activity during trauma-induced synaptogenesis.

The matrix metalloproteinase (MMP) enzyme family contributes to the regulation of a variety of brain extracellular matrix molecules. In order to assess their role in synaptic plasticity following traumatic brain injury (TBI), we compared expression of stromelysin-1 (MMP-3) protein and mRNA in two rodent models of TBI exhibiting different levels of recovery: adaptive synaptic plasticity following central fluid percussion injury and maladaptive synaptic plasticity generated by combined TBI and bilateral entorhinal cortical lesion (TBI + BEC). We sampled the hippocampus at 7 days postinjury, targeting a selectively vulnerable brain region and a survival interval exhibiting rapid synaptogenesis. We report elevated expression of hippocampal MMP-3 mRNA and protein after TBI. MMP-3 immunohistochemical staining showed increased protein levels relative to sham-injured controls, primarily localized to cell bodies within the deafferented dendritic laminae. Injury-related differences in MMP-3 protein were also observed. TBI alone elevated MMP-3 immunobinding over the stratum lacunosum moleculare (SLM), inner molecular layer and hilus, while TBI + BEC generated more robust increases in MMP-3 reactivity within the deafferented SLM and dentate molecular layer (DML). Double labeling with GFAP confirmed the presence of MMP-3 within reactive astrocytes induced by each injury model. Semi-quantitative RT-PCR revealed that MMP-3 mRNA also increased after each injury, however, the combined insult induced a much greater elevation than fluid percussion alone: 1.9-fold vs. 79%, respectively. In the TBI + BEC model, MMP-3 up-regulation was spatio-temporally correlated with increased enzyme activity, an effect which was attenuated with the neuroprotective compound MK-801. These results show that distinct pathological conditions elicited by TBI can differentially affect MMP-3 expression during reactive synaptic plasticity. Notably, these effects are both transcriptional and translational and are correlated with functionally active enzyme.

Animals↗

PubMed2005

Apoptotic signals within the basal forebrain cholinergic neurons in Alzheimer's disease.

A relatively early and substantial loss of basal forebrain cholinergic neurons is a constant feature of Alzheimer's disease (AD). However, the mechanisms that contribute to the selective vulnerability of these neurons are not fully delineated. In the present series of experiments, we determined the possible contribution of apoptotic processes and other pathologic cascades to the degeneration of the cholinergic neurons of the nucleus basalis of Meynert (NBM) in AD. In contrast to neurons in the frontal cortex which showed prominent DNA fragmentation as detected by the TUNEL method, no DNA fragmentation was observed within the NBM in any of the AD or normal brains. Similarly, immunoreactivity for the apoptotic signals Fas, Fas-ligand, Bax, Bcl-x, caspase-8, caspase-9 and caspase-3 was absent from the NBM of AD and control brains. In contrast, a substantial subpopulation of cholinergic neurons within the NBM in AD displayed prominent immunoreactivity for the apoptotic signal Fas-associated death domain (FADD) in the form of tangles. FADD immunoreactivity was also present in dystrophic neurites. FADD-positive tangle-like structures were localized in neurons which contained immunoreactivity for the cholinergic marker choline acetyltransferase (ChAT) and the low affinity neurotrophin receptor p75NTR. While many of the NBM cholinergic neurons in control brains contained immunoreactivity for the calcium binding protein calbindin-D28K (CB), the NBM neurons in AD displayed a substantial loss of CB immunoreactivity. Importantly, most of FADD-immunoreactive cholinergic neurons were devoid of CB immunoreactivity, and, conversely, most CB-positive cholinergic neurons had no FADD immunoreactivity. FADD immunoreactivity within the basal forebrain was colocalized with phosphorylated tau immunoreactive tangles and dystrophic neurites. In contrast, FADD immunoreactivity did not appear to be related to the primarily diffuse amyloid-beta deposits intermingled between cholinergic neurons in AD NBM. Finally, many CD68-positive microglia were observed surrounding the NBM cholinergic neurons in AD. In conclusion, the findings of the present study indicate that, while the FADD apoptotic signaling pathway may be triggered within the basal forebrain cholinergic neurons in AD, the apoptotic cascade is most likely aborted as no DNA fragmentation was detected and the executioner caspase-3 was not up-regulated within these neurons. The findings also suggest possible relationships between loss of CB, FADD expression and phosphorylation of tau within the basal forebrain cholinergic neurons in AD.

Acetylcholine↗

PubMed2005

Microarray analysis of gene expression in adult retinal ganglion cells.

Retinal ganglion cells (RGCs) transfer visual information to the brain and are known to be susceptible to selective degeneration in various neuropathies such as glaucoma. This selective vulnerability suggests that these highly specialized neurons possess a distinct gene expression profile that becomes altered by neuropathy-associated stresses, which lead to the RGC death. In this study, to identify genes expressed predominantly in adult RGCs, a global transcriptional profile of purified primary RGCs has been compared to that of the whole retina. To avoid alterations of the original gene expression profile by cell culture conditions, we isolated RNA directly from adult RGCs purified by immunopanning without prior sub-cultivation. Genes expressed predominantly in RGCs included: Nrg1, Rgn, 14-3-3 family (Ywhah, Ywhaz, Ywhab), Nrn1, Gap43, Vsnl1, Rgs4. Some of these genes may serve as novel markers for these neurons. Our analysis revealed enrichment in genes controlling the pro-survival pathways in RGCs as compared to other retinal cells.

Animals↗