Biomedical subjects

T G Ohm

Publications and source records attributed to T G Ohm.

At least 19 recordsLinked to original sources

PubMed1999

Quantitative autoradiography of [3H]forskolin binding sites in post-mortem brain staged for Alzheimer's disease neurofibrillary changes and amyloid deposits.

Adenylyl cyclase (AC) signal transduction has been shown to be affected in Alzheimer's disease (AD). Deficits have been described in different components of the system, from the receptor to the effector level. [3H]forskolin is a diterpene that binds with high affinity to AC. In the present report, we used autoradiography to study [3H]forskolin binding to sections of entorhinal cortex and hippocampus from 23 cases staged for AD pathology according to Braak and Braak [Acta Neuropathol. 82 (1991) 239-259]. This protocol defines six stages according to neurofibrillary changes, which start in the entorhinal region (stages I-II), spread to the hippocampus (stages III-IV) and finally to the isocortical areas (stages V-VI). The amyloid classification includes three stages in which the basal isocortex is first affected (stage A), followed by other isocortical association areas (stage B) and finally the primary isocortical areas (stage C). We also studied the effects of the GTP-analogue Gpp[NH]p on binding, in order to detect changes in G-protein-AC coupling. We used two different concentrations of Gpp[NH]p, that were previously reported to inhibit and stimulate [3H]forskolin binding via Gi and Gs, respectively. Results showed that [3H]forskolin binding declined significantly with staging for neurofibrillary changes only in the entorhinal region (P < 0.05, ANOVA). In addition, the decrease in [3H]forskolin binding observed in the presence of 1 microM Gpp[NH]p diminished significantly with staging in the entorhinal region (P < 0.05, ANOVA). No significant changes were seen with amyloid staging, with the exception of the CA1 subfield of the hippocampus, where [3H]forskolin binding in the absence of Gpp[NH]p was significantly decreased at stage B compared with all other stages (P < 0.05, ANOVA). In conclusion, our results showed a very limited decrease in [3H]forskolin binding with the progression of AD pathology, suggesting that the AC levels may be largely preserved in the disease. The specific change in the effect of a low concentration of Gpp[NH]p on the binding could indicate the loss of Ca2+/calmodulin-sensitive AC isoforms in AD.

Adenylyl Cyclases↗

PubMed1999

A quantitative autoradiographic study of [3H]cAMP binding to cytosolic and particulate protein kinase A in post-mortem brain staged for Alzheimer's disease neurofibrillary changes and amyloid deposits.

The cAMP-dependent protein kinase (PKA) has been implicated in the Alzheimer's disease pathology of abnormal tau phosphorylation leading to neurofibrillary tangle (NFT) formation, as well as in amyloid precursor protein alpha-secretase processing. In the present study, we determined whether [3H]cAMP binding to cytosolic and particulate PKA showed any relationship to the extent of Alzheimer's disease pathology at post-mortem. Autoradiographic [3H]cAMP binding to cytosolic and particulate PKA was measured in sections of entorhinal cortex/hippocampal formation from 23 cases that had been staged for Alzheimer's disease-related neurofibrillary changes and amyloid deposits according to Braak and Braak [H. Braak, E. Braak, Neuropathological staging of Alzheimer's-related changes, Acta Neuropathol. 82 (1991) 239-259]. [3H]cAMP binding to cytosolic PKA showed statistically significant reductions in the entorhinal cortex (P<0.01, ANOVA) with respect to neurofibrillary changes. Post-hoc analysis with Fisher's PLSD test showed significant reductions of [3H]cAMP binding to cytosolic PKA at the isocortical stages (V and VI), compared to the non-pathological (O) (by 55%, P<0.01), transentorhinal (I and II) (by 58%, P<0.001) and limbic (III and IV) (by 45%, P<0.05) stages. A significant reduction (by 25%, P<0.05) was also seen in the transentorhinal compared to the limbic stages. [3H]cAMP binding to cytosolic PKA showed no significant alterations with respect to neurofibrillary changes in either the subiculum, CA1-CA4 subfields of the hippocampus or the dentate gyrus. [3H]cAMP binding to cytosolic PKA also showed significant declines in the entorhinal cortex (P<0.01) and subiculum (P<0.05) with respect to staging for amyloid deposits. Post-hoc analysis with Fisher's PLSD test showed significant reductions of [3H]cAMP binding to cytosolic PKA in the entorhinal cortex at amyloid stage C compared to stages O (by 41%, P<0.01) and A (by 38%, P<0.01). In the subiculum, there were significant reductions of [3H]cAMP binding at stages C (by 41%, P<0.01) and B (by 40%, P<0.05), respectively, compared to stage O. [3H]cAMP binding to particulate PKA did not show significant relationships to staging for either neurofibrillary changes or amyloid deposits in either the entorhinal cortex or any of the hippocampal subregions. These findings suggest that whereas [3H]cAMP binding to cytosolic PKA in the entorhinal cortex is reduced with progression of neurofibrillary and amyloid pathology, other hippocampal regions show a preservation of cytosolic and particulate PKA even in late stage pathologies.

Aging↗

PubMed1999

Apolipoprotein E isoforms and the development of low and high Braak stages of Alzheimer's disease-related lesions.

In recent research, apolipoprotein-E (apoE) polymorphism has been shown to influence the formation of neurofibrillary changes and the accumulation of beta/A4-amyloid, the histopathological hallmarks of Alzheimer's disease (AD). Clinical studies associate the apoE allele epsilon4 with earlier onset of the disease, although the clinical speed of progression remains unchanged. Time course estimates have also provided evidence which indicates that the clinical phase of AD constitutes only 10-20% of the total time span needed for the development of this slowly progressing degenerative brain disorder. Due to the lack of reliable clinical tests for the detection of pre-symptomatic stages of AD, we set out with an autopsy approach to monitor neuropathology of the long pre-clinical phase of AD. This study examined beta/A4-peptide deposition and the formation of neurofibrillary changes staged according to the Braaks' classification in groups of individuals matched for age and sex with different genotypes. In comparison with epsilon3 homozygotes, the presence of the epsilon4 allele is statistically associated with a higher stage of beta/A4-peptide deposition and neurofibrillary change formation (chi2-test, P<0.01 for beta/A4-stage and P<0.001 for neurofibrillary changes). The effect of the epsilon2 allele differs. Its presence is associated with a lower stage of neurofibrillary pathology in individuals below the age of 80 but with a higher stage thereafter compared to age- and sex-matched epsilon3 homozygotes. Accordingly, the statistical juxtaposition of individuals over 80 years with epsilon4 alleles and those with epsilon2 alleles showed no significant difference with respect to the stages. Our findings indicate that apoE-variants have different effects on the speed of histopathology formation, even in the pre-clinical stages of AD. This suggests that clinical onset, course and pathogenesis of AD are influenced by the apoE genotype.

Alleles↗

PubMed1999

Basal and stimulated hippocampal adenylate cyclase activity in the experimentally lesioned rat entorhinal cortex.

Early stage development of Alzheimer-related neurofibrillary tangles occurs primarily in neurons of entorhinal cortex layers pre-alpha and pre-beta. These excitatory neurons project into the hippocampus. At this stage ('entorhinal' case), while neurofibrillary tangles are still absent from the hippocampus, a significant reduction in hippocampal adenylate cyclase activity has been detected. To test whether this reduction is a consequence of a deafferentation (and thus not a specifically disease-related alteration), we performed unilateral electrolytic lesions and sham-operations of the rat entorhinal cortex. The animals were killed 2, 12 and 55 days post lesion (dpl) and hippocampal adenylate cyclase activity was assayed. The major results were as follows: (1) both lesioned and unlesioned sides showed higher activity than a sham-operated control; (2) the adenylate cyclase activity of the lesioned side increased to a significantly lesser degree than that of the unlesioned side at 12 dpl; (3) this 'decrease' was attributed to changes in G protein-mediated activation of adenylate cyclase; (4) at no time point post lesion did the pattern of rat adenylate cyclase activity resemble that observed in Alzheimer's disease. Our data suggests that the loss of entorhinal afferents alone cannot explain the reduction in cyclase-activity seen in 'entorhinal' cases.

Adenylyl Cyclases↗

PubMed1999

Culture of autopsy-derived fibroblasts as a tool to study systemic alterations in human neurodegenerative disorders such as Alzheimer's disease--methodological investigations.

The present study was undertaken in order to analyse the possibility of culturing post mortem derived human fibroblasts. The combination of post mortem fibroblasts with the autopsy proven and histopathologically staged brain will allow the correlative investigation of dynamic biochemical processes which are systemically underlying or accompanying a neurological and/or psychiatric disorder. These studies are limited in autopsy brain or are uncertain when the neuropathological status is lacking, i.e. when fibroblasts were obtained from living patients. Our examinations of human autopsy fibroblast and those under experimentally controlled post mortem conditions with rats clearly demonstrate that autopsy-derived fibroblasts can be reliably cultured. The cells grown displayed typical morphological and staining characteristics as well as pharmacological responsiveness. Even cells obtained from a 99 years old individual or an individual with a post mortem delay of 48 hours grew in our culture system.

Aged↗

PubMed1999

Alterations in the ryanodine receptor calcium release channel correlate with Alzheimer's disease neurofibrillary and beta-amyloid pathologies.

Investigation of the integrity of the ryanodine receptor in Alzheimer's disease is important because it plays a critical role in the regulation of calcium release from the endoplasmic reticulum in brain, impairment of which is believed to contribute to the pathogenesis of Alzheimer's disease. The present study compared ryanodine receptor levels and their functional modulation in particulate fractions from control and Alzheimer's disease temporal cortex, occipital cortex and putamen. Relationships between ryanodine receptor changes and the progression of Alzheimer's disease pathology were determined by examining autoradiographic [3H]ryanodine binding in entorhinal cortex/anterior hippocampus sections from 22 cases that had been staged for neurofibrillary changes and beta-amyloid deposition. A significant (P < 0.02) 40% decrease in the Bmax for [3H]ryanodine binding and significantly higher IC50 values for both magnesium and Ruthenium Red inhibition of [3H]ryanodine binding were detected in Alzheimer's disease temporal cortex particulate fractions compared to controls. Immunoblot analyses showed Type 2 ryanodine receptor holoprotein levels to be decreased by 20% (P < 0.05) in these Alzheimer's disease cases compared to controls. No significant differences were detected in [3H]ryanodine binding comparing control and Alzheimer's disease occipital cortex or putamen samples. The autoradiography study detected increased [3H]ryanodine binding in the subiculum, CA2 and CA1 regions in cases with early (stage I-II) neurofibrillary pathology when compared to Stage 0 cases. Analysis of variance of data with respect to the different stages of neurofibrillary pathology revealed significant stage-related declines of [3H]ryanodine binding in the subiculum (P < 0.02) with trends towards significant decreases in CA1, CA2 and CA4. Post-hoc testing with Fisher's PLSD showed significant reductions (74-94%) of [3H]ryanodine binding in the subiculum, and CA1-CA4 regions of the late isocortical stage (V-VI) cases compared to the early entorhinal stage I-II cases. [3H]Ryanodine binding also showed significant declines with staging for beta-amyloid deposition in the entorhinal cortex (P < 0.01) and CA4 (P < 0.05) with trends towards a significant decrease in the dentate gyrus. We conclude that alterations in ryanodine receptor binding and function are very early events in the pathogenesis of Alzheimer's disease, and may be fundamental to the progression of both neurofibrillary and beta-amyloid pathologies.

Adult↗

PubMed1999

The betaA4 amyloid peptide complexes to and enhances the uptake of beta-very low density lipoproteins by the low density lipoprotein receptor-related protein and heparan sulfate proteoglycans pathway.

We recently suggested that soluble beta-amyloid (betaA4) is a ligand of the low density lipoprotein receptor-related protein and heparan sulfate proteoglycan pathway. In the blood and in the cerebrospinal fluid, betaA4 is bound to apolipoprotein E containing lipoproteins. We examined how binding of betaA4 to beta-very low density lipoproteins (betaVLDL) alters their cellular metabolism. Compared with betaVLDL alone, complexes of betaVLDL and betaA4 were internalized, but not degraded at increased rates in fibroblasts and in rat hippocampal cells. The uptake of complexes of betaVLDL and betaA4 was not mediated by the low density lipoprotein receptor. BetaA4 not complexed to betaVLDL competed with the endocytosis of alpha2-macroglobulin and apolipoprotein E-enriched betaVLDL. The uptake of complexes of betaVLDL and betaA4 was inhibited by heparin, suramin, lactoferrin, the 39-kd receptor-associated protein, and alpha2-macroglobulin. Complexes of betaVLDL and betaA4 were taken up at reduced rates in Chinese hamster ovary cells partially (pgsB-650) or completely lacking (pgsA-745) proteoglycans. BetaA4 in which the positively charged amino acids between positions 13 and 17 (HHQKL) were replaced by glycine (GGQGL) failed to enhance the uptake of betaVLDL. Together, the data suggest that binding of betaA4 to betaVLDL produces particles that are endocytosed by low density lipoprotein receptor-related protein and HSPG. Complexes of betaVLDL and betaA4 had an intracellular half-life 4-fold that of native betaVLDL, did not undergo lysosomal degradation, and were resecreted into the culture medium. These findings represent the first identification of an endocytotic pathway for betaA4 and may be of relevance to the pathobiochemistry of neurodegenerative disorders.

Amyloid beta-Peptides↗

PubMed1998

Loss of inositol 1,4,5-trisphosphate receptor sites and decreased PKC levels correlate with staging of Alzheimer's disease neurofibrillary pathology.

Inositol 1,4,5-trisphosphate (IP3), inositol 1,3,4,5-tetrakisphosphate (IP4) and protein kinase C (PKC) play important roles in the phosphoinositide hydrolysis signal transducing pathway. Several studies have shown severe deficits in both IP3 receptor levels and PKC levels and activity in Alzheimer's disease brain, although the relationship of these changes to disease pathology is poorly understood. In the present study, we determined the autoradiographic localization of [3H]IP3 and [3H]IP4 binding to their calcium mobilizing receptor sites and [3H]phorbol 12,13-dibutyrate ([3H]PDBu) binding to PKC in sections of entorhinal cortex/hippocampal formation and cerebellum from 24 cases that had been staged for Alzheimer's disease-related neurofibrillary changes and amyloid deposition according to Braak and Braak [Acta Neuropathol. Berl., 82 (1991) 239-259]. Results indicated that [3H]IP3 binding showed a trend towards a decline with staging for neurofibrillary changes in the entorhinal region (0.05 < P < 0.10, ANOVA) and subiculum (0.05 < P < 0.10). In the former region, [3H]IP3 binding showed a significant decline with staging for amyloid deposition (P < 0.05). [3H]IP3 binding in the CA1 region showed statistically significant declines with respect to both neurofibrillary changes and amyloid staging (P < 0.05). [3H]IP3 binding levels in the other hippocampal subregions were too low to quantify accurately. The binding of [3H]IP4 showed no significant changes with either neurofibrillary changes or amyloid staging in any of the regions investigated. In contrast, [3H]PDBu binding showed significant declines with neurofibrillary staging in the entorhinal region (P < 0.01), subiculum (P < 0.001), CA1 (P < 0.001), CA2 (P < 0.001), CA3 (P < 0.001) and CA4 (P < 0.0001) regions and the dentate gyrus (P < 0.0001). Of these regions, only the subiculum showed a significant decline of [3H]PDBu binding with amyloid staging. There were no significant neurofibrillary or amyloid stage-related changes in either [3H]IP3, [3H]IP4 or [3H]PDBu binding in the molecular layer of the cerebellum. These findings suggest that reduced IP3 receptor and PKC levels in the entorhinal cortex/hippocampal formation reflect and may be important for the progression of Alzheimer's disease neurofibrillary pathology. The data also suggests that hippocampal IP3 receptor loss is related to the extent of amyloid deposition.

Adult↗

PubMed1998

The effects of beta/A4-amyloid and its fragments on calcium homeostasis, glial fibrillary acidic protein and S100beta staining, morphology and survival of cultured hippocampal astrocytes.

Aggregated beta/A4-amyloid is known to increase intraneuronal calcium by various mechanisms and to lead eventually to the death of the cultured neuron. This study deals with the role of beta/A4-amyloid and several of its fragments in calcium homeostasis, glial fibrillary acid protein and S100beta staining, morphology and survival of cultured rat hippocampal astrocytes as determined by Fura imaging, indirect immunofluorescence and life/death assays. In contrast to cultured neurons, none of the 12 different beta/A4 fragments tested caused an increase in intra-astrocytic free calcium. However, among the compounds evaluated, the fragments 10-20mer, 25-35mer and the full-length peptides (1-40, 1-42 and 1-43mer), at 5 and 10 microM, decreased free intra-astrocytic calcium statistically significantly after the cells had been incubated for 48 and 72 h. This occurred both for astrocytes treated with vehicle alone or the reversed sequence of the 1-40mer, i.e. the 40-1mer. However, survival was not altered under the conditions examined, even when there was a change in free intracellular calcium. Concomitant with the decrease in intracellular free calcium, the shape of the astrocytes became more spider-like, normally an indication of activated astrocytes, and markedly more intense anti-S100beta and anti-glial fibrillary acidic protein staining was seen. The functional relevance of altered calcium homeostasis for apolipoprotein E secretion, potentially relevant for neuronal plasticity in general and in Alzheimer's disease, is discussed.

Amyloid beta-Protein Precursor↗

PubMed1998

Apolipoprotein E isoforms increase intracellular Ca2+ differentially through a omega-agatoxin IVa-sensitive Ca2+-channel.

Apolipoprotein E (apoE) is the major apolipoprotein in the brain and is known for its important role in plasticity and neurodegeneration. We show that apoE dose-dependently increases intracellular free Ca2+ in rat hippocampal astrocytes and neurons. This effect varies with isoforms in the order E4 > E3 > E2. It is insensitive to blockade of action potentials by tetrodotoxin or inhibition of binding of apoE by heparinase, by the LRP ligand lactoferrin and by low density lipoprotein. ApoE evoked Ca2+-increases are blocked in zero [Ca]o and by the Ca-channel antagonists nickel and omega-Agatoxin-IVa but not by nifedipine and omega-Conotoxin-GVIa, demonstrating an isoform-specific activation of P/Q type Ca2+-channels. This novel mechanism is discussed with respect to Alzheimer's disease, that is linked for most cases to the apoE epsilon-allelic variation (epsilon4 > epsilon3 > epsilon2).

Animals↗

PubMed1997

Does Alzheimer's disease start early in life?

Aging and Alzheimer's disease are two of the keynotes of our time. Since its first description by Aloys Alzheimer about 90 years ago, this neurodegenerative condition has advanced to become the fourth most common cause of death in the elderly, and is found in more than half of the very elderly demented. Despite new findings which are linked to several aspects of Alzheimer's disease, relatively little progress has been made toward the discovery of reliable methods for early diagnosis or the development of a successful therapy for this debilitating disease. It is therefore helpful to recall the major underlying questions related to our understanding of the pathogenesis of Alzheimer's disease. This article deals with two of these: What is the earliest stage at which we can diagnose the disease? What influences the onset and progression of the disease? As simple as these questions appear to be, attempts at answering them show us the complicated, multi-facetted face of Alzheimer's disease.

Age of Onset↗

PubMed1996

Apolipoprotein E polymorphism is associated with both senile plaque load and Alzheimer-type neurofibrillary tangle formation.

Recent work provided evidence that the apolipoprotein (apo) E polymorphism is associated with late-onset sporadic Alzheimer's disease. The major histological hallmarks of Alzheimer's disease are the extraneuronal deposition of A4/beta-amyloid and the intraneuronal formation of neurofibrillary tangles, the latter correlating strongly with the psychometric status. We examined the relationship between the apo E polymorphism and Alzheimer's disease-related histological changes using a staging system which accounts for the progression of the disease over time and correlates well with the cognitive decline ante mortem. We observed a significant positive correlation between both neurofibrillary changes and A4/beta-amyloid deposits and the epsilon 4 gene dose. We estimated that the presence of one apo E4 allele leads to an earlier onset of the histopathological process of about one decade. The association of both types of Alzheimer's disease-related changes with the prevalence of the epsilon 4-allele suggests that the apo E polymorphism causally contributes to the development of Alzheimer's disease.

Aging↗

PubMed1996

Long-lasting transneuronal changes in rat dentate granule cell dendrites after entorhinal cortex lesion. A combined intracellular injection and electron microscopy study.

Following entorhinal cortex lesion, inhibitory hippocampal neurons show a persistent rarefication of those dendrites formally receiving entorhinal input. Physiological data indicate a long lasting disequilibrium of inhibition and excitation in the de-entorhinated hippocampus. We analyzed the intracellularly-stained dendritic tree of de-entorhinated excitatory rat granule cells. Granule cells of controls and animals surviving 2, 8, 60 and 270 days after unilateral entorhinal cortex lesion were impaled. Dendrites of control cells were of typical shape, traced to the hippocampal fissure and a complete dye filling of dendrites was ascertained by EM-analysis. Conversely, 60 and 270 days following lesioning, dendrites were only rarely seen to extend into the outer portions of the molecular layer and the dendritic architecture became significantly rarefied. Sixty days post-lesion, intracellularly filled dendrites extending to the middle molecular layer were surrounded by cell clusters resembling glia. Some of these contained the neuronally applied dye, suggesting a close association of the cytosolic compartments with the altered dendrites. These observed alterations exceed the process of sprouting and de novo synaptogenesis of remaining afference for long periods of time. The dendritic morphology of both inhibitory and excitatory neurons seems to require specific input from the entorhinal cortex. Moreover, sprouting of remaining afferents is apparently not sufficient to compensate for this loss of input.

Animals↗

PubMed1995

Calretinin immunoreactive structures in the human hippocampal formation.

The calcium-binding protein calretinin is present in an intrinsic GABAergic and an extrinsic non-GABAergic system in the rat and monkey hippocampal formation. Important species differences have been noted in hippocampal cell types immunostained for calretinin and the termination pattern of calretinin containing hypothalamic afferents in the hippocampus. In the present study, calretinin-containing neurons were visualized using immunocytochemistry in the human hippocampal formation of individuals which showed no significant neuropathological alterations. Calretinin-immunoreactivity was present exclusively in non-granule cells of the dentate gyrus and in non-pyramidal cells of Ammon's horn. Calretinin-positive neurons were found most frequently in the hilus of the fascia dentata and in strata radiatum and lacunosum-moleculare of CA1, whereas neurons in CA2 and CA3 were rarely immunostained. The majority of calretinin-immunoreactive neurons were small, bipolar or fusiform neurons. The dendritic trees of the calretinin-positive neurons were, for the most part, parallel to the dendrites of the principal cells. In the hilus, however, we observed cells with dendrites restricted to the hilar area. These dendrites were parallel to the granule cell layer. In the stratum lacunosum-moleculare, neurons with dendrites oriented parallel to the hippocampal fissure were frequently detected. In general, dendrites were smooth or sparsely spiny, displaying small conventional spines. The axons usually emerged from the proximal dendrite and could be followed over long distances. Axons were thin, had small varicosities and displayed only few collaterals which branched relatively far away from the cell body. Distinct bands of darkly stained calretinin-positive fibers occupied the innermost portion of the dentate molecular layer and the pyramidal cell layer of CA2. This distribution of calretinin-immunoreactive structures in the human hippocampus is similar to that observed in other primates but differs from that described in lower mammals, i.e., the rat. Our findings suggest that primates may share a common hippocampal calretinin-containing system, presumably both the intrinsic GABAergic and the extrinsic hypothalamic non-GABAergic components.

Aged↗

PubMed1995

Human diseases with defects in oxidative phosphorylation. 2. F1F0 ATP-synthase defects in Alzheimer disease revealed by blue native polyacrylamide gel electrophoresis.

F1F0 ATP-synthase (complex V) deficiencies in Alzheimer's disease are reported. Tissue specimens from the hippocampus of brains from patients with Alzheimer's disease were screened by blue native electrophoresis for alterations of the proteins of oxidative phosphorylation. Ubiquinol:cytochrome-c reductase (complex III) and cytochrome-c oxidase (complex IV) were found to be present at almost normal concentrations, however, complex V was substantially reduced in most cases studied. The specific reduction of complex V and the absence of electrophoretically detectable degradation products do not exclude a secondary defect of complex V, but should stimulate the search for genetic defects related to protein subunits of complex V.

Adenine Nucleotides↗

PubMed1995

Apolipoprotein E polymorphism influences not only cerebral senile plaque load but also Alzheimer-type neurofibrillary tangle formation.

Only recently, evidence was provided that apolipoprotein E allele epsilon 4 located on Chromosome 19 is associated with late onset (i.e. senile) sporadic Alzheimer's disease. Histologically, Alzheimer's disease is associated with intraneuronal neurofibrillary changes and extraneuronal A4/beta-amyloid deposition. We set out with a histological staging system which considers the gradual development of Alzheimer's disease-related histological changes over time and correlates highly with the cognitive decline ante mortem. Our analysis revealed that both the mean stage for A4/beta-amyloid deposits and the mean stage for neurofibrillary tangles get significantly shifted upwards in epsilon 4-carriers. This represents an earlier onset of the histopathological process of about one decade. The fact that both types of Alzheimer's disease-related changes correlate positively with the prevalence of the epsilon 4-allele suggests for a causal relationship between the apolipoprotein E polymorphism and the development of Alzheimer's disease.

Age Factors↗

PubMed1995

Close-meshed prevalence rates of different stages as a tool to uncover the rate of Alzheimer's disease-related neurofibrillary changes.

The speed of progression of Alzheimer's disease-related neurofibrillary changes is unknown. One reason for this is the impossibility to histopathologically follow-up one and the same individual over decades of their life. The present approach takes advantage of a recently introduced classification system which allows for a ranking of Alzheimer's disease-related neurofibrillary changes into six stages [Braak and Braak Acta Neuropath (1991) 82, 239-259] and analyses a staged sample of 887 brains obtained from routine autopsy. It sets out to interpret these cross-sectional data in dynamic longitudinal terms, in order to estimate the rate of passing through the various stages. The time needed to attain respective stages of pathology for 5% of a given cumulative sample is determined. The resulting fifth centiles are a measure of the average rate by which the disease-related changes progress assuming that the underlying stages represent a sequence of events and do not independently emerge. Advancing age and the prevalence of Alzheimer's disease-related changes of a given stage show a nonlinear positive correlation with only slight acceleration above the age of 65 years. Statistically, it takes at least 16 years from stage I to stage II, about 14 years pass by from stage II to III, 13 years from stage III to IV and five years from stage IV to V (= Alzheimer's disease) for 5% of a given cumulative sample. Thus, the deep roots of Alzheimer's disease-related neurofibrillary changes can be traced about 50 years back and may even extend into adolescence.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1994

Long-lasting transneuronal dendritic changes of GABAergic neurons in the monkey dentate gyrus following entorhinal cortex lesion.

This study analyses dendritic changes of GABAergic neurons in the dentate gyrus of the African green monkey Cercopithecus aethiops upon lesioning of their main afferents, i.e., fibers originating form the entorhinal cortex (EC). Monkeys received a unilateral EC lesion (ECL) under visual control. Four, 10 and 365 days after surgery, GABAergic dentate neurons were immunostained for parvalbumin (PV). In comparison to the contralateral side, immunolabeled dendrites ipsilateral to the lesion appeared to be retracted from the outer portions of the molecular layer at all survival times. Dendritic changes were further analysed using an interactive neuron-tracing system. Whereas immunoreactive cell bodies were not reduced in number, the relative extension of dendrites throughout the dentate molecular layer was reduced by 40% 10 days postlesion (dpl) and recovered only up to 80% 365 dpl when compared with the control side. This was reflected by a decrease of the mean segment length, which included proximal dendrites and was apparent even after 365 dpl. The spread of the dendritic field was initially diminished by 50% and seemed to exhibit a long-lasting reduction. The findings are in line with previous results obtained in the rat, thus, indicating that similar transneuronal changes after ECL occur in the primate dentate gyrus. This may be of importance, since the EC appears to be a very early target area of affection in human neurodegenerative disorders, such as Alzheimer's disease.

Afferent Pathways↗