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PubMed2002

Axonal injury in children after motor vehicle crashes: extent, distribution, and size of axonal swellings using beta-APP immunohistochemistry.

The brains of 32 children (3 months to 16 years) who died as a result of motor vehicle collisions were examined for axonal injury using beta-APP immunohistochemistry. The extent and distribution of axonal injury was assessed and quantified throughout the forebrain, brainstem and cerebellum. The mean diameter of immunoreactive axons in the corpus callosum was measured for this pediatric group and, for comparison, a small adult sample. beta-APP immunoreactivity was seen in 14 pediatric cases (survival 35 mins to 87 h), most frequently in the parasagittal white matter (12/14), the corpus callosum (11/14), the brainstem (10/14) and cerebellum (9/14). In 2 cases, axon swelling was visualized in the internal capsule after only 35-45-min survival, earlier than has previously been reported. No immunoreactivity was seen in the remaining 18 cases who died within 1 h. The extent and distribution of axonal injury throughout the brain showed a rapid early increase with increasing survival time and then a slower progression. The diameter of individual callosal axons increased with increasing survival times, rapidly over the first 24 h and then more slowly. There was no statistical difference (p < 0.05) for callosal axon diameters at different survival times between the children and the adults sampled here. The extent and distribution of axonal injury throughout the brain appears to be similar in children to that previously reported in adults. The spatial and temporal spread of axonal damage suggests there may be therapeutic potential for the process to be arrested or slowed in its early stages.

Accidents, Traffic↗
PubMed2025

Easy and interactive taxonomic profiling with Metabuli App.

SUMMARY: Accurate metagenomic taxonomic profiling is critical for understanding microbial communities. However, computational analysis often requires command-line proficiency and high-performance computing resources. To lower these barriers, we developed Metabuli App, an all-in-one desktop application that efficiently runs taxonomic profiling locally on a consumer-grade computer. It features user-friendly graphical interfaces for custom database curation, raw read quality control (QC), taxonomic profiling, and interactive result visualization. AVAILABILITY AND IMPLEMENTATION: GPLv3-licensed source code and prebuilt apps for Windows, macOS, and Linux are available at https://github.com/steineggerlab/Metabuli-App and are archived at https://doi.org/10.5281/zenodo.15876171. Analysis scripts are available at https://github.com/jaebeom-kim/metabuli-app-analysis. The Sankey-based taxonomy visualization component is available at https://github.com/steineggerlab/taxoview for easy integration into other web projects.

Software↗
PubMed2001

Cholesterol accumulates in senile plaques of Alzheimer disease patients and in transgenic APP(SW) mice.

Mounting evidence suggests that cholesterol may contribute to the pathogenesis of Alzheimer disease (AD). We examined whether cholesterol might be present in senile plaques, a hallmark neuropathological feature of AD. We employed 2 different fluorometric-staining techniques (filipin staining and an enzymatic technique) for the determination of cholesterol in brains of postmortem confirmed AD patients and in nondemented, age-matched histopathologically normal controls. AD patient brains showed abnormal accumulation of cholesterol in congophilic/birefringent dense cores of senile plaques that was essentially absent in histopathologically normal controls. To determine whether increased senile plaque-associated cholesterol occurred generally in all plaques or was restricted to a specific subset, quantitative analysis was performed. Data indicate abnormal accumulation of cholesterol in cores of mature plaques but not in diffuse or immature plaques. Additionally, transgenic mice that overexpress the "Swedish" amyloid precursor protein (Tg APP(SW), line 2576) exhibited a similar pattern of abnormal cholesterol accumulation in mature, congophilic amyloid plaques at 24 months of age that was absent in their control littermates or in 8-month-old Tg APP(SW) mice (an age prior to amyloid deposition). Taken together, our results imply a link between cholesterol and AD pathogenesis and suggest that cholesterol plays an important role in the formation and/or progression of senile plaques.

Aged↗
PubMed2000

4-Aminopyrazolo[3,4-d]pyrimidine (4-APP) as a novel inhibitor of the RNA and DNA depurination induced by Shiga toxin 1.

Shiga toxin 1 (Stx1) catalyses the removal of a unique and specific adenine from 28S RNA in ribosomes (RNA-N-glycosidase activity) and the release of multiple adenines from DNA (DNA glycosylase activity). Added adenine behaves as an uncompetitive inhibitor of the RNA-N-glycosidase reaction binding more tightly to the Stx1-ribosome complex than to the free enzyme. Several purine derivatives and analogues have now been assayed as inhibitors of Stx1. Most of the compounds showed only minor differences in the rank order of activity on the two enzymatic reactions catalysed by Stx1. The survey highlights the importance of the amino group in the 6-position of the pyrimidine ring of adenine. Shifting (2-aminopurine) or substituting (hypoxanthine, 6-mercapto-purine, 6-methylpurine) the group greatly decreases the inhibitory power. The presence of a second ring, besides the pyrimidine one, is strictly required. Substitution, by introducing an additional nitrogen, of the imidazole ring of adenine with triazole leads to loss of inhibitory power, while rearrangement of the nitrogen atoms of the ring from the imidazole to the pyrazole configuration greatly enhances the inhibitory power. Thus 4-aminopyrazolo[3,4-d]pyrimidine (4-APP), the isomer of adenine with the five-membered ring in the pyrazole configuration, is by far the most potent inhibitor of both enzymatic reactions catalysed by Stx1. This finding opens perspectives on therapeutic strategies to protect endothelial renal cells once endocytosis of Stx1 has occurred (haemolytic uraemic syndrome). In the RNA-N-glycosidase reaction 4-APP binds, as adenine, predominantly to the Stx1-ribosome complex (uncompetitive inhibition), while inhibition of the DNA glycosylase activity by both inhibitors is of the mixed type.

Adenine↗
PubMed1997

Allelic variability in D21S11, but not in APP or APOE, is associated with cognitive decline in Down syndrome.

Genetic variation in the APOE gene and variation in chromosome 21 genotypes, including the APP locus, may influence age-associated cognitive decline in adults with Down syndrome. Molecular genetic and longitudinal neuropsychological analysis was performed for 41 unrelated Caucasian individuals (mean age 48.1 +/- 1.1 years (s.c.m.)) with free trisomy 21. Allele frequencies and genotype distributions were compared among subgroups with or without evidence of cognitive decline. Genetic variability at APOE and APP was not significantly associated with evidence of cognitive decline. However, aged individuals with Down syndrome, without evidence of cognitive decline, demonstrated unusual allelic variability at D21S11. These findings are discussed in the context of current hypotheses of Alzheimer-type dementia in Down syndrome and in the general population.

Adult↗
PubMed1997

Differential regulation of adenylyl cyclase in fibroblasts from sporadic and familial Alzheimer's disease cases with PS1 and APP mutations.

beta-Adrenoceptor- and forskolin-stimulated adenylyl cyclase activities were determined in primary skin fibroblasts established from patients with sporadic Alzheimer's disease (AD) and from individuals with familial APP KM670/671NL, PS1 M146V and PS1 H163Y mutations. Our data showed a significantly decreased beta-adrenoceptor-stimulated adenylyl cyclase activity in fibroblasts from sporadic AD compared with age-matched controls (p < 0.001, Student's unpaired t-test). In contrast, both beta-adrenoceptor- and forskolin-stimulated adenylyl cyclase activities were significantly increased in fibroblasts bearing PS1 M146V and PS1 H163Y mutations compared with controls (p < 0.01 and p < 0.05, respectively). No differences were seen between cell lines with and without the Swedish APP KM670/671NL double mutation. We suggest that various gene mutations associated with AD have different consequences for the regulation of adenylyl cyclase signal transduction in this disorder.

Adenylyl Cyclases↗
PubMed1997

Beta APP gene transfer into cultured human muscle induces inclusion-body myositis aspects.

Direct transfer of the beta-amyloid precursor protein (beta APP) gene into cultured normal human muscle, using recombinant adenovirus vector, was sufficient to induce several of the typical light microscopic, electron microscopic (EM), and EM-immunochemical aspects of the inclusion-body myositis (IBM) phenotype, including congophilia, clusters of amyloid-beta-positive 6-10 nm filaments, and 15-21 nm tubulofilamentous inclusions in the nuclei. Our results suggest that excessive production of intracellular beta APP may play an important role in the pathogenic cascade leading to the IBM phenotype.

Amyloid beta-Protein Precursor↗
PubMed2004

Cloning, expression, crystallization and initial crystallographic analysis of the C-terminal domain of the amyloid precursor protein APP.

Alzheimer's disease is associated with typical brain deposits (senile plaques) consisting mainly of neurotoxic amyloid beta-peptides. These are proteolytically derived from the large type I transmembrane protein amyloid precursor protein (APP), which is possibly involved in signal transduction. The large C-terminal domain CAPPD of the human APP ectodomain has been cloned, expressed in large amounts in Escherichia coli and purified to homogeneity. Well diffracting tetragonal crystals have been obtained and native data have been collected to 2.1 A. Initial experimental phases from a three-wavelength MAD experiment using (NH(4))(2)OsCl(6)-derivatized crystals are of good quality and show mostly alpha-helical conformations.

Amyloid beta-Protein Precursor↗
PubMed2006

Widespread axonal damage in the brain of drug abusers as evidenced by accumulation of beta-amyloid precursor protein (beta-APP): an immunohistochemical investigation.

BACKGROUND: In drug abusers, white matter changes have been described by neuroimaging analyses in different brain regions. A specific pattern of involvement or a predominance of a specific brain region could not be drawn. AIMS: To examine alterations of the white matter as a possible morphological substrate of the neuroimaging findings. METHODS: Brain specimens of 30 polydrug abusers and 20 controls were obtained at autopsy. The white matter from 11 different brain regions was analysed by means of immunohistochemistry for beta-amyloid precursor protein (beta-APP), a marker of axonal damage. FINDINGS: In the white matter of polydrug abusers, beta-APP-immunopositive accumulations were increased significantly compared to controls. They were more prominent in the brains of younger drug abusers than in those of the elderly. With the exception of five cases (four polydrug abusers and one control case), there were no significant white matter changes seen on myelin-stained sections, but there was a concomitant microglial activation. CONCLUSIONS: Our results show a significant axonal damage in the brains of polydrug abusers, which might represent the morphological substrate of a chronic-progressive drug-induced toxic-metabolic process. It is yet to be established if the observed changes are responsible for the alterations seen in different neuroimaging analyses and which drugs of abuse might be of major pathogenetic significance.

Adolescent↗
PubMedDate not supplied

APOE polymorphism and clinical duration determine regional neuropathology in Swedish APP(670, 671) mutation carriers: implications for late-onset Alzheimer's disease.

Neurofibrillary changes throughout the brain were investigated for three relatives who carried the Swedish APP(670, 671) mutation which causes overproduction of Abeta40 and Abeta42. They differed in terms of APOE genotype, age at the onset of dementia, and disease duration (P1: epsilon2/3, age 57, 11 years; P2: epsilon2/3, age 61, 5 years; P3: epsilon4/4, age 44, 12 years). For each subject, paraffin-embedded sections from diverse anatomically and cytoarchitectonically well-preserved regions were stained using the modified Bielschowsky method. Neurofibrillary tangles (NFT) and neuritic plaques (NP) were counted, and the area occupied by plaque estimated (%NP). In addition, sections from the medial frontal gyrus were stained with monoclonal antibodies to APOE. The regional patterns of neurofibrillary changes were consistent with those for late-onset AD. Longer disease duration was associated with further accumulations in earlier-affected areas, with superficial cortical layers consistently containing higher %NP than deep layers. APOE epsilon4/4 was associated with deeper limbic and frontal NFT, with an excess of NP (especially in the outer parietal cortex) which stained heavily for APOE - as well as with very early onset. APP(670, 671) mutation carriers demonstrate regional brain neurofibrillary changes characteristic of late-onset Alzheimer's disease with evidence for more Abeta deposition for epsilon4/4 than epsilon2/3. This raises the possibility that early Braak Stage I-II lesions might also follow this pattern of promotion.

Adult↗
PubMed1996

Regulation of APP processing. Potential for the therapeutical reduction of brain amyloid burden.

The role of brain amyloid in the pathogenesis of Alzheimer's disease (AD) is discussed controversially, but combined genetic and biochemical evidence points to a central role of the gene encoding the amyloid precursor APP in at least some forms of AD. This article proposes that preventing brain amyloid formation is a rational concept for drug treatment of AD. We suggest that pharmacologically active ligands for specific cell surface receptor subtypes--normally stimulated by neurotransmitters, growth factors, and cytokines--constitute a class of chemicals that might be useful to accelerate processing of APP into non-amyloidogenic, and biologically active, derivatives. This class of agents includes muscarinic m1 and m3 agonists, serotoninergic 5-HT2a and 5-HT2c agonists, glutamatergic mGluR1 agonists, as well as agonists for bradykinin and vasopressin receptors.

Alzheimer Disease↗
PubMed1996

Differential regulation of APP secretion by apolipoprotein E3 and E4.

The apolipoprotein E isozyme, apolipoprotein E4, has been implicated as a risk factor for Alzheimer's disease. One reason for the increased risk may be that apolipoprotein E binds to the A beta peptide, but there may be other factors as well. We show that apolipoprotein E is a potent regulator of the secretion of amyloid precursor protein. In cultures of PC12 cells, nanomolar levels of apolipoprotein E3 induce a rapid decrease in the secretion of APP, being observable in 30 min. and stable over 24 hours. Apolipoprotein E4, in contrast, increases secretion of APP over a similar time course. Reciprocal changes occur in cellular amyloid precursor protein. Differential characteristics are also seen in apo E binding to the cells, where apo E4 binds over a slower time course than apo E3. These results suggest a novel mechanism by which apolipoprotein E may be influencing the metabolism of amyloid precursor protein.

Amyloid beta-Protein Precursor↗
PubMedDate not supplied

Decreased plasma insulin-like growth factor-I level in familial Alzheimer's disease patients carrying the Swedish APP 670/671 mutation.

The plasma insulin-like growth factor I (IGF-I) level was determined in family members carrying the Swedish amyloid precursor protein (APP) 670/671 mutation with or without Alzheimer's disease (AD) and in age-matched controls from the same family. Plasma growth hormone (GH) and prolactin (PRL) levels were also determined. Measurement of the plasma IGF-I level by radioimmunoassay revealed a significant reduction only in the family members with AD compared to age-matched controls. However, there was no significant difference in the levels of GH and PRL between the mutation carriers with or without AD and their respective age-matched controls. These findings indicate that the mechanism(s) regulating GH and PRL were preserved and those regulating IGF-I levels might be affected in AD patients with the Swedish APP 670/671 mutation. CopyrightCopyright 1999S.KargerAG, Basel

Aged↗
PubMed2005

Dysregulation of Na+/K+ ATPase by amyloid in APP+PS1 transgenic mice.

BACKGROUND: The pathology of Alzheimer's disease (AD) is comprised of extracellular amyloid plaques, intracellular tau tangles, dystrophic neurites and neurodegeneration. The mechanisms by which these various pathological features arise are under intense investigation. Here, expanding upon pilot gene expression studies, we have further analyzed the relationship between Na+/K+ ATPase and amyloid using APP+PS1 transgenic mice, a model that develops amyloid plaques and memory deficits in the absence of tangle formation and neuronal or synaptic loss. RESULTS: We report that in addition to decreased mRNA expression, there was decreased overall Na+/K+ ATPase enzyme activity in the amyloid-containing hippocampi of the APP+PS1 mice (although not in the amyloid-free cerebellum). In addition, dual immunolabeling revealed an absence of Na+/K+ ATPase staining in a zone surrounding congophilic plaques that was occupied by dystrophic neurites. We also demonstrate that cerebral Na+/K+ ATPase activity can be directly inhibited by high concentrations of soluble Abeta. CONCLUSIONS: The data suggest that the reductions in Na+/K+ ATPase activity in Alzheimer tissue may not be purely secondary to neuronal loss, but may results from direct effects of amyloid on this enzyme. This disruption of ion homeostasis and osmotic balance may interfere with normal electrotonic properties of dendrites, blocking intraneuronal signal processing, and contribute to neuritic dystrophia. These results suggest that therapies aimed at enhancing Na+/K+ ATPase activity in AD may improve symptoms and/or delay disease progression.

Amyloid beta-Peptides↗
PubMed2004

A family with Alzheimer disease and strokes associated with A713T mutation of the APP gene.

Three members of an Italian family with autosomal dominant dementia and multiple strokes had the A713T mutation of the APP gene. The neuropathologic examination of the proband disclosed Alzheimer disease (AD) with severe cerebral amyloid angiopathy and multiple infarcts. This indicates that the A713T mutation of the APP gene, lying at the gamma-secretase cleavage site, can be responsible for AD with symptomatic cerebral amyloid angiopathy.

Alzheimer Disease↗
PubMed2002

Nonoverlapping but synergetic tau and APP pathologies in sporadic Alzheimer's disease.

OBJECTIVE: To determine the spatiotemporal mapping of tau pathologies and insoluble pools of Abeta in aging and sporadic AD, and their contribution to the physiopathologic, clinical, and neuropathologic features. METHODS: The authors studied 130 patients of various ages and different cognitive status, from nondemented controls (n = 60) to patients with severe definite AD (n = 70) who were followed prospectively. Insoluble Abeta 42 and 40 species were fully solubilized and quantified in the main neocortical areas, with a new procedure adapted to human brain tissue. Tau pathology staging was determined in 10 different brain areas, using Western blots. RESULTS: In AD, there is a constellation of amyloid phenotypes, extending from cases with exclusively aggregated Abeta 42 to cases with, in addition, large quantities of insoluble Abeta 40 species. Five other points were observed: 1) There was no spatial and temporal overlap in the distribution of these two insoluble Abeta species in cortical brain areas. 2) In contrast to solubilized Abeta 40 aggregates composed essentially of monomers and dimers, solubilized Abeta 42 was essentially observed as dimers and multimers. 3) Abeta 42 aggregates were observed at the early stages of tau pathology, whereas the insoluble Abeta 40 pool was found at the last stages. 4) During the progression of the disease, Abeta aggregates increase in quantity and heterogeneity, in close parallel to the extension of tau pathology. 5) There was no spatial overlap between Abeta aggregation that is widespread and heterogeneously distributed in cortical areas and tau pathology that is progressing sequentially, stereotypically, and hierarchically. CONCLUSIONS: These observations demonstrate that Abeta 42 aggregation, and not Abeta 40, is the marker that is close to Alzheimer etiology. It should be the main target for the early biological diagnosis of AD and modeling. Furthermore, the spatial mismatch between amyloid ss-precursor protein (APP) and tau pathologies in cortical brain areas demonstrates that neurodegeneration is not a direct consequence of extracellular Abeta neurotoxicity. Hence, there is a synergetic effect of APP dysfunction, revealed by Abeta aggregation, on the neuron-to-neuron propagation of tau pathology.

Alzheimer Disease↗
PubMed2005

Energy inhibition elevates beta-secretase levels and activity and is potentially amyloidogenic in APP transgenic mice: possible early events in Alzheimer's disease pathogenesis.

Beta-secretase [beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1)] is the key rate-limiting enzyme for the production of the beta-amyloid (Abeta) peptide involved in the pathogenesis of Alzheimer's disease (AD). BACE1 levels and activity are increased in AD brain and are likely to drive Abeta overproduction, but the cause of BACE1 elevation in AD is unknown. Interestingly, cerebral glucose metabolism and blood flow are both reduced in preclinical AD, suggesting that impaired energy production may be an early pathologic event in AD. To determine whether reduced energy metabolism would cause BACE1 elevation, we used pharmacological agents (insulin, 2-deoxyglucose, 3-nitropropionic acid, and kainic acid) to induce acute energy inhibition in C57/B6 wild-type and amyloid precursor protein (APP) transgenic (Tg2576) mice. Four hours after treatment, we observed that reduced energy production caused a approximately 150% increase of cerebral BACE1 levels compared with control. Although this was a modest increase, the effect was long-lasting, because levels of the BACE1 enzyme remained elevated for at least 7 d after a single dose of energy inhibitor. In Tg2576 mice, levels of the BACE1-cleaved APP ectodomain APPsbeta were also elevated and paralleled the BACE1 increase in both relative amount and duration. Importantly, cerebral Abeta40 levels in Tg2576 were increased to approximately 200% of control at 7 d after injection, demonstrating that energy inhibition was potentially amyloidogenic. These results support the hypothesis that impaired energy production in the brain may drive AD pathogenesis by elevating BACE1 levels and activity, which, in turn, lead to Abeta overproduction. This process may represent one of the earliest pathogenic events in AD.

Alzheimer Disease↗
PubMed2005

Pilot study of the reducing effect on amyloidosis in vivo by three FDA pre-approved drugs via the Alzheimer's APP 5' untranslated region.

A pilot study was conducted employing a well known mouse model for Alzheimer's disease to evaluate the anti-amyloid efficacy of three FDA pre-approved drugs. Paroxetine (SSRI and APP 5'UTR directed lead compound), N-acetyl cysteine (antioxidant), and erythromycin (macrolide antibiotic) were provided to the drinking water of TgCRND8 mice for three months. This report provides data that measured the steady-state levels of amyloid Abeta-40 and Abeta-42 Abeta as pmol Abeta per gram of mouse brain cortex in drug treated and placebo animals. The relative levels of Abeta peptide levels were reduced after exposure of mice to paroxetine (N=5), NAC (N=7), and erythromycin (N=7) relative to matched placebo counterparts. These results demonstrated proof-of concept for a strategy to further screen the APP 5'UTR target to identify novel drugs that exhibit anti-amyloid efficacy in vivo. These data also demonstrated a statistically significant anti-amyloid trend for paroxetine, NAC and erythromycin. The potential for conducting further studies with these compounds using larger cohorts of TgCRND8 mice is discussed.

5' Untranslated Regions↗