Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Cascade testing”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 415 records · Page 23Linked to original sources
PubMed2000

Inhibition of the ER-kinase cascade by PD98059 and UO126 counteracts ischemic preconditioning in pig myocardium.

Our previous studies suggested a protective role of the extracellular signal-regulated kinases (ERKs) cascade in ischemic preconditioning (IP) in the porcine heart. To test this hypothesis further, we studied the influence of the novel specific inhibitors of mitogen-activated protein kinase kinases (MEK 1/2) PD98059 (PD) and UO126 (UO) in IP. The substances were infused intramyocardially and UO also systemically in anesthetized, ventilated, open-chested, male pigs. The local intramyocardial PD and UO infusions occurred before IP and during both reperfusion (RP) phases of IP via four pairs of needles (three pairs verum, one solvent) into the risk area (RA). The IP design included two cycles of 10-min left anterior descending artery (LAD) occlusion and 10 min RP, followed by 40 min of occlusion (index ischemia) and of 60 min of RP. Biopsies of the areas of drug infusion were taken after the second RP cycle of IP. By Western blot analysis, the phosphorylation of ERK 1/2 and of the downstream transcription factor Elk-1 were measured, and the activities of the ERKs were tested by in gel phosphorylation. Only small infarcts were detected in the control group animals with the IP period [infarct size (IS), infarct area/risk area; IS, 2.5+/-0.1%]. Significant wedge-shaped infarcts were seen around the area of the PD and UO infusions. The effects of PD and UO were concentration dependent. The maximal dose of UO126 (7.5 mg systemically) was associated with an IS of 68.7+/-2.0%. At the end of IP, we observed a significant increase in phosphorylation and activities of ERKs. PD (50 microM) induced a 50% inhibition of ERK-1 and 56% of ERK-2 activities. Phosphorylated ERK-1 and ERK-2 were decreased after microinfusion of both PD and UO (50 microM). Microinfusion of 50 microM PD also significantly decreased the phosphorylation of Elk-1 (to 59.2+/-8.3% of control conditions). We demonstrate for the first time in vivo that the inhibition of ERKs by PD and UO results in a complete cancellation of IP.

Animals↗
PubMed2005

Activated leukocyte cell adhesion molecule (ALCAM/CD166/MEMD), a novel actor in invasive growth, controls matrix metalloproteinase activity.

Activated leukocyte cell adhesion molecule (ALCAM/CD166/MEMD) could function as a cell surface sensor for cell density, controlling the transition between local cell proliferation and tissue invasion in melanoma progression. We have tested the hypothesis that progressive cell clustering controls the proteolytic cascade for activation of gelatinase A/matrix metalloproteinase-2 (MMP-2), which involves formation of an intermediate ternary complex of membrane type 1 MMP (MT1-MMP/MMP-14), tissue inhibitor of metalloproteinase-2 (TIMP-2), and pro-MMP-2 at the cell surface. Surprisingly, truncation of ALCAM severely impaired MMP-2 activation in a nude mouse xenograft model, in which we previously observed diminished primary tumor growth and enhanced melanoma metastasis. Comparative studies of two-dimensional monolayer and three-dimensional collagen-gel cultures revealed that extensive cell-to-cell contacts, wild-type ALCAM, and cell-to-matrix interactions were all indispensable for efficient conversion of pro-MMP-2 to its active form in metastatic melanoma cells. Truncated, dominant-negative ALCAM diminished MMP-2 activation via reduced transcript levels and decreased processing of MT1-MMP. Failure of the proteolytic cascade after selective ALCAM depletion by RNA interference was mainly due to incomplete MT1-MMP processing, which was otherwise promoted by extensive cell-to-cell contacts. These data attribute a novel signaling role to ALCAM in regulation of proteolysis and support its previously postulated sensor function in invasive growth.

Animals↗
PubMed1988

Mechanism of complement activation after coronary artery occlusion: evidence that myocardial ischemia in dogs causes release of constituents of myocardial subcellular origin that complex with human C1q in vivo.

To evaluate whether ischemic myocardium releases molecules that react with the first component of complement, we studied cardiac lymph from eight dogs before and at intervals after coronary artery occlusion and reperfusion. Before occlusion, the dogs were injected intravenously with radiolabeled human C1q. Labeled C1q could be detected in the cardiac lymph within minutes following injection. Rabbit antisera, prepared against substances precipitated from postreprefusion cardiac lymph by anti-human C1q, also reacted with specific constituents of isolated cardiac sarcoplasmic reticulum and mitochondria. To evaluate whether mitochondria are the source of these C1q-binding proteins, we isolated intramyofibrillar and subsarcolemmal mitochondria from canine heart and incubated sonicates of these with purified C1q, immobilized on nitrocellulose. Molecules bound to the immobilized C1q were removed with 0.1% sodium dodecyl sulfate, fractionated under reducing conditions by polyacrylamide gel electrophoresis, and transferred electrophoretically to nitrocellulose paper. Antisera prepared against postreperfusion lymph reacted with a 31,000-32,000-dalton protein in these nitrocellulose paper replicas. Since this protein originates from mitochondria, binds to C1q, and is recognized by antibodies made against postreperfusion lymph, this protein is likely to be one of the subcellular constituents that, upon release from ischemic cells, activates the complement cascade. To evaluate the clinical relevance of these observations, we tested sera from 53 patients obtained 48-72 hours after hospitalization for suspected myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Hypertonicity, but not hypothermia, elicits substance P release from rat C-fiber neurons in primary culture.

Isocapnic dry gas hyperventilation provokes hyperpnea-induced bronchoconstriction in guinea pigs by releasing tachykinins from airway sensory C-fiber neurons. It is unknown whether dry gas hyperpnea directly stimulates C-fibers to release tachykinins, or whether this physical stimulus initiates a mediator cascade that indirectly stimulates C-fiber tachykinin release. We tested the hypotheses that mucosal hypothermia and/or hyperosmolarity--physical consequences of airway heat and water loss imposed by dry gas hyperpnea--can directly stimulate C-fiber tachykinin release. Neurons isolated from neonatal rat dorsal root ganglia were maintained in primary culture for 1 wk. Cells were then exposed for 30 min at 37 degrees C to graded concentrations of NaCl, mannitol, sucrose, or glycerol (0-600 mOsm) added to isotonic medium, or to isotonic medium at 25 degrees C without or with 462 mOsm mannitol added. Fractional release of substance P (SP) was calculated from supernatant and intracellular SP contents following exposure. Hyperosmolar solutions containing excess NaCl, mannitol, or sucrose all increased fractional SP release equivalently, in an osmolarity-dependent fashion. In marked contrast, hypothermia had no effect on fractional SP release under isotonic or hypertonic conditions. Thus, hyperosmolarity, but not hypothermia, can directly stimulate tachykinin release from cultured rat sensory C-fibers. The lack of effect of glycerol, a solute which quickly crosses cell membranes, suggests that neuronal volume change represents the physical stimulus transduced by C-fibers during hyperosmolar exposure.

Animals↗
PubMed2006

Calcium-sensitive downregulation of the transduction chain in rod photoreceptors of the rat retina.

In vertebrate rod outer segments phototransduction is suggested to be modulated by intracellular Ca. We aimed at verifying this hypothesis by recording saturated photosignals in the rat retina after single and double flashes of light and determining the time t(c) to the beginning of the signal recovery. The time course of Ca(i) after a flash was calculated from a change of the spatial Ca(2+) concentration profile recorded in the space between the rods. After single flashes t(c) increased linearly with the logarithm of flash intensity, confirming the assumption that t(c) is determined by deactivation of a single species X* in the phototransduction cascade. The photoresponse was shortened up to 45% if the test flash was preceded by a conditioning preflash. The shortening depended on the reduction of Ca(i) induced by the preflash. The data suggest that the phototransduction gain determining the amount of activated X* is regulated by a Ca(i)-dependent mechanism in a short time period (<800 ms) after the test flash. Lowering of Ca(i) by a preflash reduced the gain up to 20% compared to its value in a dark-adapted rod. The relation between phototransduction gain and Ca(i) revealed a K(1/2) value close to the dark level of Ca(i).

Animals↗
PubMedDate not supplied

Oral diagnosis you can't afford to miss.

The development of more predictable therapeutic modalities for the management of periodontitis has been preceded to a great extent by a better understanding of the underlying disease process. As the role of the immune mechanism has become more defined in the cascade of events associated with the progressing lesions, specific diagnostic tests are being developed to monitor the biochemical changes in the host. These tests, in addition to microbiological monitoring, together will help define therapeutic approaches, maintenance strategies, and endpoints in therapy.

Clinical Enzyme Tests↗
PubMed2000

Metaplasticity of mossy fiber synaptic transmission involves altered release probability.

Activity-dependent synaptic plasticity is a fundamental feature of CNS synapses. Intriguingly, the capacity of synapses to express plastic changes is itself subject to considerable activity-dependent variation, or metaplasticity. These forms of higher order plasticity are important because they may be crucial to maintain synapses within a dynamic functional range. In this study, we asked whether neuronal activity induced in vivo by application of kainate can induce lasting changes in mossy fiber short- and long-term plasticity. Several weeks after kainate-induced status epilepticus, the mossy fiber, but not the associational-commissural pathway, exhibits a marked loss of paired-pulse facilitation, augmentation, and long-term potentiation (LTP). Because the adenylyl cyclase-protein kinase A cascade is involved in mossy fiber LTP induction, we have tested the integrity of this key pathway by pharmacological activation of either adenylyl cyclase or protein kinase A. These treatments resulted in LTP in control, but not in kainate-treated animals, indicating that status-induced changes occur downstream of protein kinase A. To test whether altered neurotransmitter release might account for these changes, we measured the size of the releasable pool of glutamate in mossy fiber terminals. We find that the size of the releasable pool of glutamate was significantly increased in kainate-treated rats, indicating an increased release probability at the mossy fiber-CA3 synapse. Therefore, we suggest that lasting changes in neurotransmitter release probability caused by neuronal activity may be a powerful mechanism for metaplasticity that modulates both short- and long-term plasticity in the mossy fiber-CA3 synapse after status epilepticus.

Animals↗
PubMed1997

[Angina pectoris. Silent ischemia].

One of the most difficult problems related to coronary artery disease is the detection and eventual treatment of silent myocardial ischemia (SMI). After defining the concept of SMI and total ischemia burden, the author approaches the pathophysiology of myocardial ischemia and focuses on the ischemic cascade. Concerning the detection of SMI the importance of exercise testing and Holter ECG is stressed. Following the classification of SMI proposed by P. F. Cohn, the author analyzes SMI type III with particular interest. He refers the prevalence of SMI in patients suffering from chronic stable angina, and focuses on the prognostic importance of SMI. Afterwards, the problem of treatment and prognostic implications is approached. The paper ends with mention of the results of the most important clinical trials in this field: CASIS, CAPE, TIBBS, ASIST, ACIP, TIBET.

Angina Pectoris↗
PubMed1997

[Observations on pe-eclampsia-eclampsia and the advances in the evolution of some laboratory tests].

The preeclampsia-eclampsia syndrome is a vasospastic disorder and probably has a placental origin. Once the hypertensive syndrome is established the uteroplacental blood flow is reduced as well as the intervillous blood flow. Since 18-24 weeks of gestation and before the symptoms of preeclampsia become overt, changes in placental flow velocity can be detected with Doppler technics. The placental theories for the etiology of preeclampsia are focused on the hypoxic effect in the trophoblastic tissue of second trimester. The placental ischemic changes are evident and seen in the uteroplacental bed. They are interrelated with the stages of trophoblastic invasion of the spiral arteries during the 14 and 20 weeks. When the trophoblastic invasion is over, the spiral arteries become a high resistance system. The defect observed in preeclampsia is the lack of invasion of the trophoblast to the maternal arteries. The diminished placental perfusion probably creates endothelial damage. This damage has several effects: decreased prostaglandin production, activated coagulation cascade, stimulated fibrin aggregation, and increased vascular permeability. The ideal laboratory test for preeclampsia shall predict the onset of this entity. Recent findings seem promising. The fibronectin concentration increases 2-3 wks. prior to the clinical manifestation of preeclampsia. Severe hypertension shows an abnormal decrease in fibronectin levels. Hypocalciuria has been described as an early predictor in the development of preeclampsia. Other agents undergoing extensive evaluation as predictors are: uric acid, b-thromboglobin, prolactin and atrial natriuretic peptide. Recently high levels of b-HCG (human corionic gonadotrophin) have been linked to a lack of trophoblastic invasion during the second trimester, therefore this is a potential marker for those patients that will eventually develop preeclampsia.

Adult↗
PubMed1998

Mutagenicity and clastogenicity of gas stove emissions in bacterial and plant tests.

The aim of this research was to study the gaseous and particulate emissions of genotoxic substances during cooking with two types of methane stoves (a new one and an old one). The particulates were sampled both with a cascade impactor air sampler and an impinger with ice trap and analyzed by two bacterial mutagenicity tests (Ames and Kado tests) and by HPLC for polycyclic aromatic hydrocarbons (PAH). Gaseous emissions were studied in situ using the Ames test, a clastogenicity plant test (Tradescantia-micronucleus test), and in an automated system for chemical analyses. Clear indirect mutagenicity was found only with the Kado test (TA98-S9) in extracts of particulates emitted from the old methane stove and collected with the impinger. Similar mutagenicity (TA98+S9) was also found for the finest fraction of particulates (<0.5 um) collected from both stoves. Gaseous emissions of both stoves caused clastogenicity in the in situ experiments with the Tradescantia-micronucleus test. The physico-chemical analyses of the emissions showed also the presence of very fine particulates and trace amounts of PAH. The exposure of these genotoxins could be particularly important for occupationally exposed individuals in homes and businesses and for susceptible subjects living indoors for long periods (infants, children, the sick, and the elderly).

Air Pollutants↗
PubMed2002

Collaborative translational research leading to multicenter clinical trials in Duchenne muscular dystrophy: the Cooperative International Neuromuscular Research Group (CINRG).

Progress in the development of rationally based therapies for Duchenne muscular dystrophy has been accelerated by encouraging multidisciplinary, multi-institutional collaboration between basic science and clinical investigators in the Cooperative International Research Group. We combined existing research efforts in pathophysiology by a gene expression profiling laboratory with the efforts of animal facilities capable of conducting high-throughput drug screening and toxicity testing to identify safe and effective drug compounds that target different parts of the pathophysiologic cascade in a genome-wide drug discovery approach. Simultaneously, we developed a clinical trial coordinating center and an international network of collaborating physicians and clinics where those drugs could be tested in large-scale clinical trials. We hope that by bringing together investigators at these facilities and providing the infrastructure to support their research, we can rapidly move new bench discoveries through animal model screening and into therapeutic testing in humans in a safe, timely and cost-effective setting.

Animals↗
PubMed2002

Apolipoprotein E and Reelin ligands modulate tau phosphorylation through an apolipoprotein E receptor/disabled-1/glycogen synthase kinase-3beta cascade.

Neurofibrillary tangles comprised of highly phosphorylated tau proteins are a key component of Alzheimer's disease pathology. Mice lacking Reelin (Reln), double-knockouts lacking the VLDL receptor (VLDLR) and ApoE receptor2 (ApoER2), and mice lacking disabled-1 (Dab1) display increased levels of phosphorylated tau. Because Reln binds to recombinant ApoE receptors, assembly of a Reln/ApoE-receptor/Dab1 (RAD) complex may initiate a signal transduction cascade that controls tau phosphorylation. Conversely, disruption of this RAD complex may increase tau phosphorylation and lead to neurodegeneration. To substantiate this concept, we mated Reln-deficient mice to ApoE-deficient mice and found that in the absence of Reln, tau phosphorylation increased as the amount of ApoE decreased. Paralleling the change in tau phosphorylation levels, we found that GSK-3beta activity increased in Reln-deficient mice and further increased in mice lacking both Reln and ApoE. CDK-5 activity was similar in mice lacking Reln, ApoE, or both. GSK-3beta and CDK-5 activity increased in Dab1-deficient mice, independent of ApoE levels. Further supporting the idea that increased tau phosphorylation results primarily from increased kinase activity, the activity of two phosphatases was similar in all conditions tested. These data support a novel, ligand-mediated signal transduction cascade--initiated by the assembly of a RAD complex that suppresses kinase activity and controls tau phosphorylation.

Animals↗
PubMed2000

Trophic Cascades in Terrestrial Systems: A Review of the Effects of Carnivore Removals on Plants.

We present a quantitative synthesis of trophic cascades in terrestrial systems using data from 41 studies, reporting 60 independent tests. The studies covered a wide range of taxa in various terrestrial systems with varying degrees of species diversity. We quantified the average magnitude of direct effects of carnivores on herbivore prey and indirect effects of carnivores on plants. We examined how the effect magnitudes varied with type of carnivores in the study system, food web diversity, and experimental protocol. A metaanalysis of the data revealed that trophic cascades were common among the studies. Exceptions to this general trend did arise. In some cases, trophic cascades were expected not to occur, and they did not. In other cases, the direct effects of carnivores on herbivores were stronger than the indirect effects of carnivores on plants, indicating that top-down effects attenuated. Top-down effects usually attenuated whenever plants contained antiherbivore defenses or when herbivore species diversity was high. Conclusions about the strength of top-down effects of carnivores varied with the type of carnivore and with the plant-response variable measured. Vertebrate carnivores generally had stronger effects than invertebrate carnivores. Carnivores, in general, had stronger effects when the response was measured as plant damage rather than as plant biomass or plant reproductive output. We caution, therefore, that conclusions about the strength of top-down effects could be an artifact of the plant-response variable measured. We also found that mesocosm experiments generally had weaker effect magnitudes than open-plot field experiments or observational experiments. Trophic cascades in terrestrial systems, although not a universal phenomenon, are a consistent response throughout the published studies reviewed here. Our analysis thus suggests that they occur more frequently in terrestrial systems than currently believed. Moreover, the mechanisms and strengths of top-down effects of carnivores are equivalent to those found in other types of systems (e.g., aquatic environments).

direct effects↗
PubMedDate not supplied

Selective anticoagulation with active site blocked factor IXa in synthetic patch vascular repair results in decreased blood loss and operative time.

Heparin has been the mainstay of anti thrombic therapy in arterial repair procedures. With increasing use of synthetic patch angioplasty (polytetrafluoroethylene [PTFE] or Dacron, Medical Products, Flagstaff, AZ) to improve long-term patency and limit aneurysmal dilation, however, the use of heparin has been associated with excessive needle hole bleeding, resulting in time delay in the operating room to achieve hemostasis, as well as clinically significant blood loss. Because of the multiple sites of action of heparin in the coagulation cascade, both intravascular (desired effect) and extravascular (untoward side effect) hemostasis are impaired. The authors therefore tested the hypothesis that selective inhibition of intravascular coagulation, without significant impairment of extravascular hemostasis, would prevent clotting intraluminally while preserving hemostasis at the suture line of the patch graft. The unique position of factor IX/IXa in the coagulation cascade renders its inhibition an ideal target in this setting. The authors prepared active site blocked factor IXa (IXai) using dansyl-Glu-Gly-Arg chloromethylketone, and tested this hypothesis in a New Zealand rabbit aortotomy model with PTFE patch closure using either heparin (25 i.u./kg; n = 16) or IXai (300 micrograms/kg; n = 21). The infrarenal aorta was identified and isolated, the anti coagulant infused, aortic cross clamp placed, and aortotomy repaired with a 2 x 6 mm PTFE patch. After cross-clamp removal, blood loss was measured and time to hemostasis was recorded. Compared with heparin, IXai resulted in significantly reduce blood loss (6.97 +/- 4.4 g vs 2.72 +/- 2.51 g, respectively, p < 0.008), and time to hemostasis (2.94 +/- 0.77 min vs 2.0 +/- 0.63 min, respectively, p < 0.003). To assess long-term patency and thrombosis, 12 rabbits (given heparin; n = 6 and IXai; n = 6) were observed for up to 2 months post-operatively. No differences were observed between rabbits treated with heparin or IXai; 100% of the grafts were patent with no differences in degree of intimal hyperplasia by histologic analysis. Together, these data suggest that use of IXai in PTFE vascular repair will safely allow realization of the benefits of long-term patency and decreased aneurysmal dilatation, while eliminating the intraoperative morbidity of needle hole bleeding.

Animals↗
PubMed2004

Oxidative stress and thioredoxin-interacting protein promote intravasation of melanoma cells.

Although intravasation may be a critical rate-limiting step in the metastatic cascade, the role of oxidative stress in intravasation is unknown. We tested the hypothesis that reactive oxygen species (ROS), regulated by thioredoxin interacting protein (Txnip) through the action of thioredoxin (Trx), influence human SK-MEL-28 melanoma cell reverse (basolateral-to-apical) transendothelial migration (TEM) in vitro as a model for intravasation. Reverse transendothelial migration was dose-dependently induced by hydrogen peroxide 2.4-fold for 0.1 microM (P < 0.01) and 3.9-fold for 1 microM (P < 0.001) vs. control, and this effect was blocked by the antioxidant N-acetylcysteine. Overexpression of Txnip by infecting melanoma cells with adenovirus increased TEM 3-fold vs. control (P < 0.001), and this increase was blocked by N-acetylcysteine, indicating a redox-sensitive mechanism. Conversely, thioredoxin overexpression blocked hydrogen peroxide-induced TEM. Exposure to ultraviolet-A radiation increased ROS 1.8-fold (P < 0.01), and this was accompanied by a 45% reduction (P < 0.05) in thioredoxin activity and an 11.4-fold (P < 0.001) increase in Txnip gene expression. These data suggest that TEM of melanoma cells during intravasation is in part mediated by ROS-sensitive cellular signaling cascades, may be controlled by Txnip and its interaction with thioredoxin that in turn modulates cellular levels of oxidative stress, and may be initiated by ultraviolet-A induction of this cascade.

Blood Vessels↗
PubMed2005

The role of complement testing in dermatology.

An up-to-date knowledge of the molecular events involved in the activation and control of the complement cascade is essential to understand the pathogenesis of a number of conditions presenting to dermatologists. This knowledge underpins the pathogenesis of these conditions but allows the clinician to request the most useful tests in terms of diagnosis and monitoring. In this review we aim to discuss complement biology, the diseases in which complement testing is of particular relevance, the types of laboratory tests available, their utility and interpretation. Additionally it is of critical importance for clinicians not only to choose the most appropriate tests but also to choose to send these to an appropriately accredited laboratory.

Complement Activation↗
PubMed1997

Potentiation of beta-adrenergic signaling by adenoviral-mediated gene transfer in adult rabbit ventricular myocytes.

Our laboratory has been testing the hypothesis that genetic modulation of the beta-adrenergic signaling cascade can enhance cardiac function. We have previously shown that transgenic mice with cardiac overexpression of either the human beta2-adrenergic receptor (beta2AR) or an inhibitor of the beta-adrenergic receptor kinase (betaARK), an enzyme that phosphorylates and uncouples agonist-bound receptors, have increased myocardial inotropy. We now have created recombinant adenoviruses encoding either the beta2AR (Adeno-beta2AR) or a peptide betaARK inhibitor (consisting of the carboxyl terminus of betaARK1, Adeno-betaARKct) and tested their ability to potentiate beta-adrenergic signaling in cultured adult rabbit ventricular myocytes. As assessed by radioligand binding, Adeno-beta2AR infection led to approximately 20-fold overexpression of beta-adrenergic receptors. Protein immunoblots demonstrated the presence of the Adeno-betaARKct transgene. Both transgenes significantly increased isoproterenol-stimulated cAMP as compared to myocytes infected with an adenovirus encoding beta-galactosidase (Adeno-betaGal) but did not affect the sarcolemmal adenylyl cyclase response to Forskolin or NaF. beta-Adrenergic agonist-induced desensitization was significantly inhibited in Adeno-betaARKct-infected myocytes (16+/-2%) as compared to Adeno-betaGal-infected myocytes (37+/-1%, P < 0.001). We conclude that recombinant adenoviral gene transfer of the beta2AR or an inhibitor of betaARK-mediated desensitization can potentiate beta-adrenergic signaling.

Adenoviridae↗
PubMed2002

Modeling Alzheimer's disease and other proteopathies in vivo: is seeding the key?

Protein misfolding and aberrant polymerization are salient features of virtually all central neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease, triplet repeat disorders, tauopathies, and prion diseases. In many instances, a single amino acid change can predispose to disease by increasing the production and/or changing the biophysical properties of a specific protein. Possible pathogenic similarities among the cerebral proteopathies suggest that therapeutic agents interfering with the proteopathic cascade might be effective against a wide range of diseases. However, testing compounds preclinically will require disease-relevant animal models. Numerous transgenic mouse models of beta-amyloidosis, tauopathy, and other aspects of AD have now been produced, but none of the existing models fully recapitulates the pathology of AD. In an attempt to more faithfully replicate the human disease, we infused dilute AD-brain extracts into Tg2576 mice at 3-months of age (i.e. 5-6 months prior to the usual onset of beta-amyloid deposition). We found that intracerebral infusion of AD brain extracts results in: 1). Premature deposition of beta-amyloid in eight month-old, beta-amyloid precursor protein ( betaAPP)-transgenic mice (Kane et al., 2000); 2). augmented amyloid load in the injected hemisphere of 15 month-old transgenic mice; 3). evidence for the spread of pathology to other brain areas, possibly by neuronal transport mechanisms; and 4). tau hyperphosphorylation (but not neurofibrillary pathology) in axons passing through the injection site. The seeding of beta-amyloid in vivo by AD brain extracts suggests pathogenic similarities between beta-amyloidoses such as AD and other cerebral proteopathies such as the prionoses, and could provide a new model for studying the proteopathic cascade and its neuronal consequences in neurodegenerative diseases.

Alzheimer Disease↗