Biomedical subjects

R Schliebs

Publications and source records attributed to R Schliebs.

At least 37 records · Page 2Linked to original sources

PubMed2000

Expression of beta-secretase mRNA in transgenic Tg2576 mouse brain with Alzheimer plaque pathology.

On the basis of the recent cloning of the beta-secretase, the beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE), (Science, 286 (1999) 735), digoxigenin-labelled riboprobes were generated to localize the cellular expression pattern of BACE mRNA in brain sections of transgenic Tg2576 mice, overexpressing the Swedish mutation of the APP695 isoform. Non-radioactive in situ hybridization in combination with immunohistochemistry to identify the cell types and beta-amyloid deposits revealed strong BACE mRNA hybridization signals in neurons of the cerebral cortex, hippocampal formation, thalamus and cholinergic basal forebrain nuclei, while astrocytes did not display any labeling. Neurons surrounding beta-amyloid deposits did not demonstrate altered expression level of BACE mRNA as compared to neurons in cortical areas that are free of beta-amyloid deposits, and the regional expression pattern of BACE mRNA did not correlate with the distribution of beta-amyloid deposits. These data suggest that high level of expression of BACE mRNA is not necessarily related to enhanced deposition of beta-amyloid plaques. To elucidate those factors that contribute to beta-amyloid plaque deposition in a particular region, the transgenic Tg2576 mouse may represent an appropriate tool.

Alzheimer Disease↗

PubMed2000

Intracerebroventricular infusion of CHO5, a rat monoclonal antibody directed against mouse low-affinity nerve growth factor receptor (p75NTR), specifically labels basal forebrain cholinergic neurons in mouse brain.

The finding that basal forebrain cholinergic cells are specifically endowed with the low-affinity nerve growth factor receptor p75NTR has been employed to develop a cholinergic immunotoxin in rats by covalently linking the monoclonal antibody 192IgG against the rat p75NTR with the cytotoxic protein saporin (192IgG-saporin). Following intracebroventricular application of 192IgG-saporin, the antibody conjugate is taken up into cholinergic cells via the p75NTR, retrogradely transported to the cell body, where saporin exerts cytotoxic action. The lack of an appropriate antibody directed against mouse p75NTR has been hampered the development of a mouse-specific cholinergic immunotoxin, which should be a useful tool to study effects of cortical cholinergic deficits on processing of amyloid precursor protein in transgenic mice with Alzheimer pathology. To develop an appropriate mouse-specific immunotoxin, a variety of antibodies directed against mouse p75NTR were tested. Using double labeling immunocytochemistry, the rat monoclonal antibody CHO5 against mouse p75NTR was found to label mouse basal forebrain neurons, which also demonstrated immunoreactivity for choline acetyltransferase and the high-affinity nerve growth factor receptor, TrkA. Intracerebroventricular infusion of CHO5 in mice resulted in an accumulation of the antibody in cholinergic cells within the basal forebrain, suggesting that CHO5 is a suitable candidate to develop a mouse-specific cholinergic immunotoxin.

Animals↗

PubMed2000

In vivo [125I]-iodobenzovesamicol binding reflects cortical cholinergic deficiency induced by specific immunolesion of rat basal forebrain cholinergic system.

In this study, radiolabeled iodobenzovesamicol (IBVM), which is known to bind with high affinity to the vesicular acetylcholine transporter, was tested for its usefulness in imaging cortical cholinergic deficits in vivo. To induce reductions in cortical cholinergic input, the cholinergic immunotoxin 192IgG-saporin was employed. This has been shown to selectively and efficiently destroy basal forebrain cholinergic neurons in rats. The efficiency of the immunolesion was verified by histochemical acetylcholinesterase staining. [125I]-IBVM binding before and after lesioning was measured using autoradiography. Basal forebrain cholinergic cell loss resulted in a considerable reduction in [125I]-IBVM binding in the cholinoceptive target regions, but not in the striatum and cerebellum, brain regions that do not receive a cholinergic input by the basal forebrain cholinergic nuclei, suggesting that [123I]-IBVM has potential in imaging cortical cholinergic deficits in vivo, at least in animals.

Acetylcholinesterase↗

PubMed2000

Constitutive overactivation of protein kinase C in guinea pig brain increases alpha-secretory APP processing without decreasing beta-amyloid generation.

Whilst it is generally accepted that the activation of protein kinase C (PKC) increases amyloid precursor protein (APP) secretion in vitro, the role of PKC in the regulation of APP processing and beta-amyloid generation in vivo is still not well understood. In order to address this question, we established the animal model of neocortical microencephalopathy in guinea pigs caused by in utero treatment with methylazoxymethanol acetate, a DNA-methylating substance that eliminates proliferating cells of neuroepithelial origin. The induction of this neocortical malformation is accompanied by constitutive overactivation of PKC in the neocortex of the offspring. In the cortical and hippocampal tissues of juvenile microencephalic guinea pigs (postnatal day 30), we observed significant increases in basal (by 58% and 74%, respectively,) and phorbol ester-stimulated PKC enzyme activity (by 47% and 71%) as compared to age-matched control animals. In the same cortical/hippocampal preparations of methylazoxymethanol-treated animals, there was increased alpha-secretion of APP by 35% and 30% as measured by Western blot analysis using the antibody 6E10, whilst total APP secretion as well as APP mRNA expression remained unaltered. This upregulation of APP alpha-secretion was limited to brain areas that displayed elevated PKC activity. However, constitutive overactivation of neocortical PKC did not affect the generation of beta-amyloid peptides 1-40 or 1-42 as measured by ELISA, suggesting that only the alpha-secretase pathway of APP processing is affected by chronic PKC overactivation in vivo.

Amyloid Precursor Protein Secretases↗

PubMed2000

Inhibition of the neuronal insulin receptor. An in vivo model for sporadic Alzheimer disease?

It has been hypothesized that a central even in the early pathogenesis of sporadic Alzheimer disease (SAD) is the dysfunction of the neuronal insulin receptor signal transduction. To prove this, this receptor was inhibited by a triplicate icv application of STZ. Insulin binding sites were upregulated as in SAD. With respect to glucose transport proteins, detailed investigations are necessary.

ATP-Binding Cassette Transporters↗

PubMed1999

Acute effect of KA-672, a putative cognitive enhancer, on neurotransmitter receptor binding in mouse brain.

7-Methoxy-6-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy]-3,4-dim ethyl-2H-1-benzopyran-2-one hydro-chloride (KA-672), structurally related to naturally occurring coumarins, has been described as a potential drug for enhancing cognitive functions. However, a detailed characterization of the pharmacological profile of KA-672 in vivo is still lacking. Quantitative neurotransmitter receptor autoradiography was used as a tool to screen for KA-672-induced changes in a number of transmitter receptors including cholinergic, noradrenergic, glutamatergic, GABAergic, and serotonergic subtypes throughout the brain. Two hours following treatment of mice with 1 mg/kg KA-672 per os, slight increases of nicotinic and M1-muscarinic cholinergic receptor binding, of alpha2-and beta-adrenoceptor as well as 5-HT1A receptors in various cerebral cortical regions were observed, whereas 5-HT2A binding sites were strikingly increased throughout the brain following KA-672 treatment. In contrast, (+/-)-alphaamino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor binding was significantly decreased in some cortical regions after drug treatment. No effects of KA-672 treatment on N-methyl-D-aspartate, kainate, GABA(A) and benzodiazepine receptor as well as M2-muscarinic cholinergic and high-affinity choline uptake binding were observed. As interactions between the cholinergic, noradrenergic and serotonergic neurotransmission have been stressed to play important roles in realizing learning and memory events, the cognition-enhancing effects of KA-672 may be due to this complex in vivo pharmacological profile of KA-672.

Animals↗

PubMed1999

Insulin-sensitive GLUT4 glucose transporters are colocalized with GLUT3-expressing cells and demonstrate a chemically distinct neuron-specific localization in rat brain.

The insulin-sensitive glucose transporter (GLUT) 4, expressed primarily in peripheral tissue, has recently been detected also in the brain, demonstrating a region-specific distribution. To identify the chemical nature of neurons expressing GLUT4 and to disclose whether GLUT4-containing neurons also express the GLUT3 isoform, combined in situ hybridization for GLUT3 mRNA and double-labeling immunocytochemistry for GLUT4 and different cellular markers was performed in brain sections through rat basal forebrain, cerebral cortex, hippocampus, and cerebellum. In all brain regions examined, GLUT4 immunoreactivity was exclusively found in neurons, and GLUT4-immunoreactive cells were colocalized with neurons expressing GLUT3 mRNA. In rat basal forebrain, cholinergic and parvalbumin-containing gamma-aminobutyric acid-ergic cells demonstrated GLUT4 immunoreactivity, whereas calretinin-, calbindin-D-, and neuronal nitric oxide synthase-containing neurons did not express GLUT4 protein. Because brain GLUT4 transporters have been suggested to play a role in rapidly providing additional glucose to neurons under conditions of high-energy demand, the selective presence of GLUT4 in basal forebrain cholinergic cells may explain the specific vulnerability of these cells to a lack of glucose supply.

Animals↗

PubMed1999

Regulated secretion of amyloid precursor protein by TrkA receptor stimulation in rat pheochromocytoma-12 cells is mitogen activated protein kinase sensitive.

We have shown recently in the pheochromocytoma PC-12 cell line, that the activation of the high-affinity receptor for nerve growth factor (NGF), tyrosine kinase receptor (TrkA), results in increased secretion of the amyloid precursor protein (APP) into the culture medium. In order to reveal through which TrkA-associated signaling pathway the secretory APP processing is mediated, signaling cascades activated by TrkA stimulation were selectively inhibited under conditions of selective TrkA stimulation via non-NGF mechanisms and APP secretion into the culture medium was followed by Western analysis. Our data demonstrate, that activation of mitogen activated protein (MAP) kinase alone is sufficient to promote APP secretion, whereas inhibition of MAP kinase will reduce APP secretion only when phospholipase Cgamma or phosphatidylinositol 3-kinase are additionally inhibited. This suggests that pharmacological manipulations activating the MAP kinase pathway may result in increased secretory APP processing.

Amyloid beta-Protein Precursor↗

PubMed1999

Interleukin-1beta, inducible nitric oxide synthase, and nuclear factor-kappaB are induced in morphologically distinct microglia after rat hippocampal lipopolysaccharide/interferon-gamma injection.

In a number of pathological states of the brain, the activation of the inducible nitric oxide synthase (iNOS) plays a major role. Interleukin (IL)-1beta is believed to be an essential factor in the induction of iNOS. However, little is known about the cascade of events culminating in iNOS expression in vivo. To identify the morphological as well as temporal relationship of lipopolysaccharide (LPS)/interferon-gamma (IFN-gamma) -induced microglial iNOS- and IL-1beta expression, a mixture of LPS and IFN-gamma was injected into the rat hippocampus. IL-1beta immunoreactivity was detected as early as 3 hr following surgery in ramified microglia in the lesioned hippocampus and in distal cortical layers adjacent to the pia mater. By 12 hr post-injection, IL-1beta immunoreactive, ramified microglia with swollen processes were widely distributed throughout hippocampal and neocortical areas, and staining was observed up to 48 hr after treatment. In contrast, iNOS immunostaining was seen in activated amoeboid microglia/macrophages in the ipsilateral hippocampus and around blood vessels but not earlier than 12 hr post-surgery. The temporal pattern of iNOS and IL-1beta expression corresponded to newly induced transcriptional activity as revealed by RT-PCR. Activation of NF-kappaB was restricted to brain regions in which IL-1beta was expressed and was detected both in microglia and astrocytes. A number of LPS/IFN-gamma-stimulated, IL-1beta-expressing microglia exhibited co-staining for activated NF-kappaB. The finding that IL-1beta precedes iNOS expression is consistant with a role of IL-1beta in the intercellular signaling events leading to microglial iNOS-induction. Co-localization of IL-1beta and NF-kappaB suggests an association between IL-1beta and NF-kappaB induction.

Animals↗

PubMed1999

Leukemia inhibitory factor expression is not induced in activated microglia and reactive astrocytes in response to rat basal forebrain cholinergic lesion.

In adult intact rat brain, leukemia inhibitory factor (LIF) mRNA has been found to be constitutively expressed in basal forebrain cholinergic neurons. To reveal a functional role of LIF in neurodegenerative events, the cellular expression pattern of LIF was determined by combining in situ hybridization and immunocytochemistry after specific and selective degeneration of basal forebrain cholinergic cells by a single intracerebroventricular application of the cholinergic immunotoxin 192IgG-saporin. Although basal forebrain cholinergic lesion resulted in a dramatic activation of micro- and astroglial cells at the lesion site, LIF mRNA expression was not detected in any of the lesion-induced activated glial cell types. As the cholinergic immunotoxin exerts its degenerative action by the ribosome-inactivating property of saporin, the lack of glial LIF induction might be due to the incapability of the dying cholinergic cell to form and release factors which induce LIF expression in activated glial cells.

Animals↗

PubMed1999

Iodo-QNB cortical binding and brain perfusion: effects of a cholinergic basal forebrain lesion in the rat.

This study deals with the question of whether in vivo application of [125I]iodo-quinuclidinyl-benzilate (QNB) is able to demonstrate changes in cortical muscarinic receptor density induced by a cholinergic immunolesion of the rat basal forebrain cholinergic system, and whether the potential effects on IQNB distribution in vivo are also associated with effects on regional cerebral perfusion. Immunolesioned and control animals were injected with (R,S) [125]iodo-QNB and with [99mTc]-d,l-hexamethylpropyleneamine oxime (HMPAO). The cerebral distribution of both tracers was imaged using double tracer autoradiography. Impaired cholinergic transmission was paralleled by a 10-15% increase of [125I]iodo-QNB binding in the regions of cortex and hippocampus. The local cerebral blood flow remained unchanged after cholinergic lesion.

Acetylcholine↗

PubMed1999

Differential injury-dependent glial expression of interleukins-1 alpha, beta, and interleukin-6 in rat brain.

Interleukins (IL)-1 alpha, beta and IL-6 may play essential roles in early inflammatory processes in response to degenerating cholinergic cells observed in the basal forebrain of Alzheimer patients. To address this question in vivo, two distinct lesion paradigms were used. A specific and selective basal forebrain cholinergic cell loss was achieved by a single intracerebroventricular application of the cholinergic immunotoxin, 192IgG-saporin. Intrahippocampal injection of lipopolysaccharide and interferon-gamma was used to produce an exogenously-induced acute inflammation in the brain. In order to disclose the lesion-induced temporal cascade of the expression pattern of IL-1 alpha, IL-1 beta, and IL-6, and the cell types expressing IL-1 alpha, beta/IL-6 mRNA, Western analysis, RT-PCR, and double labeling immunocytochemistry were applied. In the intact brain, IL-6, IL-1 alpha and IL-1 beta demonstrated a constitutive expression in neurons. Following cholinergic lesion neither IL-1 beta nor IL-6 expression could be detected in any of the activated glial cell types, whereas IL-1 alpha was found to be expressed in astroglial cells only. In contrast, hippocampal administration of lipopolysaccharides/interferon-gamma resulted in expression of IL-1 alpha in microglial but not astroglial cells. These in vivo studies clearly demonstrate that the cellular expression of IL-1 alpha, IL-1 beta, and IL-6 in the brain is differentially regulated depending on the kind of injury producing the inflammatory response in the brain. The data suggest that each glial cell seems to be equally capable of expressing a number of various cytokines, but it depends on the kind of stimulus which temporal and cellular cascade of cytokine expression pattern is initiated under a particular pathological condition in the brain.

Animals↗

PubMed1998

Electron microscopic evidence for a cholinergic innervation of GABAergic parvalbumin-immunoreactive neurons in the rat medial septum.

The presence of interconnections between cholinergic and parvalbumin (PARV)-containing gamma aminobutyric acid (GABA)ergic septohippocampal projection neurons is still a matter of debate. To search for contacts of cholinergic collateral axon terminals in the septal-diagonal band region the immunotoxin 192IgG-saporin was applied, which was proved to selectively destroy cholinergic basal forebrain neurons. Seven and 10 days after administration of the immunotoxin, choline acetyltransferase immunoreactivity had disappeared, and numerous neuronal somata and dendrites as well as axonal terminals revealed characteristics of electron-lucent degeneration. Electron-dense degeneration was never observed in dendrites and synaptic boutons. Degenerating terminals were found in contact with PARV-immunopositive and PARV-negative neurons. Because only cholinergic cells were degenerating, the terminals should be collaterals from cholinergic neurons. In addition to such contacts, PARV-immunoreactive boutons were seen in contact with PARV-positive and PARV-negative cells, but were not identified at degenerating postsynaptic profiles. As suggested in other studies, cholinergic boutons contacting GABAergic PARV-containing septal projection cells may influence hippocampal theta activity. Furthermore, multiple synaptic connections of both neuronal populations forming the septohippocampal pathway may contribute to their high rate of survival after fimbria-fornix transection.

Animals↗

PubMed1998

Interleukin-6 is not expressed in activated microglia and in reactive astrocytes in response to lesion of rat basal forebrain cholinergic system as demonstrated by combined in situ hybridization and immunocytochemistry.

Interleukin-6 may play an essential role in early inflammatory processes as response to degenerating cholinergic cells in the nucleus basalis of Meynert in patients suffering Alzheimer's disease. The cholinergic immunotoxin, 192IgG-saporin, was applied to produce selective and specific degenerations of basal forebrain cholinergic cells. To disclose the lesion-induced temporal cascade of the expression pattern of IL-6, and to reveal the cellular source for production and secretion of IL-6 in vivo after endogeneously induced basal forebrain cholinergic cell loss, both in situ hybridization and immunocytochemistry for IL-6 were performed. To identify the cell types expressing IL-6 mRNA, double labeling techniques were applied combining in situ hybridization technique with immunocytochemistry and lectin histochemistry for both micro- and astroglia and a number of neuronal markers including choline acetyltransferase, parvalbumin, and neurofilaments. In the intact brain, IL-6 is mainly localized in neurons, in particular in both cholinergic and GABAergic neurons of the basal forebrain. Although basal forebrain cholinergic lesion resulted in a dramatic increase in the number of micro- and astroglial cells at the lesion site, IL-6 expression could not be detected in any of the lesion-induced activated glial cell types. Moreover, cholinergic lesion led to a reduced number of IL-6-expressing cells in the basal forebrain, which is assumed to be due to the loss of cholinergic cells. The predominantly neuronal localization in rat brain suggests a role for IL-6 in activating micro- and astroglial cells in response to degenerating cholinergic neurons.

Animals↗

PubMed1998

Simulation of cortical cholinergic deficits--a novel experimental approach to study pathogenetic aspects of Alzheimer's disease.

Cholinergic lesion paradigms have been used to study the role of the cholinergic system in cognitive function, and its implication in cognitive deficits that occur in Alzheimer's disease. In the last few years an increasing number of studies have applied neurotoxins including excitotoxins or cholinotoxins to produce reductions in cortical cholinergic activity. One of the most serious limitations of these lesion paradigms is the fact that the cytotoxins used are far from being selective to cholinergic cells. Recently, a monoclonal antibody to the low-affinity nerve growth factor (NGF) receptor, 192IgG, coupled to a cytotoxin, saporin, has been described as an efficient and selective immunotoxin for the NGF-receptor bearing cholinergic neurons in rat basal forebrain. Here we demonstrate the usefulness of 192IgG-saporin as a powerful tool for producing an animal model with selective and specific basal forebrain cholinergic lesions in rats which can be applied to simulate some neurochemical sequelae of Alzheimer's disease including cholinergic mechanisms in processing of the amyloid precursor protein, and could be of particular value to elaborate and to test therapeutical strategies compensating for the reduced cortical cholinergic input.

Acetylcholinesterase↗

PubMed1998

Neurotrophin binding to the p75 neurotrophin receptor is necessary but not sufficient to mediate NGF-effects on APP secretion in PC-12 cells.

In the present study the pheochromocytoma cell line (PC-12) was used as a model system to determine the role of the two neurotrophin receptors in the regulation of amyloid precursor protein (APP) secretion by nerve growth factor (NGF). To stimulate TrkA and/or p75NTR signaling in PC-12 cells, we used NGF, brain-derived neurotrophic factor (BDNF), and NGF in the presence of an excess of BDNF or the monoclonal antibody 192IgG, to block p75NTR binding to NGF. Our results demonstrate that NGF stimulates APP secretion in a dose dependent fashion with maximum effects at 10 ng/ml, known to saturate high-affinity NGF binding sites. Treatment of PC-12 cells with varying concentrations of BDNF, 1-1,000 ng/ml, did not alter APP secretion, suggesting that binding to p75NTR alone is not sufficient to affect APP secretion. When blocking NGF binding to p75NTR with BDNF or 192IgG, on the other hand, NGF effects on APP secretion were abolished. These findings suggest that in cells expressing p75NTR and TrkA receptors, binding of NGF to the p75NTR is required to mediate NGF effects on APP secretion. Our data are also consistent with a proposed function of the p75NTR in receptor recruitment and "presentation" of NGF to receptors.

Amyloid beta-Protein Precursor↗

PubMed1998

The regulation of amyloid precursor protein metabolism by cholinergic mechanisms and neurotrophin receptor signaling.

The increased expression and/or abnormal processing of the amyloid precursor protein (APP) is associated with the formation of amyloid plaques and cerebrovascular amyloid deposits, which are one of the major morphological hallmarks of Alzheimer's disease (AD). Among the processes regulating APP metabolism, the proteolytic cleavage of APP into amyloidogenic or nonamyloidogenic fragments is of special interest. The cleavage of the APP by the alpha-secretase within the beta-amyloid sequence generates nonamyloidogenic C-terminal APP fragments and soluble APPs alpha, which has neurotrophic and neuroprotective activities. Proteolytic processing of APP by beta-secretase, on the other hand, exposes the N-terminus of beta-amyloid, which is liberated after gamma-secretase cleavage at the variable amyloid C-terminus. The resulting 39-43 amino acid beta-amyloid may be neurotoxic and disrupt neuronal connectivity after its accumulation in senile plaques. In this review, we discuss evidence derived from in vitro experiments, suggesting that the stimulation of protein kinase C (PKC)-coupled M1/M3 muscarinic acetylcholine receptors increases the nonamyloidogenic, secretory pathway of APP processing. It has also been shown in animal models that under conditions of reduced M1/M3 muscarinic acetylcholine receptor stimulation the secretory pathway of APP processing is inhibited and that constitutive upregulation of M1/M3-associated PKC increases APP secretion. Thus, the cortical cholinergic hypoactivity characteristic of AD may inhibit the nonamyloidogenic APP processing pathway and lead to increased beta-amyloid generation. It has been shown in vitro that nerve growth factor (NGF)-associated signaling also influences the expression and catabolism of APP. Recent experiments with NGF-responsive cells revealed a specific role for the high-affinity NGF receptor, TrkA, in the increases in secretory APP processing and a role for the low-affinity neurotrophin receptor, p75NTR, in the transcriptional regulation of APP. Therefore, treatments with NGF could ameliorate cortical cholinergic dysfunction in AD. These findings may influence the design of therapeutic strategies aimed at stimulating cholinergic function and at increasing nonamyloidogenic APP processing without elevating APP expression.

Acetylcholine↗

PubMed1998

p75 and TrkA receptor signaling independently regulate amyloid precursor protein mRNA expression, isoform composition, and protein secretion in PC12 cells.

The pheochromocytoma PC12 cell line was used as a model system to characterize the role of the p75 neurotrophin receptor (p75NTR) and tyrosine kinase (Trk) A nerve growth factor (NGF) receptors on amyloid precursor protein (APP) expression and processing. NGF increased in a dose-dependent fashion neurite outgrowth, APP mRNA expression, and APP secretion with maximal effects at concentrations known to saturate TrkA receptor binding. Displacement of NGF binding to p75NTR by addition of an excess of brain-derived neurotrophic factor abolished NGF's effects on neurite outgrowth and APP metabolism, whereas addition of brain-derived neurotrophic factor alone did not induce neurite outgrowth or affect APP mRNA or protein processing. However, treatment of PC12 cells with C2-ceramide, an analogue of ceramide, the endogenous product produced by the activity of p75NTR-activated sphingomyelinase, mimicked the effects of NGF on cell morphology and stimulation of both APP mRNA levels and APP secretion. Specific stimulation of TrkA receptors by receptor cross-linking, on the other hand, selectively stimulated neurite outgrowth and APP secretion but not APP mRNA levels, which were decreased. These findings demonstrate that in PC12 cells expressing p75NTR and TrkA receptors, binding of NGF to the p75NTR is required to mediate NGF effects on cell morphology and APP metabolism. Furthermore, our data are consistent with NGF having specific effects on p75NTR not shared with other neurotrophins. Lastly, we have shown that specific activation of TrkA receptors--in contrast to p75NTR-associated signaling--stimulates neurite outgrowth and increases nonamyloidogenic secretory APP processing without increases in APP mRNA levels.

Amyloid beta-Protein Precursor↗