Reduction in p140-TrkA Receptor Protein within the Nucleus Basalis and Cortex in Alzheimer's Disease

Mufson, Elliott J.; Lavine, Natalie; Jaffar, Syed Raza; Kordower, Jeffrey H.; Quirion, Rémi; Saragovi, H. Uri

doi:10.1006/exnr.1997.6504

Cited by 179 publications

(120 citation statements)

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“…Quantitative Western blot analysis (20) with a polyclonal antibody directed to the Trk intracellular domain (203 antisera, a gift of David Kaplan, University of Toronto) indicated that the stable HEK293 4.1 TrkA/B cells express 40,000 -150,000 chimeric receptors/cell (data not shown) (18). All cells were grown in RPMI 1640 supplemented with 5% fetal calf serum, antibiotics, and glutamine.…”

Section: Methodsmentioning

confidence: 99%

TrkA Receptor “Hot Spots” for Binding of NT-3 as a Heterologous Ligand

Ivanisevic

Zheng

Woo

et al. 2007

Journal of Biological Chemistry

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Neurotrophins signal via Trk tyrosine kinase receptors. Nerve growth factor (NGF) is the cognate ligand for TrkA, the brainderived neurotrophic factor for TrkB, and NT-3 for TrkC. NT-3 also binds TrkA as a lower affinity heterologous ligand. Because neurotrophin-3 (NT-3) interactions with TrkA are biologically relevant, we aimed to define the TrkA "hot spot" functional docking sites of NT-3. The Trk extracellular domain consists of two cysteine-rich subdomains (D1 and D3), flanking a leucinerich subdomain (D2), and two immunoglobulin-like subdomains IgC1(D4) and IgC2(D5). Previously, the D5 subdomain was defined as the primary ligand-binding site of neurotrophins for their cognate receptors (e.g. NGF binds and activates through TRKA-D5 hot spots). Here binding studies with truncated and chimeric extracellular subdomains show that TRKA-D5 also includes an NT-3 docking and activation hot spot (site 1), and competition studies show that the NGF and NT-3 hot spots on TRKA-D5 are distinct but partially overlapping. In addition, ligand binding studies provide evidence for an NT-3-binding/allosteric site on TRKA-D4 (site 2). NT-3 docking on sites 1 and/or 2 partially blocks NGF binding. Functional survival studies showed that sites 1 and 2 regulate TrkA activation. NT-3 docking on both sites 1 and 2 affords full agonism, which can be additive with NGF activation of Trk. However, NT-3 docking solely on site 1 is partially agonistic but noncompetitively antagonizes NGF binding and activation of Trk. This study demonstrates that Trk signaling is more complex than previously thought because it involves several receptor subdomains and hot spots.

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Section: Methodsmentioning

confidence: 99%

TrkA Receptor “Hot Spots” for Binding of NT-3 as a Heterologous Ligand

Ivanisevic

Zheng

Woo

et al. 2007

Journal of Biological Chemistry

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“…TrkA, p75, Sortilin (Lu et al, 2005). While a marked decrease of TrkA is assessed in basal forebrain and in cortex (Chu et al, 2001;Mufson et al, 1996Mufson et al, , 1997Mufson et al, , 2000Salehi et al, 1996;Boissiere et al, 1997;Hock et al, 1998;Savaskan et al, 2000;Counts et al, 2004;Ginsberg et al, 2006), p75NGF receptor levels appear to be up-regulated (Hu et al, 2002), downregulated (Kerwin et al, 1992;Salehi et al, 2000;Mufson et al, 2002) or unchanged (Mufson et al, 2003;Ginsberg et al, 2006) in different models of aging and of AD. In addition, an unbalance in TrKA and p75 activity favoring the binding of NGF to p75 and the Ab mediated neuronal death has been recently reported in mild AD patients (Wu et al, 2007) and in in vitro AD neuronal models (Sotthinbundhu et al, 2008;Matrone et al, 2009).…”

Section: Ngf and Its Receptors In Admentioning

confidence: 98%

“…Since PC12 cells do not constitute an ideal in vitro system because they may not reproduce what in vivo occurs due to their tumor derived origin, analogous studies have been subsequently carried out on cultured hippocampal neurons, which drastically contributes to selective neuronal loss and progressive cognitive deficits observed in AD patients (Hefti et al, 1986;Mufson et al, 1997;Chao et al, 2003;Tuszynski et al, 2005). We observed that primary hippocampal neurons after 48 h of NGF exposure, die following NGF withdrawal, with an increase of APP processing and an intra and extracellular Ab accumulation (Matrone et al, 2008b; Fig.…”

Section: Ngf Signaling and Amyloidogenesismentioning

confidence: 99%

Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease

Calissano

Matrone

Amadoro

2010

Developmental Neurobiology

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Converging lines of evidence on the possible connection between NGF signaling and Alzheimer's diseases (AD) are unraveling new facets which could depict this neurotrophin (NTF) in a more central role. AD animal models have provided evidence that a shortage of NGF supply may induce an AD-like syndrome. In vitro experiments, moreover, are delineating a possible temporal and causal link between APP amiloydogenic processing and altered post-translational tau modifications. After NGF signaling interruption, the pivotal upstream players of the amyloid cascade (APP, b-secretase, and active form of c-secretase) are up-regulated, leading to an increased production of amyloid b peptide (Ab) and to its intracellular aggregation in molecular species of different sizes. Contextually, the Ab released pool generates an autocrine toxic loop in the same healthy neurons. At the same time tau protein undergoes anomalous, GSKb-mediated, phosphorylation at specific pathogenetic sites (Ser262 and Thr 231), caspase(s) and calpain-I-mediated truncation, detachment from microtubules with consequent cytoskeleton collapse and axonal transport impairment. All these events are inhibited when the amyloidogenic processing is reduced by b and c secretase inhibitors or anti-Ab antibodies and appear to be causally correlated to TrkA, p75CTF, Ab, and PS1 molecular association in an Ab-mediated fashion. In this scenario, the so-called trophic action exerted by NGF (and possibly also by other neurotrophins) in these targets neurons is actually the result of an anti-amyloidogenic activity. '

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“…Basal forebrain neurons in patients with Alzheimer's disease have decreased amounts of trkA mRNA (Mufson et al, 1996) and TrkA-like immunoreactivity (Salehi et al, 1996), and TrkA protein levels are lower in the cerebral cortex of these patients (Mufson et al, 1997). In addition, NGF levels are increased in cerebral cortex and decreased in nucleus basalis in Alzheimer's disease (Scott et al, 1995), suggesting that this disease could be associated with impaired TrkA-dependent retrograde transport of NGF.…”

Section: Alzheimer's Disease and Retrograde Transportmentioning

confidence: 99%

Infusion of nerve growth factor (NGF) into kitten visual cortex increases immunoreactivity for NGF, NGF receptors, and choline acetyltransferase in basal forebrain without affecting ocular dominance plasticity or column development

Silver¹,

Fagiolini²,

Gillespie³

et al. 2001

Neuroscience

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AbstractöIntracerebroventricular or intracortical administration of nerve growth factor (NGF) has been shown to block or attenuate visual cortical plasticity in the rat. In cats and ferrets, the e¡ects of exogenous NGF on development and plasticity of visual cortex have been reported to be small or nonexistent. To determine whether locally delivered NGF a¡ects ocular dominance column formation or the plasticity produced by monocular deprivation in cats at the height of the critical period, we infused recombinant human NGF into the primary visual cortex of kittens using an implanted cannula minipump. NGF had no e¡ect on the normal developmental segregation of geniculocortical a¡erents into ocular dominance columns as determined both physiologically and anatomically. The plasticity of binocular visual cortical responses induced by monocular deprivation was also normal in regions of immunohistochemically detectable NGF infusion, as measured using intrinsic signal optical imaging and single-unit electrophysiology. Immunohistochemical analysis of the basal forebrain regions of the same animals demonstrated that the NGF infused into cortex was biologically active, producing an increase in the number of NGF-, TrkA-, p75 NTR -, and choline acetyltransferase-positive neurons in basal forebrain nuclei in the hemisphere ipsilateral to the NGF minipump compared to the contralateral basal forebrain neurons.We conclude that NGF delivered locally to axon terminals of cholinergic basal forebrain neurons resulted in increases in protein expression at the cell body through retrograde signaling. ß 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.Key words: TrkA, p75, choline acetyltransferase, retrograde transport, acetylcholine, monocular deprivation.Monocular deprivation (MD) is a well-studied model of experience-dependent cortical plasticity. When one eye of an animal is occluded during a critical period of development, that eye loses most of its ability to drive neurons in primary visual cortex, shifting the distribution of visual responses to favor the nondeprived eye (Wiesel and Hubel, 1963). Intracerebroventricular (ICV) administration of the neurotrophin nerve growth factor (NGF) to rats during a critical period of development blocks the e¡ects of MD (Domenici et al., 1991;Ma¡ei et al., 1992). This has been demonstrated at several levels of analysis, including physiological, anatomical, immunocytochemical, and behavioral (for a review, see Cellerino and Ma¡ei, 1996). Infusion of NGF directly into developing rat visual cortex also prevents physiological ocular dominance plasticity (Lodovichi et al., 2000).In addition, anti-NGF antibodies prevent normal anatomical and physiological development of the visual system when they are administered to rats by implantation of antibody-secreting hybridoma cells in the lateral ventricle (Berardi et al., 1994). These antibodies also prolong the critical period for ocular dominance plasticity in the rat (Domenici et al., 1994a). Together, these results demonstrate an imp...

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Reduction in p140-TrkA Receptor Protein within the Nucleus Basalis and Cortex in Alzheimer's Disease

Cited by 179 publications

References 43 publications

TrkA Receptor “Hot Spots” for Binding of NT-3 as a Heterologous Ligand

TrkA Receptor “Hot Spots” for Binding of NT-3 as a Heterologous Ligand

Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease

Infusion of nerve growth factor (NGF) into kitten visual cortex increases immunoreactivity for NGF, NGF receptors, and choline acetyltransferase in basal forebrain without affecting ocular dominance plasticity or column development

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