Towards Non Invasive Nerve Growth Factor Therapies for Alzheimer's Disease

Cattaneo, Antonino; Capsoni, Simona; Paoletti, Francesca

doi:10.3233/jad-2008-15210

Cited by 86 publications

(76 citation statements)

References 247 publications

(339 reference statements)

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“…Growing evidence suggests that imbalance in the NGF signal, transport, and processing are crucial factors in AD (3,4,22). Gene therapy trials using NGF-grafted autologous fibroblasts injected into the basal nucleus of Meynert (23) or drugs that maintain a homeostatic balance between TrkA and p75 (24) further validate the hypothesis of an involvement of neurotrophins in AD (25) and are promising in terms of AD therapy.…”

Section: Discussionmentioning

confidence: 90%

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Tyrosine kinase nerve growth factor receptor switches from prosurvival to proapoptotic activity via Abeta-mediated phosphorylation

Matrone

Marolda

Ciafrè

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The present study shows that increased Abeta production in hippocampal neurons, due to a failure of NGF signal, induces an unexpected phosphorylation of tyrosine kinase receptor A (TrkA), followed by activation of the phospholipase C ␥ (PLC␥) pathway and neuronal death. Such phosphorylation seems causally connected with 2 kinases known be involved in amyloidogenesis, Src and CDK5, and associated with ␣ and ␥ secretase-mediated p75 processing. Pharmacologic inhibition of TrkA phosphorylation and partial silencing of TrkA and/or p75 receptors prevent PLC␥ activation and protect neurons from death. Concomitantly with these events, TrkA, p75, Abeta peptides, and PS1 protein coimmunoprecipitate, suggesting their direct interplay in the subsequent onset of apoptotic death. Together, these findings depict a cellular mechanism whereby the same cellular transducing system may invert its intracellular message from trophic and antiapoptotic to a death signaling, which could also have relevance in the onset of Alzheimer's disease.N GF mediates survival, differentiation, growth, and apoptosis of neurons by binding to 2 types of cell-surface receptors. Whereas tyrosine kinase receptor A (TrkA) has been shown to transduce specific prosurvival signals via an intricate network of intracellular pathways (1), the pan-p75 receptor (p75) modulates NGF affinity for TrkA and has been shown to be involved in transducing or directly carrying out death signals (2).Recently several articles have summarized evidence for a causal link between deficit in NGF signaling, transport, and processing and the onset of Alzheimer's disease (AD) (3,4).We have recently demonstrated that the interruption of NGF signaling in neurons activates the amyloidogenic pathway and induces death through a still-unclear mechanism (5, 6).Here we show that 24 h after NGF deprivation, TrkA undergoes an unexpected NGF-independent phosphorylation. This posttranslational modification is induced either by the overproduced pool of Abeta or by exogenously added Abeta and is strictly connected to neuronal death. Such TrkA phosphorylation is largely prevented by inhibitors of CDK5 and Src intracellular pathways, both involved in amyloid processing (7-9), and by TrkA and p75 silencing.Concomitantly with TrkA phosphorylation, the amounts of p75 C-terminal fragments, which are the products of ␣ and ␥ secretase cleavage on p75 (10, 11), increase and associate with TrkA to form a molecular complex also including a full length of p75, Abeta peptides, and PS1 protein.

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Section: Discussionmentioning

confidence: 90%

“…Recently several articles have summarized evidence for a causal link between deficit in NGF signaling, transport, and processing and the onset of Alzheimer's disease (AD) (3,4).…”

mentioning

confidence: 99%

Tyrosine kinase nerve growth factor receptor switches from prosurvival to proapoptotic activity via Abeta-mediated phosphorylation

Matrone

Marolda

Ciafrè

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, AD11 transgenic mouse-expressing recombinant antibodies that neutralize up to 50% of endogenous NGF-shows a neurodegenerative phenotype similar to human sporadic forms of AD with loss of basal forebrain cholinergic neurons, tau hyperphosphorylation, accumulation of Ab plaques, synaptic plasticity deficits and an incorrect balance between unprocessed proNGF and NGF signaling Capsoni et al, 2000Capsoni et al, , 2002aPesavento et al, 2002;Origlia et al, 2006;Sola et al, 2006;Cattaneo et al, 2008).…”

Section: Ngf and Its Receptors In Admentioning

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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“…Alzheimer | β-amyloid | proNGF | signaling unbalance D ecreased neurotrophic support of NGF (1) to cholinergic neurons in the basal forebrain (BFCNs), caused by failure in its retrograde transport or by processing defects (2)(3)(4)(5), has been associated with Alzheimer's disease (AD) (6) because of the selective vulnerability of BFCNs in AD (7).…”

mentioning

confidence: 99%

Dissecting the involvement of tropomyosin-related kinase A and p75 neurotrophin receptor signaling in NGF deficit-induced neurodegeneration

Capsoni

Tiveron²,

Vignone³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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NGF, the principal neurotrophic factor for basal forebrain cholinergic neurons (BFCNs), has been correlated to Alzheimer's disease (AD) because of the selective vulnerability of BFCNs in AD. These correlative links do not substantiate a comprehensive cause-effect mechanism connecting NGF deficit to overall AD neurodegeneration. A demonstration that neutralizing NGF activity could have consequences beyond a direct interference with the cholinergic system came from studies in the AD11 mouse model, in which the expression of a highly specific anti-NGF antibody determines a neurodegeneration that encompasses several features of human AD. Because the transgenic antibody binds to mature NGF much more strongly than to proNGF and prevents binding of mature NGF to the tropomyosin-related kinase A (TrkA) receptor and to p75 neurotrophin receptor (p75NTR), we postulated that neurodegeneration in AD11 mice is provoked by an imbalance of proNGF/NGF signaling and, consequently, of TrkA/p75NTR signaling. To test this hypothesis, in this study we characterize the phenotype of two lines of transgenic mice, one in which TrkA signaling is inhibited by neutralizing anti-TrkA antibodies and a second one in which anti-NGF mice were crossed to p75NTR exonIII(−/−) mice to abrogate p75NTR signaling. TrkA neutralization determines a strong cholinergic deficit and the appearance of β-amyloid peptide (Aβ) but no tau-related pathology. In contrast, abrogating p75NTR signaling determines a full rescue of the cholinergic and Aβ phenotype of anti-NGF mice, but tau hyperphosphorylation is exacerbated. Thus, we demonstrate that inhibiting TrkA signaling activates Aβ accumulation and that different streams of AD neurodegeneration are related in complex ways to TrkA versus p75NTR signaling.Alzheimer | β-amyloid | proNGF | signaling unbalance

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Towards Non Invasive Nerve Growth Factor Therapies for Alzheimer's Disease

Cited by 86 publications

References 247 publications

Tyrosine kinase nerve growth factor receptor switches from prosurvival to proapoptotic activity via Abeta-mediated phosphorylation

Tyrosine kinase nerve growth factor receptor switches from prosurvival to proapoptotic activity via Abeta-mediated phosphorylation

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

Dissecting the involvement of tropomyosin-related kinase A and p75 neurotrophin receptor signaling in NGF deficit-induced neurodegeneration

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