Alzheimer-like neurodegeneration in aged anti-nerve growth factor transgenic mice

Capsoni, Simona; Ugolini, Gabriele; Comparini, A; Ruberti, Francesca; Berardi, Nicoletta; Cattaneo, Antonino

doi:10.1016/s0197-4580(00)82608-1

Cited by 16 publications

(31 citation statements)

References 20 publications

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“…5A) (8,13,21). In 4-to 6-mo-old AD12 mice, however, we found a lower number of AT8-immunoreactive neurons, faintly labeled, in all brain regions described (Fig.…”

Section: Resultsmentioning

confidence: 61%

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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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“…5A) (8,13,21). In 4-to 6-mo-old AD12 mice, however, we found a lower number of AT8-immunoreactive neurons, faintly labeled, in all brain regions described (Fig.…”

Section: Resultsmentioning

confidence: 61%

“…AD11 mice express a highly specific anti-NGF antibody (10,11) in the adult brain, which induces a progressive, NGF-dependent neurodegeneration encompassing several neuropathological features of human AD, including accumulation of Aβ and neuronal expression of hyperphosphorylated, truncated, and insoluble tau (12)(13)(14)(15)(16).…”

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.

Self Cite

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show abstract

“…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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“…59 Interestingly, these anti-NGF transgenic AD11 mice, in which the in vivo phenotypic knockout of mature NGF is achieved by the expression of recombinant neutralizing antibodies, resemble an AD-like neurodegeneration. 60,61 Furthermore, a caspase(s)-mediated truncation of N-terminal tau domain, which possibly interacts with dynactin/dynein motor complex, 62 also occurs in vitro and in vivo on NGF signaling interruption. 48 GSK3b-mediated tau phosphorylation is associated with a proper anterograde organelle transport 63 in NGF-dependent differentiated PC12, and synthetic Ab peptides cause a GSK3b-mediated impairment of mitochondrial transport in hippocampal cultured neurons.…”

Section: Ngf-deprived Hippocampal Neurons: the Amyloid Cascade And Tamentioning

confidence: 99%

Does the term ‘trophic’ actually mean anti-amyloidogenic? The case of NGF

et al. 2010

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Alzheimer-like neurodegeneration in aged anti-nerve growth factor transgenic mice

Cited by 16 publications

References 20 publications

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

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

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

Does the term ‘trophic’ actually mean anti-amyloidogenic? The case of NGF

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