Failed retrograde transport of NGF in a mouse model of Down's syndrome: Reversal of cholinergic neurodegenerative phenotypes following NGF infusion

Cooper, Jonathan D.; Salehi, Ahmad; Delcroix, Jean-Dominique; Howe, Charles L.; Belichenko, Pavel V.; Chua-Couzens, Jane; Kilbridge, Joshua; Carlson, Elaine J.; Epstein, Charles J.; Mobley, William C.

doi:10.1073/pnas.181219298

Cited by 310 publications

(325 citation statements)

References 33 publications

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“…Retrograde, microtubule-dependent, NGF signaling appears to be diminished in aged compared with young rats (Niewiadomska et al, 2005(Niewiadomska et al, , 2006a, and the same event also occurred in Ts65Dn mouse, a model of Down Syndrome and AD (Cooper et al, 2001). Since NGF mRNA is unchanged (Goedert et al, 1986;Jetté et al, 1994;Fahnestock et al, 1996), the impairment of NGF axonal transport in AD brain may result in its accumulation at productions sites (hippocampus and neocortical cortex) (Cooper et al, 1994) and in a deficiency at the transport end sites (basal forebrain cholinergic neurons, BFCNs).…”

Section: Ngf and Its Receptors In Admentioning

confidence: 89%

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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Section: Ngf and Its Receptors In Admentioning

confidence: 89%

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

Calissano

Matrone

Amadoro

2010

Developmental Neurobiology

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“…3b). All Ts65Dn animals and their control littermates were killed between 3 and 5 months of age, thereby ruling out any contribution to this phenomenon of neurodegeneration, which typically begins after 6 months of age (22)(23)(24). Lower levels of PtdIns(4,5)P 2 were also observed in the brain of transgenic mice overexpressing Synj1 (9 Ϯ 1%, P Ͻ 0.01, n ϭ 3) (Fig.…”

Section: Synaptojanin 1 Overexpression In the Brain Of Ds Mouse Modelsmentioning

confidence: 96%

Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down's syndrome

Voronov

Frère²,

Giovedì³

et al. 2008

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

152

138

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Phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2] is a signaling phospholipid implicated in a wide variety of cellular functions. At synapses, where normal PtdIns(4,5)P 2 balance is required for proper neurotransmission, the phosphoinositide phosphatase synaptojanin 1 is a key regulator of its metabolism. The underlying gene, SYNJ1, maps to human chromosome 21 and is thus a candidate for involvement in Down's syndrome (DS), a complex disorder resulting from the overexpression of trisomic genes. Here, we show that PtdIns(4,5)P2 metabolism is altered in the brain of Ts65Dn mice, the most commonly used model of DS. This defect is rescued by restoring Synj1 to disomy in Ts65Dn mice and is recapitulated in transgenic mice overexpressing Synj1 from BAC constructs. These transgenic mice also exhibit deficits in performance of the Morris water maze task, suggesting that PtdIns(4,5)P 2 dyshomeostasis caused by gene dosage imbalance for Synj1 may contribute to brain dysfunction and cognitive disabilities in DS.Alzheimer's disease ͉ inositol 5-phosphatase ͉ phosphatidylinositol-4,5-bisphosphate ͉ phosphatidylinositol phosphate kinase ͉ synapse

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“…163,164 There is evidence that degeneration of BFCNs in Ts65Dn mice is related to a marked decrease in the NGF retrograde transport from the hippocampus to the basal forebrain. 165,166 Intracerebroventricular NGF infusion reverses BFCN morphological abnormalities, restoring the deficit in cholinergic innervation. 165 BDNF signalling in Ts65Dn mice is also disrupted.…”

Section: Impact Of Ee On the Brain L Baroncelli Et Almentioning

confidence: 99%

“…165,166 Intracerebroventricular NGF infusion reverses BFCN morphological abnormalities, restoring the deficit in cholinergic innervation. 165 BDNF signalling in Ts65Dn mice is also disrupted. In the frontal cortex, lower levels of BDNF with respect to diploid animals are found and negatively correlated with the progressive deterioration of working memory performance.…”

Section: Impact Of Ee On the Brain L Baroncelli Et Almentioning

confidence: 99%

Nurturing brain plasticity: impact of environmental enrichment

et al. 2009

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Environmental enrichment (EE) is known to profoundly affect the central nervous system (CNS) at the functional, anatomical and molecular level, both during the critical period and during adulthood. Recent studies focusing on the visual system have shown that these effects are associated with the recruitment of previously unsuspected neural plasticity processes. At early stages of brain development, EE triggers a marked acceleration in the maturation of the visual system, with maternal behaviour acting as a fundamental mediator of the enriched experience in both the foetus and the newborn. In adult brain, EE enhances plasticity in the cerebral cortex, allowing the recovery of visual functions in amblyopic animals. The molecular substrate of the effects of EE on brain plasticity is multi-factorial, with reduced intracerebral inhibition, enhanced neurotrophin expression and epigenetic changes at the level of chromatin structure. These findings shed new light on the potential of EE as a non-invasive strategy to ameliorate deficits in the development of the CNS and to treat neurological disorders.

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Failed retrograde transport of NGF in a mouse model of Down's syndrome: Reversal of cholinergic neurodegenerative phenotypes following NGF infusion

Cited by 310 publications

References 33 publications

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

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

Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down's syndrome

Nurturing brain plasticity: impact of environmental enrichment

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