Transforming Growth Factor-β1 Potentiates Amyloid-β Generation in Astrocytes and in Transgenic Mice

Lesné, Sylvain; Docagne, Fabián; Gabriel, C.; Liot, Géraldine; Lahiri, Debomoy K.; Buée, Luc; Laurent, Pascale; Delacourte, André; MacKenzie, Eric T.; Buisson, Alain; Vivien, Denis

doi:10.1074/jbc.m300819200

Cited by 130 publications

(122 citation statements)

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“…15 In parallel, we have previously demonstrated that TGF-b treatment in both murine and human cultured astrocytes leads to an increased transcription of APP and subsequent accumulation of Ab. 5 Although brain TGF-b levels are highly increased following cerebral ischemia, 29 TGF-b was reported to protect hippocampal, cerebellar and cortical 35 neurons receptors and through a recruitment of Smad3. 4 Here, we provide evidence that neurons lose both TGF-b signalling and PAI-1 expression with neuronal differentiation, a phenomenon associated to an overexpression of HtrA1.…”

Section: Discussionmentioning

confidence: 99%

“…5 TGF-b isoforms elicit their cell type-specific responses through the ligand-induced formation of a heteromeric receptor complex between the serine/threonine kinases TbR-I and TbR-II: the type II receptor binds TGF-b by its own, then recruits the type I receptor, allowing the transphosphorylation-mediated activation of TbR-I. The subsequent activation of the Smad (signalling mother against decapentaplegic peptide) transcription factor cascade thus regulates the transcription of key target genes.…”

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confidence: 99%

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HtrA1-dependent proteolysis of TGF-β controls both neuronal maturation and developmental survival

et al. 2008

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Transforming growth factor-b (TGF-b) signalling controls a number of cerebral functions and dysfunctions including synaptogenesis, amyloid-b accumulation, apoptosis and excitotoxicity. Using cultured cortical neurons prepared from either wild type or transgenic mice overexpressing a TGF-b-responsive luciferase reporter gene (SBE-Luc), we demonstrated a progressive loss of TGF-b signalling during neuronal maturation and survival. Moreover, we showed that neurons exhibit increasing amounts of the serine protease HtrA1 (high temperature responsive antigen 1) and corresponding cleavage products during both in vitro neuronal maturation and brain development. In parallel of its ability to promote degradation of TGF-b1, we demonstrated that blockage of the proteolytic activity of HtrA1 leads to a restoration of TGF-b signalling, subsequent overexpression of the serpin type -1 plasminogen activator inhibitor (PAI-1) and neuronal death. Altogether, we propose that the balance between HtrA1 and TGF-b could be one of the critical events controlling both neuronal maturation and developmental survival.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

HtrA1-dependent proteolysis of TGF-β controls both neuronal maturation and developmental survival

et al. 2008

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“…This is suggested by the presence of a TGF-␤1-responsive element in the APP promoter and TGF-␤1-stimulated release of endogenous A␤ 1-40/42 peptides by cultured human astrocytes. 47 Alternatively, TGF-␤1 production may be triggered by A␤, 48 or both peptides may be up-regulated concomitantly in neurons, glia, and vascular cells by acute ischemic events or chronic cerebrovascular insufficiency. 49,50 In A/T mice, A␤ and TGF-␤1 are overproduced from birth and throughout the lifespan, and it seems that their interaction is responsible for the progressive hemodynamic deficit of A/T animals.…”

Section: Ad-like Cerebrovascular Pathology In A/t Mice and Therapeutimentioning

confidence: 99%

Transgenic Mice Overexpressing APP and Transforming Growth Factor-β1 Feature Cognitive and Vascular Hallmarks of Alzheimer's Disease

Ongali

Nicolakakis

Lecrux

et al. 2010

The American Journal of Pathology

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High brain levels of amyloid-␤ (A␤) and transforming growth factor-␤1 (TGF-␤1) have been implicated in the cognitive and cerebrovascular alterations of Alzheimer's disease (AD). We sought to investigate the impact of combined increases in A␤ and TGF-␤1 on cerebrovascular, neuronal, and mnemonic function using transgenic mice overproducing these peptides (A/T mice). In particular, we measured cerebrovascular reactivity, evoked cerebral blood flow and glucose uptake during brain activation, cholinergic status, and spatial memory, along with cerebrovascular fibrosis, amyloidosis, and astrogliosis, and their evolution with age. An assessment of perfusion and metabolic responses was considered timely, given ongoing efforts for their validation as AD biomarkers. Relative to wild-type littermates, A/T mice displayed an early progressive decline in cerebrovascular dilatory ability, preserved contractility, and reduction in constitutive nitric oxide synthesis that establishes resting vessel tone. Altered levels of vasodilator-synthesizing enzymes and fibrotic proteins, resistance to antioxidant treatment, and unchanged levels of the antioxidant enzyme, superoxide dismutase-2, accompanied these impairments. A/T mice featured deficient neurovascular and neurometabolic coupling to whisker stimulation, cholinergic denervation, cerebral and cerebrovascular A␤ deposition, astrocyte activation , and impaired Morris water maze performance , which gained severity with age. The combined A␤-and TGF-␤1-driven pathology recapitulates salient cerebrovascular, neuronal, and cognitive AD landmarks and yields a versatile model toward highly anticipated diagnostic and therapeutic tools for patients featuring A␤ and TGF-␤1 increments.

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“…With the development of P301L mouse models that develop neurofibrillary pathology, intense interest be- Increases vascular deposition, decreases plaque deposition [190][191][192] came focused on how A␤ would affect NFT formation. Injection of synthetic A␤ 42 into somatosensory cortex and contralateral hippocampus of P301L mice caused a fivefold increase in NFT numbers in the amygdala, which receives projections from both cortex and hippocampus.…”

Section: Tau-interacting Proteinsmentioning

confidence: 99%

Transgenic models of Alzheimer’s disease: Learning from animals

2005

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Summary:As the scope of the problem of Alzheimer's disease (AD) grows due to an aging population, research into the devastating condition has taken on added urgency. Rare inherited forms of AD provide insight into the molecular pathways leading to degeneration and have made possible the development of transgenic animal models. Several of these models are based on the overexpression of amyloid precursor protein (APP), presenilins, or tau to cause production and accumulation of amyloid-␤ into plaques or hyperphosphorylated tau into neurofibrillary tangles. Producing these characteristic neuropathological lesions in animals causes progressive neurodegeneration and in some cases similar behavioral disruptions to those seen in AD patients. Knockout models of proteins involved in AD have also been generated to explore the native functions of these genes and examine whether pathogenesis is due to loss of function or toxic gain of function in these systems. Although none of the transgenic lines models the human condition exactly, the ability to study similar pathological processes in living animals have provided numerous insights into disease mechanisms and opportunities to test therapeutic agents. This chapter reviews animal models of AD and their contributions to developing therapeutic approaches for AD.

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Transforming Growth Factor-β1 Potentiates Amyloid-β Generation in Astrocytes and in Transgenic Mice

Cited by 130 publications

References 45 publications

HtrA1-dependent proteolysis of TGF-β controls both neuronal maturation and developmental survival

HtrA1-dependent proteolysis of TGF-β controls both neuronal maturation and developmental survival

Transgenic Mice Overexpressing APP and Transforming Growth Factor-β1 Feature Cognitive and Vascular Hallmarks of Alzheimer's Disease

Transgenic models of Alzheimer’s disease: Learning from animals

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