TGF-β1 is increased in a transgenic mouse model of familial Alzheimer's disease and causes neuronal apoptosis (original) (raw)
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Role of TGFβ signaling in the pathogenesis of Alzheimer’s disease
Frontiers in Cellular Neuroscience, 2015
Aging is the main risk factor for Alzheimer's disease (AD); being associated with conspicuous changes on microglia activation. Aged microglia exhibit an increased expression of cytokines, exacerbated reactivity to various stimuli, oxidative stress, and reduced phagocytosis of β-amyloid (Aβ). Whereas normal inflammation is protective, it becomes dysregulated in the presence of a persistent stimulus, or in the context of an inflammatory environment, as observed in aging. Thus, neuroinflammation can be a self-perpetuating deleterious response, becoming a source of additional injury to host cells in neurodegenerative diseases. In aged individuals, although transforming growth factor β (TGFβ) is upregulated, its canonical Smad3 signaling is greatly reduced and neuroinflammation persists. This age-related Smad3 impairment reduces protective activation while facilitating cytotoxic activation of microglia through several cellular mechanisms, potentiating microglia-mediated neurodegeneration. Here, we critically discuss the role of TGFβ-Smad signaling on the cytotoxic activation of microglia and its relevance in the pathogenesis of AD. Other protective functions, such as phagocytosis, although observed in aged animals, are not further induced by inflammatory stimuli and TGFβ1. Analysis in silico revealed that increased expression of receptor scavenger receptor (SR)-A, involved in Aβ uptake and cell activation, by microglia exposed to TGFβ, through a Smad3-dependent mechanism could be mediated by transcriptional co-factors Smad2/3 over the MSR1 gene. We discuss that changes of TGFβ-mediated regulation could at least partially mediate age-associated microglia changes, and, together with other changes on inflammatory response, could result in the reduction of protective activation and the potentiation of cytotoxicity of microglia, resulting in the promotion of neurodegenerative diseases.
Dysfunction of TGF-β1 signaling in Alzheimer’s disease: perspectives for neuroprotection
Cell and Tissue Research, 2012
Alzheimer's disease (AD) is a neurodegenerative disorder that affects about 35 million people worldwide. Current drugs for AD only treat the symptoms and do not interfere with the underlying pathogenic mechanisms of the disease. AD is characterized by the presence of β-amyloid (Aβ) plaques, neurofibrillary tangles, and neuronal loss. Identification of the molecular determinants underlying Aβ-induced neurodegeneration is an essential step for the development of disease-modifying drugs. Recently, an impairment of the transforming growth factor-β1 (TGF-β1) signaling pathway has been demonstrated to be specific to the AD brain and, particularly, to the early phase of the disease. TGF-β1 is a neurotrophic factor responsible for the initiation and maintenance of neuronal differentiation and synaptic plasticity. The deficiency of TGF-β1 signaling is associated with Aβ pathology and neurofibrillary tangle formation in AD animal models. Reduced TGF-β1 signaling seems to contribute both to microglial activation and to ectopic cell-cycle re-activation in neurons, two events that contribute to neurodegeneration in the AD brain. The neuroprotective features of TGF-β1 indicate the advantage of rescuing TGF-β1 signaling as a means to slow down the neurodegenerative process in AD.
Amyloidogenic role of cytokine TGF-beta1 in transgenic mice and in Alzheimer's disease
Nature, 1997
Deposition of amyoid-beta peptide in the central nervous system is a hallmark of Alzheimer's disease and a possible cause of neurodegeneration. The factors that initiate or promote deposition of amyloid-beta peptide are not known. The transforming growth factor TGF-beta1 plays a central role in the response of the brain to injury, and increased TGF-beta1 has been found in the central nervous system of patients with Alzheimer's disease. Here we report that TGF-beta1 induces amyloid-beta deposition in cerebral blood vessels and meninges of aged transgenic mice overexpressing this cytokine from astrocytes. Co-expression of TGF-beta1 in transgenic mice overexpressing amyloid-precursor protein, which develop Alzheimer's like pathology, accelerated the deposition of amyloid-beta peptide. More TGF-beta1 messenger RNA was present in post-mortem brain tissue of Alzheimer's patients than in controls, the levels correlating strongly with amyloid-beta deposition in the damaged c...
2019
chain-enhancer of activated B cells; IL-6, interleuken-6; TGF β1, transforming growth factor β; PBS, phosphate buffered saline; PDTC, pyrrolidinedithiocarbamic acid ammonium salt; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; WT, wild-type; Real-time polymerase chain reaction (RT-PCR) mRNA, messenger RNA; ELISA, enzyme-linked immunosorbent assay; WB, western blot; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; VEGF, vascular endothelial growth factor; BDNF, brain-derived neurotrophic factor; GFAP, glial fibrillary acidic protein .
TGF-β1 Pathway as a New Target for Neuroprotection in Alzheimer's Disease
CNS Neuroscience & Therapeutics, 2009
Alzheimer's disease (AD) is a neurodegenerative disorder that affects more than 37 million people worldwide. Current drugs for AD are only symptomatic, but do not interfere with the underlying pathogenic mechanisms of the disease. AD is characterized by the presence of ß-amyloid (Aβ) plaques, neurofibrillary tangles, and neuronal loss. The identification of the molecular determinants underlying AD pathogenesis is a fundamental step to design new disease-modifying drugs. Recently, a specific impairment of transforminggrowth-factor-β1 (TGF-β1) signaling pathway has been demonstrated in AD brain. The deficiency of TGF-β1 signaling has been shown to increase both Aβ accumulation and Aβ-induced neurodegeneration in AD models. The loss of function of TGF-ß1 pathway seems also to contribute to tau pathology and neurofibrillary tangle formation. Growing evidence suggests a neuroprotective role for TGF-β1 against Aβ toxicity both in vitro and in vivo models of AD. Different drugs, such as lithium or group II mGlu receptor agonists are able to increase TGF-β1 levels in the central nervous system (CNS), and might be considered as new neuroprotective tools against Aβ-induced neurodegeneration. In the present review, we examine the evidence for a neuroprotective role of TGF-β1 in AD, and discuss the TGF-β1 signaling pathway as a new pharmacological target for the treatment of AD.
Interaction between Smad7 and -Catenin: Importance for Transforming Growth Factor -Induced Apoptosis
Molecular and Cellular Biology, 2005
Members of the transforming growth factor  (TGF-) and Wnt/wingless superfamilies regulate cell fate during development and tissue maintenance. Here we report that Smad7 interacts with -catenin and lymphoid enhancer binding factor 1/T-cell-specific factor (LEF1/TCF), transcriptional regulators in Wnt signaling, in a TGF--dependent manner. Smad7 was found to be required for TGF-1-induced accumulation of -catenin and LEF1 in human prostate cancer (PC-3U) cells as well as in human keratinocytes (HaCaT cells). Moreover, when the endogenous Smad7 was repressed by specific small interfering RNA, TGF--induced increase of activated p38, Akt phosphorylated on Ser473, glycogen synthase kinase 3 phosphorylated on Ser9 was prevented, as well as the TGF--induced association between -catenin and LEF1. Notably, the observed physical association of Smad7 and -catenin was found to be important for TGF--induced apoptosis, since suppression of -catenin expression by small interfering RNA decreased the apoptotic response to TGF-.
Journal of Molecular Neuroscience, 2018
Alzheimer's disease (AD) is the most common neurodegenerative disturbances. Dysfunction of synaptic plasticity and decline in cognitive functions are the most prominent features of AD, but the mechanisms of pathogenesis have not been well elucidated. In this paper, transforming growth factor-β1 (TGF-β1) was found to be reduced in the hippocampus of AD mouse which was accompanied by impaired pine density, synaptic plasticity, and memory function. Hippocampal injection of TGF-β1 rescued the AD-induced memory function impairment. In addition, TGF-β1 ameliorated synaptic plasticity and increased synaptic plasticityassociated protein expression including Arc, NR2B, and PSD-95 in mouse model of AD. Furthermore, we demonstrated that Akt/Wnt/β-catenin pathway protein expression in the hippocampus was suppressed in a mouse model of AD and TGF-β1 significantly enhanced the phosphorylation Akt, GSK3β, and increased the nuclear β-catenin. These results indicate that TGF-β1activates PI3K/Akt/Wnt/β-catenin signaling in mouse model of AD, which is important for promoting synaptic plasticity related to memory function. More importantly, suppression of PI3K/Akt/Wnt/β-catenin pathway compromised the beneficial effects of TGFβ1 in Alzheimer's model. Hence, TGF-β1 shows protective effect on neurons, which might be through the PI3K/Akt/Wnt/β-catenin signaling pathway, serving as a potential target in AD pathology.
Transforming growth factor-β1 potentiates amyloid-β generation in astrocytes and in transgenic mice
2003
Accumulation of the amyloid- peptide (A) in the brain is crucial for development of Alzheimer's disease. Expression of transforming growth factor-1 (TGF-1), an immunosuppressive cytokine, has been correlated in vivo with A accumulation in transgenic mice and recently with A clearance by activated microglia. Here, we demonstrate that TGF-1 drives the production of A40/42 by astrocytes leading to A production in TGF-1 transgenic mice. First, TGF-1 induces the overexpression of the amyloid precursor protein (APP) in astrocytes but not in neurons, involving a highly conserved TGF-1-responsive element in the 5-untranslated region (؉54/؉74) of the APP promoter. Second, we demonstrated an increased release of soluble APP- which led to TGF-1-induced A generation in both murine and human astrocytes. These results demonstrate that TGF-1 potentiates A production in human astrocytes and may enhance the formation of plaques burden in the brain of Alzheimer's disease patients. The proteolytic cleavage of the amyloid precursor protein (APP) 1 leads to the production of A with a large amount of the 40-amino acid variant, A40, and to a lesser extent of the 42-amino acid variant, A42. In Alzheimer's disease, this amyloidogenesis can lead to the formation of amyloid deposits within the cerebral parenchyma and vascular walls (1, 2). Many studies have identified increased levels of a variety of cytokines in patients developing chronic neurodegenerative disorders such as AD (3-8). Among these factors, recent reports have associated transforming growth factor-1 (TGF-1), a potent immunosuppressive cytokine, with AD. First, recent data suggest that a genetic polymorphism of the TGF-1 gene may be associated with a higher risk to develop AD (9). Second, post-mortem brain tissue analyses of AD patients show an increased expression of TGF-1 correlated with the degree of cerebral amyloid angiopathy (8). Third, 16-month-old transgenic mice overexpressing TGF-1 in astrocytes elicit A deposition (8). In the same study, these authors generated biogenic mice expressing both human APP and TGF-1. In these hAPP/ TGF-1 mice, A deposits were observed after 3 months of age compared with TGF-1 mice, suggesting that TGF-1 would be able to influence APP metabolism or processing. In addition to its amyloidogenic effects (8), TGF-1 was recently associated with A clearance from the brain parenchyma to the cerebral blood vasculature in aged hAPP/TGF-1 mice by activated microglia (10). Despite this dual effect of TGF-1 in the amyloid plaque metabolism, the mechanism(s) by which TGF-1 promotes the production of A remained to be elucidated. EXPERIMENTAL PROCEDURES Semiquantitative Reverse Transcription-PCR (RT-PCR)-Total RNAs were prepared using either the RNAxel extraction kit (Eurobio, Paris, France) or RNAeasy extraction columns (Qiagen, Courtaboeuf, France). Samples (1 g) of total mRNA were transcribed into cDNA. cDNA libraries (1 l from 20 l) were amplified by PCR with oligonucleotides for -actin, APP 770 , APP 751 , and APP 695 (respectively 539, 242, 222, and 401 bp of PCR products). All PCR were established in the linear range of amplification by performing multicycle amplification to reach half of the saturation curve. The -actin oligonucleotides were: