Astrocyte Protection of Neurons

Dhandapani, Krishnan M.; Hadman, Martin; Sevilla, Liesl De; Wade, Marlene; Mahesh, Virendra B.; Brann, Darrell W.

doi:10.1074/jbc.m305835200

Cited by 122 publications

(28 citation statements)

References 67 publications

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“…TGF- β 1 is a member of the TGF- β superfamily and it has been implicated in such diverse processes as regulation of growth, differentiation, extracellular matrix formation, and immune regulation as well as induction of neuronal survival and repair following injury [48, 49]. TGF- β 1 is recognized as determinant in the protective astrocytic functions for neuron homeostasis by the c-Jun/AP-1 transcription factor pathway [50]. The role of TGF- β 1 in the orchestration of repair processes has been evidenced in many neurodegenerative diseases and following vascular accident in the brain [51–53]; furthermore, TGF- β 1 attenuates spinal neuroinflammation and excitatory amino acid system in rats with neuropathic pain [54], leading to pain relief after intrathecal administration [55].…”

Section: Discussionmentioning

confidence: 99%

α7 Nicotinic Receptor Promotes the Neuroprotective Functions of Astrocytes against Oxaliplatin Neurotoxicity

et al. 2015

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Neuropathies are characterized by a complex response of the central nervous system to injuries. Glial cells are recruited to maintain neuronal homeostasis but dysregulated activation leads to pain signaling amplification and reduces the glial neuroprotective power. Recently, we highlighted the property of α7 nicotinic-acetylcholine-receptor (nAChR) agonists to relieve pain and induce neuroprotection simultaneously with a strong increase in astrocyte density. Aimed to study the role of α7 nAChR in the neuron-glia cross-talk, we treated primary rat neurons and astrocytes with the neurotoxic anticancer drug oxaliplatin evaluating the effect of the α7 nAChR agonist PNU-282987 (PNU). Oxaliplatin (1 μM, 48 h) reduced cell viability and increased caspase-3 activity of neuron monocultures without damaging astrocytes. In cocultures, astrocytes were not able to protect neurons by oxaliplatin even if glial cell metabolism was stimulated (pyruvate increase). On the contrary, the coculture incubation with 10 μM PNU improved neuron viability and inhibited apoptosis. In the absence of astrocytes, the protection disappeared. Furthermore, PNU promoted the release of the anti-inflammatory cytokine TGF-β1 and the expression of the glutamate-detoxifying enzyme glutamine synthetase. The α7 nAChR stimulation protects neurons from oxaliplatin toxicity through an astrocyte-mediated mechanism. α7 nAChR is suggested for recovering the homeostatic role of astrocytes.

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Section: Discussionmentioning

confidence: 99%

α7 Nicotinic Receptor Promotes the Neuroprotective Functions of Astrocytes against Oxaliplatin Neurotoxicity

et al. 2015

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“…To verify these results in a cell culture system that is not subject to lentiviral infection, we performed siRNA knockdown of LRP1 expression in GT1-7 cells, a mouse central nervous system neuronal cell line previously used for studying cell death mechanisms in vitro, including trophic withdrawal-and A␤42-induced cell death (34,35). We transfected GT1-7 cells with control, nontargeting siRNA or LRP1 siRNA and analyzed the effect of serum deprivation on apoptosis activation and Akt phosphorylation (supplemental Fig.…”

Section: Lrp1 Activates Akt In Primary Neurons and In Mousementioning

confidence: 99%

Low Density Lipoprotein Receptor-related Protein 1 Promotes Anti-apoptotic Signaling in Neurons by Activating Akt Survival Pathway

Fuentealba

Liu

Kanekiyo

et al. 2009

Journal of Biological Chemistry

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The low density lipoprotein receptor-related protein 1 (LRP1) is a multi-ligand receptor abundantly expressed in neurons. Previous work has shown that brain LRP1 levels are decreased during aging and in Alzheimer disease. Although mounting evidence has demonstrated a role for LRP1 in the metabolism of apolipoprotein E/lipoprotein and amyloid-␤ peptide, whether LRP1 also plays a direct role in neuronal survival is not clear. Here, we show that LRP1 expression is critical for the survival of primary neurons under stress conditions including trophic withdrawal, the presence of apoptosis inducers, or amyloid-␤-induced neurotoxicity. Using lentiviral short hairpin RNA to knock down endogenous LRP1 expression, we showed that a depletion of LRP1 leads to an activation of caspase-3 and increased neuronal apoptosis, an effect that was rescued by a caspase-3 inhibitor. A correlation between decreased Akt phosphorylation and the activation of caspase-3 was demonstrated in LRP1 knocked down neurons. Notably, LRP1 knockdown decreased insulin receptor levels in primary neurons, suggesting that decreased neuronal survival might be a consequence of an impaired insulin receptor signaling pathway. Correspondingly, both insulin receptor and phospho-Akt levels were decreased in LRP1 forebrain knock-out mice. These results demonstrate that LRP1 mediates anti-apoptotic function in neurons by regulating insulin receptor and the Akt survival pathway and suggest that restoring LRP1 expression in Alzheimer disease brain might be beneficial to inhibiting neurodegeneration.Originally described as a clearance receptor for lipoproteins in the liver, the low density lipoprotein receptor-related protein 1 (LRP1) 2 plays essential roles in development and mediates important tissue-specific functions throughout adulthood. These include regulation of glutamatergic synaptic transmission in the nervous system, prevention of vascular smooth muscle cell proliferation and atherosclerosis development, catabolism of activated coagulation factor VIII in hepatocytes, and regulation of body energy by adipocytes (1, 2). Mounting evidence suggests an important role for LRP1 in the pathogenesis of Alzheimer disease (AD). LRP1 regulates the production and clearance of amyloid-␤ (A␤) peptide and the metabolism of several AD-associated ligands, including apolipoprotein E (apoE), which has three isoforms in humans with apoE4 being a major risk factor for late onset AD (3). LRP1 is abundantly expressed in the cell body and proximal processes of cortical and hippocampal neurons in the brain (4 -6). It consists of an extracellular 515-kDa subunit (LRP1-515) that binds more than 30 different ligands and a transmembrane 85-kDa chain (LRP1-85) that interacts with several adaptor proteins for efficient endocytic trafficking and signaling (7). LRP1 binds to A␤ either directly or via A␤ chaperones, such as apoE, to mediate A␤ clearance (3,8,9). In AD patients and in the elderly, brain LRP1 levels are significantly decreased and inversely correlate with the age of onset of...

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“…The growth-inhibitory/pro-apoptotic effects of TGF-␤1 have been well demonstrated in various cell types, including immune cells (22) and epithelial cells (23), consistent with its anti-inflammatory and tumor-suppressive functions. However, substantial evidence suggests that TGF-␤1 also possesses the ability to inhibit apoptosis in some cell types, such as murine macrophages (24), human lung carcinoma cells (25), fibroblasts, myofibroblasts (5, 26 -28), murine neurons (29), lung mesenchymal cells (30), and pulmonary artery endothelial cells (31). The effect of TGF-␤1 on apoptosis and autophagy in primary mesangial cells has not been previously examined.…”

mentioning

confidence: 99%

TGF-β1 Protects against Mesangial Cell Apoptosis via Induction of Autophagy

Ding

Kim

Kim³

et al. 2010

Journal of Biological Chemistry

123

119

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Autophagy can lead to cell death in response to stress, but it can also act as a protective mechanism for cell survival. We show that TGF-␤1 induces autophagy and protects glomerular mesangial cells from undergoing apoptosis during serum deprivation. Serum withdrawal rapidly induced autophagy within 1 h in mouse mesangial cells (MMC) as determined by increased microtubule-associated protein 1 light chain 3 (LC3) levels and punctate distribution of the autophagic vesicle-associated-form LC3-II. We demonstrate that after 1 h there was a time-dependent decrease in LC3 levels that was accompanied by induction of apoptosis, evidenced by increases in cleaved caspase 3. However, treatment with TGF-␤1 resulted in induction of the autophagy protein LC3 while suppressing caspase 3 activation. TGF-␤1 failed to rescue MMC from serum deprivation-induced apoptosis upon knockdown of LC3 by siRNA and in MMC from LC3 null (LC3 ؊/؊ ) mice. We show that TGF-␤1 induced autophagy through TAK1 and Akt activation, and inhibition of PI3K-Akt pathway by LY294002 or dominant-negative Akt suppressed LC3 levels and enhanced caspase 3 activation. TGF-␤1 also up-regulated cyclin D1 and E protein levels while down-regulating p27, thus stimulating cell cycle progression. Bafilomycin A1, but not MG132, blocked TGF-␤1 down-regulation of p27, suggesting that p27 levels were regulated through autophagy. Taken together, our data indicate that TGF-␤1 rescues MMC from serum deprivationinduced apoptosis via induction of autophagy through activation of the Akt pathway. The autophagic process may constitute an adaptive mechanism to glomerular injury by inhibiting apoptosis and promoting mesangial cell survival.

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Astrocyte Protection of Neurons

Cited by 122 publications

References 67 publications

α7 Nicotinic Receptor Promotes the Neuroprotective Functions of Astrocytes against Oxaliplatin Neurotoxicity

α7 Nicotinic Receptor Promotes the Neuroprotective Functions of Astrocytes against Oxaliplatin Neurotoxicity

Low Density Lipoprotein Receptor-related Protein 1 Promotes Anti-apoptotic Signaling in Neurons by Activating Akt Survival Pathway

TGF-β1 Protects against Mesangial Cell Apoptosis via Induction of Autophagy

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