Neuroprotective effects of LMW and HMW FGF2 against amyloid beta toxicity in primary cultured hippocampal neurons

Cheng, Yong; Li, Zhaojin; Kardami, Elissavet; Loh, Y. Peng

doi:10.1016/j.neulet.2016.08.031

Cited by 16 publications

(17 citation statements)

References 36 publications

(40 reference statements)

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“…Our data further indicate that both FGF-2 isoforms also similarly increase AKT and ERK phosphorylation in the brain. The AKT and ERK signaling pathways were shown to be involved in the ability of HMW FGF-2 to ameliorate depressive symptoms in the CUMS model, which was consistent with a previous study showing that AKT and ERK were similarly activated in neurons by HMW and LMW FGF-2 ( Cheng et al, 2016 ). The present report is the first to show that ERK and AKT pathway activation, Bcl-2 upregulation and caspase-3 inhibition are all required for HMW FGF-2 to improve depressive symptoms in mouse models of non-hereditary depression.…”

Section: Discussionsupporting

confidence: 90%

Antidepressant-Like Effects of Low- and High-Molecular Weight FGF-2 on Chronic Unpredictable Mild Stress Mice

Wang¹,

Li²,

Chen³

et al. 2018

Front. Mol. Neurosci.

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The occurrence of depressive disorder has long been attributed to changes in monoamines, with the focus of drug treatment strategies being to change the effectiveness of monoamines. However, the success achieved by changing these processes is limited and further stimulates the exploration of alternative mechanisms and treatments. Fibroblast growth factor 2 (FGF-2), which occurs in a high-molecular weight (HMW) and low-molecular weight (LMW) form, is a potent developmental modulator and nervous system regulator that has been suggested to play an important role in various psychiatric disorders. In this study, we investigated the antidepressant effects of HMW and LMW FGF-2 on depression induced by chronic stress. Both peripheral LMW and HMW FGF-2 attenuated the depression-like behaviors in chronic unpredictable mild stress (CUMS) mice to a similar extent, as determined by the forced swimming, tail suspension, and sucrose preference tests. We then showed that CUMS-induced oxidative stresses in mice were inhibited by FGF-2 treatments both in central and peripheral. We also showed that both forms of FGF-2 increased the phosphorylation of ERK and AKT, increased Bcl-2 expression and inhibited caspase-3 activation in CUMS mice. Interestingly, HMW FGF-2 enhanced the activity of the brain-derived neurotrophic factor (BDNF) to a greater extent than did LMW FGF-2 in the hippocampus. Taken together, these results suggest that depressive symptoms can be relieved by administering different forms of FGF-2 peripherally in a CUMS-induced depression model through a similar antidepressant signaling pathway, therefore suggesting a potential clinical use for FGF-2 as a treatment for depression.

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Section: Discussionsupporting

confidence: 90%

Antidepressant-Like Effects of Low- and High-Molecular Weight FGF-2 on Chronic Unpredictable Mild Stress Mice

Wang¹,

Li²,

Chen³

et al. 2018

Front. Mol. Neurosci.

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“…These pathways mediate FGF2's function. For example, FGF2-induced glutamate release (Numakawa et al, 2002) and axonal branching (Abe et al, 2001) are mediated by MAPK/ERK signaling, and FGF2 neuroprotective effects against amyloid ␤ toxicity in cultured hippocampal neurons are mediated through PI3K/AKT signaling (Cheng et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of FGF Receptor-1 Suppresses Alcohol Consumption: Role of PI3 Kinase Signaling in Dorsomedial Striatum

Even-Chen

Barak

2019

J. Neurosci.

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Excessive alcohol intake leads to mesostriatal neuroadaptations, and to addiction phenotypes. We recently found in rodents that alcohol increases fibroblast growth factor 2 (FGF2) expression in the dorsomedial striatum (DMS), which promotes alcohol consumption. Here, we show that systemic or intra-DMS blockade of the FGF2 receptor, FGF receptor-1 (FGFR1), suppresses alcohol consumption, and that the effects of FGF2-FGFR1 on alcohol drinking are mediated via the phosphoinositide 3 kinase (PI3K) signaling pathway. Specifically, we found that sub-chronic alcohol treatment (7 d ϫ 2.5 g/kg, i.p.) increased Fgfr1 mRNA expression in the dorsal hippocampus and dorsal striatum. However, prolonged and excessive voluntary alcohol consumption in a two-bottle choice procedure increased Fgfr1 expression selectively in DMS. Importantly, systemic administration of the FGFR1 inhibitor PD173074 to mice, as well as its infusion into the DMS of rats, decreased alcohol consumption and preference, with no effects on natural reward consumption. Finally, inhibition of the PI3K, but not of the mitogen-activated protein kinase (MAPK) signaling pathway, blocked the effects of FGF2 on alcohol intake and preference. Our results suggest that activation of FGFR1 by FGF2 in the DMS leads to activation of the PI3K signaling pathway, which promotes excessive alcohol consumption, and that inhibition of FGFR1 may provide a novel therapeutic target for alcohol use disorder.

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“…These results indicate that these functions of LMW or HMW FGF-2 were mediated by activating FGFR1. FGF-2 is known to activate ERK and AKT signaling pathways (Cheng et al, 2016). Here, we showed that treatment of astrocytes with LMW and HMW FGF-2 for 30 min both resulted in increased phosphorylation of ERK, AKT (Ser473) and GSK-3β compared with the control group ( Figure 4A).…”

Section: Lmw Fgf-2 Promotes Astrocyte Proliferationmentioning

confidence: 69%

Low and High Molecular Weight FGF-2 Have Differential Effects on Astrocyte Proliferation, but Are Both Protective Against Aβ-Induced Cytotoxicity

Chen

Cheng

et al. 2020

Front. Mol. Neurosci.

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Astrocytes are the most abundant type of glial cells in the brain, and they play a key role in Alzheimer's disease (AD). Fibroblast Growth Factor-2 (FGF-2) has been implicated as a potential therapeutic agent for treating AD. In the present study, we investigated the protective effects of low molecular weight (LMW; 17 KDa) and high molecular weight (HMW; 23 KDa) forms of FGF-2 on Aβ 1-42-induced toxicity, and proliferation in astrocytes. We show that both isoforms of FGF-2 have similar protective effects against Aβ 1-42-induced cytotoxicity in primary cultured cortical astrocytes as measured by Lactate Dehydrogenase (LDH) release assay. Additionally, 17 KDa FGF-2 significantly promoted astrocyte proliferation as measured by Trypan Blue, DRAQ5 and 5-ethynyl-2'-deoxyuridine (EdU) staining, but not 23 kDa FGF-2. Furthermore, our results demonstrated that AKT signaling pathway was required for the protective and proliferative effects of FGF-2. Downstream effector studies indicated that 17 kDa FGF-2 promoted astrocyte proliferation by enhanced expression of c-Myc, Cyclin D1, Cyclin E. Furthermore, our data suggested that Cyclin D1 was required for the proliferative effect of LMW FGF2 in astrocytes. Taken together, our findings provide important information for the similarities and differences between 23 kDa and17 kDa isoforms of FGF-2 on astrocyte survival and proliferation.

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Neuroprotective effects of LMW and HMW FGF2 against amyloid beta toxicity in primary cultured hippocampal neurons

Cited by 16 publications

References 36 publications

Antidepressant-Like Effects of Low- and High-Molecular Weight FGF-2 on Chronic Unpredictable Mild Stress Mice

Antidepressant-Like Effects of Low- and High-Molecular Weight FGF-2 on Chronic Unpredictable Mild Stress Mice

Inhibition of FGF Receptor-1 Suppresses Alcohol Consumption: Role of PI3 Kinase Signaling in Dorsomedial Striatum

Low and High Molecular Weight FGF-2 Have Differential Effects on Astrocyte Proliferation, but Are Both Protective Against Aβ-Induced Cytotoxicity

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