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STIM2 protects hippocampal mushroom spines from amyloid synaptotoxicity.

Popugaeva E, Pchitskaya E, Speshilova A, Alexandrov S, Zhang H, Vlasova O, Bezprozvanny I - Mol Neurodegener (2015)

Bottom Line: Generation of amyloidogenic peptides and accumulation of amyloid plaques is one of the pathological hallmarks of AD.We discovered that application of Aβ42 oligomers to hippocampal cultures or injection of Aβ42 oligomers directly into hippocampal region resulted in reduction of mushroom spines and activity of synaptic calcium-calmodulin-dependent kinase II (CaMKII).Obtained results suggest that downregulation of STIM2-dependent stability of mushroom spines and reduction in activity of synaptic CaMKII is a mechanism of hippocampal synaptic loss in AD model of amyloid synaptotoxicity and that modulators/activators of this pathway may have a potential therapeutic value for treatment of AD.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Neurodegeneration, Department of Medical Physics, Peter the Great St.Petersburg Polytechnic University, St. Petersburg, Russian Federation. lena.popugaeva@gmail.com.

ABSTRACT

Background: Alzheimer disease (AD) is a disease of lost memories. Mushroom postsynaptic spines play a key role in memory storage, and loss of mushroom spines has been proposed to be linked to memory loss in AD. Generation of amyloidogenic peptides and accumulation of amyloid plaques is one of the pathological hallmarks of AD. It is important to evaluate effects of amyloid on stability of mushroom spines.

Results: In this study we used in vitro and in vivo models of amyloid synaptotoxicity to investigate effects of amyloid peptides on hippocampal mushroom spines. We discovered that application of Aβ42 oligomers to hippocampal cultures or injection of Aβ42 oligomers directly into hippocampal region resulted in reduction of mushroom spines and activity of synaptic calcium-calmodulin-dependent kinase II (CaMKII). We further discovered that expression of STIM2 protein rescued CaMKII activity and protected mushroom spines from amyloid toxicity in vitro and in vivo.

Conclusions: Obtained results suggest that downregulation of STIM2-dependent stability of mushroom spines and reduction in activity of synaptic CaMKII is a mechanism of hippocampal synaptic loss in AD model of amyloid synaptotoxicity and that modulators/activators of this pathway may have a potential therapeutic value for treatment of AD.

No MeSH data available.


Related in: MedlinePlus

STIM2 overexpression protects mushroom spines from amyloid toxicity in vitro.a Primary hippocampal cultures were co-transfected with TD-Tomato and mSTIM2 plasmids or transfected with TD-Tomato. After transfection cells were treated with Aβ42 oligomers or vehicle (Ctrl). Spine morphology was visualized by confocal imaging. Scale bar corresponds to 5 μm. Mushroom spines are indicated with an arrow. b Percentages of mushroom spines (MS) in hippocampal cultures co-transfected with TD-Tomato and mSTIM2 or transfected with TD-Tomato. Data collected from the three batches of cultures are shown for vehicle treated cultures (Ctrl) and cultures treated with Aβ42 oligomers. For spine quantification n = 6–8 (for each treatment per one experiment) neurons were analyzed. Experiment was repeated three times. Values are shown as mean ± SEM. *: p < 0.05 by t-test
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Fig4: STIM2 overexpression protects mushroom spines from amyloid toxicity in vitro.a Primary hippocampal cultures were co-transfected with TD-Tomato and mSTIM2 plasmids or transfected with TD-Tomato. After transfection cells were treated with Aβ42 oligomers or vehicle (Ctrl). Spine morphology was visualized by confocal imaging. Scale bar corresponds to 5 μm. Mushroom spines are indicated with an arrow. b Percentages of mushroom spines (MS) in hippocampal cultures co-transfected with TD-Tomato and mSTIM2 or transfected with TD-Tomato. Data collected from the three batches of cultures are shown for vehicle treated cultures (Ctrl) and cultures treated with Aβ42 oligomers. For spine quantification n = 6–8 (for each treatment per one experiment) neurons were analyzed. Experiment was repeated three times. Values are shown as mean ± SEM. *: p < 0.05 by t-test

Mentions: In the previous publication [10] we demonstrated that expression of STIM2 protein and upregulation of synaptic nSOC pathway results in rescue of mushroom spines in PS1-M146V-KI neurons. We supposed that the same approach could protect mushroom spines from amyloid toxicity. In the next series of experiments we co-transfected hippocampal neurons at DIV7 with TD-Tomato plasmid and the plasmid encoding mouse STIM2 (mSTIM2). On DIV11 the cells were treated with Aβ42 oligomers or vehicle treated. The neurons were fixed at DIV14 and morphology of the spines was visualized by confocal imaging (Fig. 4a). Consistent with the previous findings (Fig. 2), we discovered that application of Aβ42 oligomers resulted in significant reduction in a fraction of mushroom spines in hippocampal neurons (Fig. 4a, 4b). Expression of STIM2 had no significant effect on the fraction of mushroom spines in control cultures, but resulted in complete rescue of mushroom spine loss in Aβ42-treated cultures (Fig. 4a, 4b). From these results we concluded that expression of STIM2 is able to protect hippocampal mushroom spines from synaptotoxic effects of Aβ42.Fig. 4


STIM2 protects hippocampal mushroom spines from amyloid synaptotoxicity.

Popugaeva E, Pchitskaya E, Speshilova A, Alexandrov S, Zhang H, Vlasova O, Bezprozvanny I - Mol Neurodegener (2015)

STIM2 overexpression protects mushroom spines from amyloid toxicity in vitro.a Primary hippocampal cultures were co-transfected with TD-Tomato and mSTIM2 plasmids or transfected with TD-Tomato. After transfection cells were treated with Aβ42 oligomers or vehicle (Ctrl). Spine morphology was visualized by confocal imaging. Scale bar corresponds to 5 μm. Mushroom spines are indicated with an arrow. b Percentages of mushroom spines (MS) in hippocampal cultures co-transfected with TD-Tomato and mSTIM2 or transfected with TD-Tomato. Data collected from the three batches of cultures are shown for vehicle treated cultures (Ctrl) and cultures treated with Aβ42 oligomers. For spine quantification n = 6–8 (for each treatment per one experiment) neurons were analyzed. Experiment was repeated three times. Values are shown as mean ± SEM. *: p < 0.05 by t-test
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Related In: Results  -  Collection

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Fig4: STIM2 overexpression protects mushroom spines from amyloid toxicity in vitro.a Primary hippocampal cultures were co-transfected with TD-Tomato and mSTIM2 plasmids or transfected with TD-Tomato. After transfection cells were treated with Aβ42 oligomers or vehicle (Ctrl). Spine morphology was visualized by confocal imaging. Scale bar corresponds to 5 μm. Mushroom spines are indicated with an arrow. b Percentages of mushroom spines (MS) in hippocampal cultures co-transfected with TD-Tomato and mSTIM2 or transfected with TD-Tomato. Data collected from the three batches of cultures are shown for vehicle treated cultures (Ctrl) and cultures treated with Aβ42 oligomers. For spine quantification n = 6–8 (for each treatment per one experiment) neurons were analyzed. Experiment was repeated three times. Values are shown as mean ± SEM. *: p < 0.05 by t-test
Mentions: In the previous publication [10] we demonstrated that expression of STIM2 protein and upregulation of synaptic nSOC pathway results in rescue of mushroom spines in PS1-M146V-KI neurons. We supposed that the same approach could protect mushroom spines from amyloid toxicity. In the next series of experiments we co-transfected hippocampal neurons at DIV7 with TD-Tomato plasmid and the plasmid encoding mouse STIM2 (mSTIM2). On DIV11 the cells were treated with Aβ42 oligomers or vehicle treated. The neurons were fixed at DIV14 and morphology of the spines was visualized by confocal imaging (Fig. 4a). Consistent with the previous findings (Fig. 2), we discovered that application of Aβ42 oligomers resulted in significant reduction in a fraction of mushroom spines in hippocampal neurons (Fig. 4a, 4b). Expression of STIM2 had no significant effect on the fraction of mushroom spines in control cultures, but resulted in complete rescue of mushroom spine loss in Aβ42-treated cultures (Fig. 4a, 4b). From these results we concluded that expression of STIM2 is able to protect hippocampal mushroom spines from synaptotoxic effects of Aβ42.Fig. 4

Bottom Line: Generation of amyloidogenic peptides and accumulation of amyloid plaques is one of the pathological hallmarks of AD.We discovered that application of Aβ42 oligomers to hippocampal cultures or injection of Aβ42 oligomers directly into hippocampal region resulted in reduction of mushroom spines and activity of synaptic calcium-calmodulin-dependent kinase II (CaMKII).Obtained results suggest that downregulation of STIM2-dependent stability of mushroom spines and reduction in activity of synaptic CaMKII is a mechanism of hippocampal synaptic loss in AD model of amyloid synaptotoxicity and that modulators/activators of this pathway may have a potential therapeutic value for treatment of AD.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Neurodegeneration, Department of Medical Physics, Peter the Great St.Petersburg Polytechnic University, St. Petersburg, Russian Federation. lena.popugaeva@gmail.com.

ABSTRACT

Background: Alzheimer disease (AD) is a disease of lost memories. Mushroom postsynaptic spines play a key role in memory storage, and loss of mushroom spines has been proposed to be linked to memory loss in AD. Generation of amyloidogenic peptides and accumulation of amyloid plaques is one of the pathological hallmarks of AD. It is important to evaluate effects of amyloid on stability of mushroom spines.

Results: In this study we used in vitro and in vivo models of amyloid synaptotoxicity to investigate effects of amyloid peptides on hippocampal mushroom spines. We discovered that application of Aβ42 oligomers to hippocampal cultures or injection of Aβ42 oligomers directly into hippocampal region resulted in reduction of mushroom spines and activity of synaptic calcium-calmodulin-dependent kinase II (CaMKII). We further discovered that expression of STIM2 protein rescued CaMKII activity and protected mushroom spines from amyloid toxicity in vitro and in vivo.

Conclusions: Obtained results suggest that downregulation of STIM2-dependent stability of mushroom spines and reduction in activity of synaptic CaMKII is a mechanism of hippocampal synaptic loss in AD model of amyloid synaptotoxicity and that modulators/activators of this pathway may have a potential therapeutic value for treatment of AD.

No MeSH data available.


Related in: MedlinePlus