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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, PSD95 and pCaMKII are downregulated in mice injected with Aβ42. a The expression levels of STIM2, STIM1, PSD95, pCaMKII, CaMKII were analyzed by Western blotting of hippocampal lysates taken from wild type mice injected with Aβ42 and from the control mice. Each band on WB panel represents one mice. Actin was used as a loading control. b Expression of STIM2, STIM1, PSD95, pCaMKII, and CaMKII proteins was normalized to actin. Values are shown as mean ± SEM for control mice and the mice injected with Aβ42. *: p < 0.05, **: p < 0.005 by t-test
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Fig6: STIM2, PSD95 and pCaMKII are downregulated in mice injected with Aβ42. a The expression levels of STIM2, STIM1, PSD95, pCaMKII, CaMKII were analyzed by Western blotting of hippocampal lysates taken from wild type mice injected with Aβ42 and from the control mice. Each band on WB panel represents one mice. Actin was used as a loading control. b Expression of STIM2, STIM1, PSD95, pCaMKII, and CaMKII proteins was normalized to actin. Values are shown as mean ± SEM for control mice and the mice injected with Aβ42. *: p < 0.05, **: p < 0.005 by t-test

Mentions: In order to investigate effects of Aβ42 injections in vivo, we performed Western blotting analyses of hippocampal lysates prepared from wild type mice injected with Aβ42 oligomers. Mice injected with the secondary antibody were used as a control. Consistent with hippocampal culture data (Fig. 3) we observed 20 % reduction of STIM2 levels in the hippocampus of the mice injected with Aβ42 oligomers (Fig. 6a, 6b). Also consistent with the culture data (Fig. 3), we observed 45 % reduction in the levels of pCaMKII following injection of Aβ42 oligomers (Fig. 6a, 6b). Levels of STIM1 protein were reduced by less than 5 % and the total levels of CaMKII were not affected in Aβ42-injected mice (Fig. 6a, 6b). We also evaluated levels of PSD95 protein, that is enriched in postsynaptic density of mushroom spines. Levels of PSD95 were also reduced by 40 % in hippocampus of Aβ42-injected mice (Fig. 6a, 6b). Significant reduction of PSD95 and pCaMKII levels in these experiments is consistent with the loss of mushroom spines in hippocampal neurons of the mice injected with Aβ42 oligomers (Fig. 5) and with our previous studies with PS1-M146V-KI mice [10].Fig. 6


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, PSD95 and pCaMKII are downregulated in mice injected with Aβ42. a The expression levels of STIM2, STIM1, PSD95, pCaMKII, CaMKII were analyzed by Western blotting of hippocampal lysates taken from wild type mice injected with Aβ42 and from the control mice. Each band on WB panel represents one mice. Actin was used as a loading control. b Expression of STIM2, STIM1, PSD95, pCaMKII, and CaMKII proteins was normalized to actin. Values are shown as mean ± SEM for control mice and the mice injected with Aβ42. *: p < 0.05, **: p < 0.005 by t-test
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig6: STIM2, PSD95 and pCaMKII are downregulated in mice injected with Aβ42. a The expression levels of STIM2, STIM1, PSD95, pCaMKII, CaMKII were analyzed by Western blotting of hippocampal lysates taken from wild type mice injected with Aβ42 and from the control mice. Each band on WB panel represents one mice. Actin was used as a loading control. b Expression of STIM2, STIM1, PSD95, pCaMKII, and CaMKII proteins was normalized to actin. Values are shown as mean ± SEM for control mice and the mice injected with Aβ42. *: p < 0.05, **: p < 0.005 by t-test
Mentions: In order to investigate effects of Aβ42 injections in vivo, we performed Western blotting analyses of hippocampal lysates prepared from wild type mice injected with Aβ42 oligomers. Mice injected with the secondary antibody were used as a control. Consistent with hippocampal culture data (Fig. 3) we observed 20 % reduction of STIM2 levels in the hippocampus of the mice injected with Aβ42 oligomers (Fig. 6a, 6b). Also consistent with the culture data (Fig. 3), we observed 45 % reduction in the levels of pCaMKII following injection of Aβ42 oligomers (Fig. 6a, 6b). Levels of STIM1 protein were reduced by less than 5 % and the total levels of CaMKII were not affected in Aβ42-injected mice (Fig. 6a, 6b). We also evaluated levels of PSD95 protein, that is enriched in postsynaptic density of mushroom spines. Levels of PSD95 were also reduced by 40 % in hippocampus of Aβ42-injected mice (Fig. 6a, 6b). Significant reduction of PSD95 and pCaMKII levels in these experiments is consistent with the loss of mushroom spines in hippocampal neurons of the mice injected with Aβ42 oligomers (Fig. 5) and with our previous studies with PS1-M146V-KI mice [10].Fig. 6

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