STIM2 protects hippocampal mushroom spines from amyloid synaptotoxicity

Abstract

BackgroundAlzheimer 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.ResultsIn 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.ConclusionsObtained 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0034-7) contains supplementary material, which is available to authorized users.

STIM2 regulates AMPA receptor trafficking and plasticity at hippocampal synapses

“…While SOCE is the predominant Ca 2+ influx pathway in non-excitable cells 4 , the magnitude and relevance of SOCE in neurons remains a topic of debate [5][6][7] . Recent studies, however, reported SOCE responses in dendritic spines 8,9 , small dendritic protrusions at the tip of which terminate most excitatory inputs. Synaptic SOCE is STIM2-dependent, has been linked to spine maturation and is dysregulated in mouse models of Alzheimer's and Huntington's disease [8][9][10][11] .…”

“…Recent studies, however, reported SOCE responses in dendritic spines 8,9 , small dendritic protrusions at the tip of which terminate most excitatory inputs. Synaptic SOCE is STIM2-dependent, has been linked to spine maturation and is dysregulated in mouse models of Alzheimer's and Huntington's disease [8][9][10][11] .…”

Restoring Calcium Homeostasis to Treat Alzheimer’s Disease: A Future Perspective

“…We observed that the STIM2-nSOC-CaMKII mushroom spine maintenance pathway is also disrupted in recently developed APP-KI mouse models of AD [26], in conditions of amyloid toxicity [27], in aging neurons and in sporadic AD brains [19]. Intriguingly, pharmacological or genetic rescuing of this pathway in KI mice restores mushroom spines as well as expression of synaptic proteins such as pCaMKII and postsynaptic density protein 95 [19,26,27]. Therefore, we think that the formation and stability of mushroom spines is regulated by the balance of CaMKII and CaN activity.…”

“…Indeed, CaN phosphatase activity is enhanced in aging neurons and plays an important role in increased long-term depression [24,25]. We observed that the STIM2-nSOC-CaMKII mushroom spine maintenance pathway is also disrupted in recently developed APP-KI mouse models of AD [26], in conditions of amyloid toxicity [27], in aging neurons and in sporadic AD brains [19]. Intriguingly, pharmacological or genetic rescuing of this pathway in KI mice restores mushroom spines as well as expression of synaptic proteins such as pCaMKII and postsynaptic density protein 95 [19,26,27].…”

STIM Proteins As Regulators of Neuronal Store-Operated Calcium Influx

“…Our laboratory reported that virus-mediated knockdown of STIM2 protein expression causes mushroom spine shrinkage and causes loss of nSOC in hippocampal dendritic spines [19]. Moreover, it has been observed that STIM2 hyperexpression as well as pharmacological activation of nSOC in the hippocampus is able to protect mushroom spines in different models of Alzheimer's disease (AD) pathology [15,[19][20]. Downregulation of STIM2 proteins was observed in cells from AD patients and in AD mouse models [19,21].…”