STIM2 protects hippocampal mushroom spines from amyloid synaptotoxicity.
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.
Laboratory of Molecular Neurodegeneration, Department of Medical Physics, Peter the Great St.Petersburg Polytechnic University, St. Petersburg, Russian Federation. lena.popugaeva@gmail.com.
Elena
E
Popugaeva
Laboratory of Molecular Neurodegeneration, Department of Medical Physics, Peter the Great St.Petersburg Polytechnic University, St. Petersburg, Russian Federation. katrincreative@yandex.ru.
Ekaterina
E
Pchitskaya
Laboratory of Microscopy and Microanalysis, Department of Physics-chemistry and Microsystem Technique, Institute of Metallurgy, Mechanical Engineering and Transport, Peter the Great St.Petersburg Polytechnic University, St. Petersburg, Russian Federation. speshaab@yandex.ru.
Anastasiya
A
Speshilova
Laboratory of Microscopy and Microanalysis, Department of Physics-chemistry and Microsystem Technique, Institute of Metallurgy, Mechanical Engineering and Transport, Peter the Great St.Petersburg Polytechnic University, St. Petersburg, Russian Federation. salexsandrov@spbstu.ru.
Sergey
S
Alexandrov
Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX, 75390, USA. hua.zhang@utsouthwestern.edu.
Hua
H
Zhang
Laboratory of Molecular Neurodegeneration, Department of Medical Physics, Peter the Great St.Petersburg Polytechnic University, St. Petersburg, Russian Federation. olvlasova@yandex.ru.
Olga
O
Vlasova
Laboratory of Molecular Neurodegeneration, Department of Medical Physics, Peter the Great St.Petersburg Polytechnic University, St. Petersburg, Russian Federation. ilya.bezprozvanny@utsouthwestern.edu.|Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX, 75390, USA. ilya.bezprozvanny@utsouthwestern.edu.
Ilya
I
Bezprozvanny
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology; D002478:Cells, Cultured; D003712:Dendrites / Q000187:drug effects* / Q000648:ultrastructure; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005813:Genes, Synthetic; D005822:Genetic Vectors / Q000494:pharmacology; D006801:Humans; D007267:Injections; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010446:Peptide Fragments / Q000633:toxicity*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D000071738:Stromal Interaction Molecule 2; D013569:Synapses / Q000201:enzymology; D014162:Transfection
D016229:Amyloid beta-Peptides; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; C525024:Stim2 protein, mouse; D000071738:Stromal Interaction Molecule 2; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2