Reduced synaptic STIM2 expression and impaired store-operated calcium entry cause destabilization of mature spines in mutant presenilin mice.
Mushroom dendritic spine structures are essential for memory storage, and the loss of mushroom spines may explain memory defects in Alzheimer's disease (AD). Here we show a significant reduction in the fraction of mushroom spines in hippocampal neurons from the presenilin-1 M146V knockin (KI) mouse model of familial AD (FAD). The stabilization of mushroom spines depends on STIM2-mediated neuronal store-operated calcium influx (nSOC) and continuous activity of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). We demonstrate that STIM2-nSOC-CaMKII pathway is compromised in KI neurons, in aging neurons, and in sporadic AD brains due to downregulation of STIM2 protein. We further establish that overexpression of STIM2 rescues synaptic nSOC, CaMKII activity, and mushroom spine loss in KI neurons. Our results identify STIM2-nSOC-CaMKII synaptic maintenance pathway as a novel potential therapeutic target for treatment of AD and age-related memory decline.
Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Suya
S
Sun
Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Hua
H
Zhang
Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Jie
J
Liu
Laboratory of Molecular Neurodegeneration, Saint Petersburg State Polytechnical University, Saint Petersburg, 195251, Russia.
Elena
E
Popugaeva
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Nan-Jie
NJ
Xu
Department of Pathology, New York University Langone Medical Center, New York, NY 10016, USA.
Stefan
S
Feske
Department of Pathology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Charles L
CL
White
Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA; Laboratory of Molecular Neurodegeneration, Saint Petersburg State Polytechnical University, Saint Petersburg, 195251, Russia. Electronic address: Ilya.Bezprozvanny@UTSouthwestern.edu.
Ilya
I
Bezprozvanny
D000367:Age Factors; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics*; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000166:cytology*; D053764:Presenilin-1 / Q000235:genetics*; D053766:Presenilin-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors
D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D053766:Presenilin-2; C095101:Psen2 protein, mouse; D002118:Calcium