title: Neuronal Store-Operated Calcium Entry and Mushroom Spine Loss in Amyloid Precursor Protein Knock-In Mouse Model of Alzheimer's Disease.
abstract: Alzheimer's disease (AD) is the most common reason for elderly dementia in the world. We proposed that memory loss in AD is related to destabilization of mushroom postsynaptic spines involved in long-term memory storage. We demonstrated previously that stromal interaction molecule 2 (STIM2)-regulated neuronal store-operated calcium entry (nSOC) in postsynaptic spines play a key role in stability of mushroom spines by maintaining activity of synaptic Ca(2+)/calmodulin kinase II (CaMKII). Furthermore, we demonstrated previously that the STIM2-nSOC-CaMKII pathway is downregulated in presenilin 1 M146V knock-in (PS1-M146V KI) mouse model of AD, leading to loss of hippocampal mushroom spines in this model. In the present study, we demonstrate that hippocampal mushroom postsynaptic spines are also lost in amyloid precursor protein knock-in (APPKI) mouse model of AD. We demonstrated that loss of mushroom spines occurs as a result of accumulation of extracellular β-amyloid 42 in APPKI culture media. Our results indicate that extracellular Aβ42 acts by overactivating mGluR5 receptor in APPKI neurons, leading to elevated Ca(2+) levels in endoplasmic reticulum, compensatory downregulation of STIM2 expression, impaired synaptic nSOC, and reduced CaMKII activity. Pharmacological inhibition of mGluR5 or overexpression of STIM2 rescued synaptic nSOC and prevented mushroom spine loss in APPKI hippocampal neurons. Our results indicate that downregulation of synaptic STIM2-nSOC-CaMKII pathway causes loss of mushroom synaptic spines in both presenilin and APPKI mouse models of AD. We propose that modulators/activators of this pathway may have a potential therapeutic value for treatment of memory loss in AD. Significance statement: A direct connection between amyloid-induced synaptic mushroom spine loss and neuronal store-operated calcium entry pathway is shown. These results provide strong support for the calcium hypothesis of neurodegeneration and further validate the synaptic store-operated calcium entry pathway as a potential therapeutic target for Alzheimer's disease.
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Lili
authors.initials: L
authors.lastname: Wu
authors.affiliation: Laboratory of Molecular Neurodegeneration, St. Petersburg State Polytechnical University, St. Petersburg 195251, Russia.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Pchitskaya
authors.affiliation: Laboratory of Molecular Neurodegeneration, St. Petersburg State Polytechnical University, St. Petersburg 195251, Russia.
authors.forename: Olga
authors.identifier: http://orcid.org/0000-0002-2384-0681
authors.initials: O
authors.lastname: Zakharova
authors.affiliation: Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 351-0198 Saitama, Japan, and Japan Science and Technology Agency, 332-0012 Saitama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
authors.affiliation: Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 351-0198 Saitama, Japan, and.
authors.forename: Takaomi
authors.initials: T
authors.lastname: Saido
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, Laboratory of Molecular Neurodegeneration, St. Petersburg State Polytechnical University, St. Petersburg 195251, Russia, Ilya.Bezprozvanny@UTSouthwestern.edu.
authors.forename: Ilya
authors.initials: I
authors.lastname: Bezprozvanny
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D049229:Dendritic Spines / Q000473:pathology*; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000502:physiology*; D064529:Receptor, Metabotropic Glutamate 5 / Q000235:genetics; D015398:Signal Transduction; D000071738:Stromal Interaction Molecule 2
chemical_list: D016564:Amyloid beta-Protein Precursor; D015220:Calcium Channels; C578936:Grm5 protein, mouse; D008562:Membrane Glycoproteins; D064529:Receptor, Metabotropic Glutamate 5; C525024:Stim2 protein, mouse; D000071738:Stromal Interaction Molecule 2; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: calcium; imaging; synaptic; transgenic