title: Distinct dendritic spine and nuclear phases of calcineurin activation after exposure to amyloid-β revealed by a novel fluorescence resonance energy transfer assay.
abstract: Calcineurin (CaN) activation is critically involved in the regulation of spine morphology in response to oligomeric amyloid-β (Aβ) as well as in synaptic plasticity in normal memory, but no existing techniques can monitor the spatiotemporal pattern of CaN activity. Here, we use a spectral fluorescence resonance energy transfer approach to monitor CaN activation dynamics in real time with subcellular resolution. When oligomeric Aβ derived from Tg2576 murine transgenic neurons or human AD brains were applied to wild-type murine primary cortical neurons, we observe a dynamic progression of CaN activation within minutes, first in dendritic spines, and then in the cytoplasm and, in hours, in the nucleus. CaN activation in spines leads to rapid but reversible morphological changes in spines and in postsynaptic proteins; longer exposure leads to NFAT (nuclear factor of activated T-cells) translocation to the nucleus and frank spine loss. These results provide a framework for understanding the role of calcineurin in synaptic alterations associated with AD pathogenesis.
authors.affiliation: Department of Neurology/Alzheimer's Disease Research Laboratory, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Wu
authors.forename: Eloise
authors.initials: E
authors.lastname: Hudry
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Kengo
authors.initials: K
authors.lastname: Uemura
authors.forename: Zhan-Yun
authors.initials: ZY
authors.lastname: Fan
authors.forename: Oksana
authors.initials: O
authors.lastname: Berezovska
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Grosskreutz
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bacskai
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D019703:Calcineurin / Q000502:physiology*; D002460:Cell Line; D002467:Cell Nucleus / Q000502:physiology*; D002850:Chromatography, Gel; D017077:Culture Media, Conditioned; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D049229:Dendritic Spines / Q000502:physiology*; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D050778:NFATC Transcription Factors / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D021381:Protein Transport; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D013347:Subcellular Fractions / Q000378:metabolism; D013569:Synapses / Q000502:physiology
chemical_list: D000199:Actins; D016229:Amyloid beta-Peptides; D019703:Calcineurin; D017077:Culture Media, Conditioned; D018076:DNA, Complementary; D050778:NFATC Transcription Factors; D018091:Receptors, AMPA; C494007:Nfatc2 protein, mouse