title: Early Activation of Experience-Independent Dendritic Spine Turnover in a Mouse Model of Alzheimer's Disease.
abstract: Synaptic loss is critical in Alzheimer's disease (AD), but the dynamics of synapse turnover are poorly defined. We imaged dendritic spines in transgenic APPswe/PSen1∆E9 (APP/PS1) cerebral cortex. Dendritic spine turnover is increased far from plaque in aged APP/PS1 mice, and in young APP/PS1 mice prior to plaque formation. Dysregulation occurs in the presence of soluble Aβ oligomer and requires cellular prion protein (PrPC). APP/PS1 mice lack responsiveness of spine turnover to sensory stimulation. Critically, enhanced spine turnover is coupled with the loss of persistent spines starting early and continuing with age. To evaluate mechanisms of experience-independent supranormal spine turnover, we analyzed the transcriptome of young APP/PS1 mouse brain when turnover is altered but synapse density and memory are normal, and plaque and inflammation are absent. Early PrPC-dependent expression changes occur in synaptic and lipid-metabolizing genes. Thus, pathologic synaptic dysregulation underlying AD begins at a young age prior to Aβ plaque.
authors.affiliation: Program in Cellular Neuroscience, Neurodegeneration & Repair, Yale University School of Medicine, New Haven, CT 06536, USA.|Department of Pharmacology, Yale University School of Medicine, New Haven CT 06520, USA.
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: Heiss
authors.affiliation: Program in Cellular Neuroscience, Neurodegeneration & Repair, Yale University School of Medicine, New Haven, CT 06536, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Barrett
authors.affiliation: Program in Cellular Neuroscience, Neurodegeneration & Repair, Yale University School of Medicine, New Haven, CT 06536, USA.
authors.forename: Zizi
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Program in Cellular Neuroscience, Neurodegeneration & Repair, Yale University School of Medicine, New Haven, CT 06536, USA.
authors.forename: Laura T
authors.initials: LT
authors.lastname: Haas
authors.affiliation: Program in Cellular Neuroscience, Neurodegeneration & Repair, Yale University School of Medicine, New Haven, CT 06536, USA.
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Kostylev
authors.affiliation: Program in Cellular Neuroscience, Neurodegeneration & Repair, Yale University School of Medicine, New Haven, CT 06536, USA.|Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA.|Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Strittmatter
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002540:Cerebral Cortex / Q000473:pathology*; D049229:Dendritic Spines / Q000473:pathology* / Q000648:ultrastructure; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D021621:Imaging, Three-Dimensional; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D059906:Neuroimaging; D058225:Plaque, Amyloid / Q000209:etiology / Q000473:pathology*; D053764:Presenilin-1 / Q000235:genetics; D000072002:Prion Proteins / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012683:Sensory Deprivation; D013997:Time Factors; D014738:Vibrissae / Q000294:innervation
chemical_list: D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D053764:Presenilin-1; D000072002:Prion Proteins; C512657:Prnp protein, mouse; D016760:Proto-Oncogene Proteins c-fos; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
keywords: Alzheimer; dendritic spine; plasticity; prion protein; somatosensory cortex