title: Evidence for Alzheimer's disease-linked synapse loss and compensation in mouse and human hippocampal CA1 pyramidal neurons.
abstract: Alzheimer's disease (AD) is associated with alterations in the distribution, number, and size of inputs to hippocampal neurons. Some of these changes are thought to be neurodegenerative, whereas others are conceptualized as compensatory, plasticity-like responses, wherein the remaining inputs reactively innervate vulnerable dendritic regions. Here, we provide evidence that the axospinous synapses of human AD cases and mice harboring AD-linked genetic mutations (the 5XFAD line) exhibit both, in the form of synapse loss and compensatory changes in the synapses that remain. Using array tomography, quantitative conventional electron microscopy, immunogold electron microscopy for AMPARs, and whole-cell patch-clamp physiology, we find that hippocampal CA1 pyramidal neurons in transgenic mice are host to an age-related synapse loss in their distal dendrites, and that the remaining synapses express more AMPA-type glutamate receptors. Moreover, the number of axonal boutons that synapse with multiple spines is significantly reduced in the transgenic mice. Through serial section electron microscopic analyses of human hippocampal tissue, we further show that putative compensatory changes in synapse strength are also detectable in axospinous synapses of proximal and distal dendrites in human AD cases, and that their multiple synapse boutons may be more powerful than those in non-cognitively impaired human cases. Such findings are consistent with the notion that the pathophysiology of AD is a multivariate product of both neurodegenerative and neuroplastic processes, which may produce adaptive and/or maladaptive responses in hippocampal synaptic strength and plasticity.
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, Chicago, IL, 60612, USA.
authors.forename: Krystina M
authors.initials: KM
authors.lastname: Neuman
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, Chicago, IL, 60612, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Molina-Campos
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, Chicago, IL, 60612, USA.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Musial
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, Chicago, IL, 60612, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Price
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, Chicago, IL, 60612, USA.
authors.forename: Kwang-Jin
authors.initials: KJ
authors.lastname: Oh
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, Chicago, IL, 60612, USA.
authors.forename: Malerie L
authors.initials: ML
authors.lastname: Wolke
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, Chicago, IL, 60612, USA.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Buss
authors.affiliation: Sanders Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scheff
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, Chicago, IL, 60612, USA.
authors.forename: Elliott J
authors.initials: EJ
authors.lastname: Mufson
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, Chicago, IL, 60612, USA. dan_nicholson@rush.edu.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Nicholson
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001369:Axons / Q000378:metabolism; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D017729:Presynaptic Terminals / Q000378:metabolism / Q000473:pathology; D017966:Pyramidal Cells / Q000378:metabolism / Q000473:pathology*; D018091:Receptors, AMPA / Q000378:metabolism; D013569:Synapses / Q000473:pathology
chemical_list: D018091:Receptors, AMPA
keywords: AMPA receptor; Alzheimer’s disease; Array tomography; Dendrite; EPSP; Electron microscopy; Hippocampus; Immunogold; Patch-clamp physiology; Serial section; Synapse