caa a22 4500 606201645 CHVBK 20210128100949.0 cr unu---uuuuu 210128e20151101xx s 000 0 eng 10.1007/s00429-014-0848-z doi (NATIONALLICENCE)springer-10.1007/s00429-014-0848-z Evidence for Alzheimer's disease-linked synapse loss and compensation in mouse and human hippocampal CA1 pyramidal neurons [Elektronische Daten] [Krystina Neuman, Elizabeth Molina-Campos, Timothy Musial, Andrea Price, Kwang-Jin Oh, Malerie Wolke, Eric Buss, Stephen Scheff, Elliott Mufson, Daniel Nicholson] 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. Springer-Verlag Berlin Heidelberg, 2014 Hippocampus nationallicence Synapse nationallicence AMPA receptor nationallicence Dendrite nationallicence Electron microscopy nationallicence Patch-clamp physiology nationallicence Array tomography nationallicence Alzheimer's disease nationallicence Serial section nationallicence Immunogold nationallicence EPSP nationallicence Neuman Krystina Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, 60612, Chicago, IL, USA aut Molina-Campos Elizabeth Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, 60612, Chicago, IL, USA aut Musial Timothy Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, 60612, Chicago, IL, USA aut Price Andrea Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, 60612, Chicago, IL, USA aut Oh Kwang-Jin Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, 60612, Chicago, IL, USA aut Wolke Malerie Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, 60612, Chicago, IL, USA aut Buss Eric Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, 60612, Chicago, IL, USA aut Scheff Stephen Sanders Brown Center on Aging, University of Kentucky, 40536, Lexington, KY, USA aut Mufson Elliott Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, 60612, Chicago, IL, USA aut Nicholson Daniel Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, 60612, Chicago, IL, USA aut Brain Structure and Function Springer Berlin Heidelberg 220/6(2015-11-01), 3143-3165 1863-2653 220:6<3143 2015 220 429 https://doi.org/10.1007/s00429-014-0848-z text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00429-014-0848-z text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Neuman Krystina Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, 60612, Chicago, IL, USA aut NATIONALLICENCE 700 1- Molina-Campos Elizabeth Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, 60612, Chicago, IL, USA aut NATIONALLICENCE 700 1- Musial Timothy Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, 60612, Chicago, IL, USA aut NATIONALLICENCE 700 1- Price Andrea Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, 60612, Chicago, IL, USA aut NATIONALLICENCE 700 1- Oh Kwang-Jin Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, 60612, Chicago, IL, USA aut NATIONALLICENCE 700 1- Wolke Malerie Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, 60612, Chicago, IL, USA aut NATIONALLICENCE 700 1- Buss Eric Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, 60612, Chicago, IL, USA aut NATIONALLICENCE 700 1- Scheff Stephen Sanders Brown Center on Aging, University of Kentucky, 40536, Lexington, KY, USA aut NATIONALLICENCE 700 1- Mufson Elliott Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, 60612, Chicago, IL, USA aut NATIONALLICENCE 700 1- Nicholson Daniel Department of Neurological Sciences, Rush University Medical Center, 1653 West Harrison Street, 60612, Chicago, IL, USA aut NATIONALLICENCE 773 0- Brain Structure and Function Springer Berlin Heidelberg 220/6(2015-11-01), 3143-3165 1863-2653 220:6<3143 2015 220 429