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Region-specific neuron and synapse loss in the hippocampus of APPSL/PS1 knock-in mice

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Translational Neuroscience

Abstract

Transgenic mouse models with knock-in (KI) expression of human mutant amyloid precursor protein (APP) and/or human presenilin 1 (PS1) may be helpful to elucidate the cellular consequences of APP and PS1 misprocessing in the aging brain. Age-related alterations in total numbers of neurons and in numbers of synaptophysin-immunoreactive presynaptic boutons (SIPB), as well as the amyloid plaque load were analyzed in the hippocampal dentate gyrus (DG), CA3, and CA1-2 of 2- and 10-month-old APPSL/PS1 homozygous KI, APPSL (expressing human mutant APP751 carrying the Swedish [K670N/M671L] and London [V717I] mutations under Thy-1 promoter), and PS1 homozygous KI mice (expressing human PS1 mutations [M233T and L235P]). APPSL/PS1 homozygous KI mice, but neither APPSL mice nor PS1 homozygous KI mice, showed substantial agerelated loss of neurons (−47.2%) and SIPB (−22.6%), specifically in CA1-2. PS1 homozygous KI mice showed an age-related increase in hippocampal granule cell numbers (+37.9%). Loss of neurons and SIPB greatly exceeded the amount of local extracellular Aβ aggregation and astrocytes, whereas region-specific accumulation of intraneuronal Aβ preceded neuron and synapse loss. An age-related increase in the ratio of SIPB to neuron numbers in CA1-2 of APPSL/PS1 homozygous KI mice was suggestive of compensatory synaptic plasticity. These findings indicate a region-selectivity in intra- and extraneuronal Aβ accumulation in connection with neuron and synapse loss in the hippocampus of APPSL/PS1 homozygous KI mice.

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Authors and Affiliations

  1. Department of Psychiatry and Neuropsychology, Maastricht University, 6200 MD, Maastricht, The Netherlands

    Ivona Brasnjevic, Roy Lardenoije, Nicolien Van Der Kolk, Harry W. M. Steinbusch & Bart P. F. Rutten

  2. European Graduate School of Neuroscience (EURON), 6200 MD, Maastricht, The Netherlands

    Ivona Brasnjevic, Nicolien Van Der Kolk, Harry W. M. Steinbusch & Bart P. F. Rutten

  3. Department of Anatomy II, Institute of Anatomy, Ludwig-Maximilians-University, 80336, Munich, Germany

    Christoph Schmitz

  4. Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Dara L. Dickstein & Patrick R. Hof

  5. Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, 791-0295, Ehime, Japan

    Hisaaki Takahashi

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  1. Ivona Brasnjevic
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  2. Roy Lardenoije
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  3. Christoph Schmitz
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  4. Nicolien Van Der Kolk
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  5. Dara L. Dickstein
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  6. Hisaaki Takahashi
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  7. Patrick R. Hof
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  8. Harry W. M. Steinbusch
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  9. Bart P. F. Rutten
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Correspondence to Bart P. F. Rutten.

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Brasnjevic, I., Lardenoije, R., Schmitz, C. et al. Region-specific neuron and synapse loss in the hippocampus of APPSL/PS1 knock-in mice. Translat.Neurosci. 4, 8–19 (2013). https://doi.org/10.2478/s13380-013-0111-8

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  • DOI: https://doi.org/10.2478/s13380-013-0111-8

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