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

Walter de Gruyter GmbH - Tập 4 - Trang 8-19 - 2013
Ivona Brasnjevic1,2, Roy Lardenoije1, Christoph Schmitz3, Nicolien Van Der Kolk1,2, Dara L. Dickstein4, Hisaaki Takahashi5, Patrick R. Hof4, Harry W. M. Steinbusch1,2, Bart P. F. Rutten1,2
1Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands
2European Graduate School of Neuroscience (EURON), Maastricht, The Netherlands
3Department of Anatomy II, Institute of Anatomy, Ludwig-Maximilians-University, Munich, Germany
4Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA
5Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Ehime, Japan

Tóm tắt

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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