期刊
TRANSLATIONAL NEUROSCIENCE
卷 4, 期 1, 页码 8-19出版社
SCIENDO
DOI: 10.2478/s13380-013-0111-8
关键词
Alzheimer's disease; Amyloid precursor protein; Neuron loss; Synapse loss; Hippocampus; Presenilin-1; Stereology; Image analysis
资金
- NIH [AG05138]
- Internationale Stichting Alzheimer Onderzoek (ISAO) [09552]
- Netherlands Organisation for Scientific Research (NWO) [916.11.086]
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 APP(SL)/PS1 homozygous KI, APP(SL) (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]). APP(SL)/PS1 homozygous KI mice, but neither APP(SL) 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 A beta aggregation and astrocytes, whereas region-specific accumulation of intraneuronal A beta preceded neuron and synapse loss. An age-related increase in the ratio of SIPB to neuron numbers in CA1-2 of APP(SL)/PS1 homozygous KI mice was suggestive of compensatory synaptic plasticity. These findings indicate a region-selectivity in intra- and extraneuronal A beta accumulation in connection with neuron and synapse loss in the hippocampus of APP(SL)/PS1 homozygous KI mice.
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