Several genetically engineered models exist that mimic aspects of the pathological and cognitive hallmarks of Alzheimer's disease (AD). Here we report on a novel mouse model generated by targeted knock-in of transgenes containing mutated human amyloid precursor protein (APP) and microtubule-associated protein tau genes, inserted into the HPRT locus and controlled by the CaMKIIa regulatory element. These mice were crossed with an asymptomatic presenilin1(A246E) overexpressing line to generate PLB1(Triple) mice. Gene expression analysis and in situ hybridization confirmed stable, forebrain-specific, and gene-dose-dependent transgene expression. Brain tissue harvested from homozygous, heterozygous, and wild-type cohorts aged between 3 and 24 months was analyzed immunohistochemically and electrophysiologically. Homozygous PLB1(Triple) offspring presented with mostly intracellular cortical and hippocampal human APP/amyloid, first detected reliably at 6 months. Human tau was already uncovered at 3 months (phospho-tau at 6 months) and labeling intensifying progressively with age. Gene-dose dependence was confirmed in age-matched heterozygous females that accumulated less tau and amyloid protein. General excitability of hippocampal neurones was not altered in slices from PLB1(Triple) mice up to 12 months, but 2-year-old homozygous PLB1(Triple) mice had smaller synaptically evoked postsynaptic potentials compared with wild types. Synaptic plasticity (paired-pulse depression/facilitation and long-term potentiation) of synaptic CA1 pyramidal cell responses was deficient from 6 months of age. Long-term depression was not affected at any age or in any genotype. Therefore, despite comparatively subtle gene expression and protein build-up, PLB1(Triple) mice develop age-dependent progressive phenotypes, suggesting that aggressive protein accumulation is not necessary to reconstruct endophenotypes of AD.
- transgenic mice
- synaptic plasticity
Koss, D. J., Drever, B. D., Stoppelkamp, S., Riedel, G., & Platt, B. (2013). Age-dependent changes in hippocampal synaptic transmission and plasticity in the PLB1(Triple) Alzheimer mouse. Cellular and Molecular Life Sciences, 70(14), 2585-2601. https://doi.org/10.1007/s00018-013-1273-9