Abnormal cognition, sleep, EEG and brain metabolism in a novel knock-in Alzheimer mouse, PLB1

Bettina Platt, Benjamin Drever, David Koss, Sandra Stoppelkamp, Amar Jyoti, Andrea Plano, Aneli Utan, Georgina Merrick, Duncan Ryan, Valeria Melis, Hong Wan, Marco Mingarelli, Emanuele Porcu, Louise Scrocchi, Andy Welch, Gernot Riedel

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Abstract

Late-stage neuropathological hallmarks of Alzheimer's disease (AD) are ß-amyloid (ßA) and hyperphosphorylated tau peptides, aggregated into plaques and tangles, respectively. Corresponding phenotypes have been mimicked in existing transgenic mice, however, the translational value of aggressive over-expression has recently been questioned. As controlled gene expression may offer animal models with better predictive validity, we set out to design a transgenic mouse model that circumvents complications arising from pronuclear injection and massive over-expression, by targeted insertion of human mutated amyloid and tau transgenes, under the forebrain- and neurone-specific CaMKIIa promoter, termed PLB1Double. Crossing with an existing presenilin 1 line resulted in PLB1Triple mice. PLB1Triple mice presented with stable gene expression and age-related pathology of intra-neuronal amyloid and hyperphosphorylated tau in hippocampus and cortex from 6 months onwards. At this early stage, pre-clinical 18FDG PET/CT imaging revealed cortical hypometabolism with increased metabolic activity in basal forebrain and ventral midbrain. Quantitative EEG analyses yielded heightened delta power during wakefulness and REM sleep, and time in wakefulness was already reliably enhanced at 6 months of age. These anomalies were paralleled by impairments in long-term and short-term hippocampal plasticity and preceded cognitive deficits in recognition memory, spatial learning, and sleep fragmentation all emerging at ~12 months. These data suggest that prodromal AD phenotypes can be successfully modelled in transgenic mice devoid of fibrillary plaque or tangle development. PLB1Triple mice progress from a mild (MCI-like) state to a more comprehensive AD-relevant phenotype, which are accessible using translational tools such as wireless EEG and microPET/CT.

Original languageEnglish
Article numbere27068
Number of pages13
JournalPloS ONE
Volume6
Issue number11
DOIs
Publication statusPublished - 11 Nov 2011

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Keywords

  • EEG Alzheimer wireless

Cite this

Platt, B., Drever, B., Koss, D., Stoppelkamp, S., Jyoti, A., Plano, A., Utan, A., Merrick, G., Ryan, D., Melis, V., Wan, H., Mingarelli, M., Porcu, E., Scrocchi, L., Welch, A., & Riedel, G. (2011). Abnormal cognition, sleep, EEG and brain metabolism in a novel knock-in Alzheimer mouse, PLB1. PloS ONE, 6(11), [e27068]. https://doi.org/10.1371/journal.pone.0027068