Abnormal cognition, sleep, eeg and brain metabolism in a novel knock-in alzheimer mouse, plb1

TY - JOUR

T1 - Abnormal cognition, sleep, eeg and brain metabolism in a novel knock-in alzheimer mouse, plb1

AU - Platt, Bettina

AU - Drever, Benjamin

AU - Koss, David

AU - Stoppelkamp, Sandra

AU - Jyoti, Amar

AU - Plano, Andrea

AU - Utan, Aneli

AU - Merrick, Georgina

AU - Ryan, Duncan

AU - Melis, Valeria

AU - Wan, Hong

AU - Mingarelli, Marco

AU - Porcu, Emanuele

AU - Scrocchi, Louise

AU - Welch, Andy

AU - Riedel, Gernot

N1 - Copyright: © 2011 Platt et al.

PY - 2011/11/11

Y1 - 2011/11/11

N2 - Late-stage neuropathological hallmarks of Alzheimer's disease (AD) are β-amyloid (βA) 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 CaMKIIα promoter, termed PLB1 Double. Crossing with an existing presenilin 1 line resulted in PLB1 Triple mice. PLB1 Triple 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. PLB1 Triple 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.

AB - Late-stage neuropathological hallmarks of Alzheimer's disease (AD) are β-amyloid (βA) 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 CaMKIIα promoter, termed PLB1 Double. Crossing with an existing presenilin 1 line resulted in PLB1 Triple mice. PLB1 Triple 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. PLB1 Triple 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.

UR - https://www.scopus.com/pages/publications/80855156783

U2 - 10.1371/journal.pone.0027068

DO - 10.1371/journal.pone.0027068

M3 - Article

C2 - 22096518

AN - SCOPUS:80855156783

SN - 1932-6203

VL - 6

JO - PLoS ONE

JF - PLoS ONE

IS - 11

M1 - e27068

ER -