Abnormal Cognition, Sleep, EEG and Brain Metabolism in a Novel Knock-In Alzheimer Mouse, PLB1

Abstract

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 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.

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

“…hTau‐A152T was more detrimental in this regard than hTau‐WT. This functional synergism with hAPP/Aβ may be a special, if not unique, feature of the A152T substitution, as it was not observed in mice co‐expressing hAPP/Aβ with hTau bearing FTDP‐17 mutations 89, 90, 91, 92, 93. Thus, besides increasing hTau levels, the A152T substitution appears to enhance tau's ability to support network hyperexcitability, a mechanism through which it could promote excitotoxicity and neurodegeneration.…”

Mapping Changes in Mouse Brain Metabolism with PET/CT

“…We have previously described the generation and phenotypic profile of a novel Alzheimer mouse model termed PLB1 Triple (17,18,30). These mice were generated on a background of C57BL/6, and all animals recorded here were wild-type offspring of that colony (PLB1 WT ).…”

“…The ability to follow single animals or groups of animals using repeated scans should improve accuracy (by potentially reducing the effect of variability between animals) and reduce the number of animals required for studies, with the corollary of a significant lowering of costs when working with transgenic cohorts. However, attempts to measure changes in mouse brain metabolism have met with mixed results: uptake of 18 F-FDG correlated well with 14 C-DG uptake in normoglycemic animals (10), and 18 F-FDG PET has been used to reveal metabolic phenotypes in models of epilepsy (11,12) and Alzheimer disease (13)(14)(15)(16)(17)(18)(19)(20)(21). However, others have failed to detect differences in mouse models of Alzheimer disease (22,23) and the question may be raised of whether phenotypes are due to different acquisition and analysis methods yielding different sensitivities in identifying neuronal alterations.…”

“…Some studies applied SPM (12,17,18), whereas others examined predefined regions of interest (ROIs) (15,16,19,20,22,23). Also, although there is increasing consensus that 18 F-FDG PET is a useful tool for studying rodent brain metabolism (29), there is still uncertainty over the best way to acquire and process images.…”

TMS-induced EEG Artifacts Removal Methods based on Cross-Correlation Coefficients of ICA Components

“…EEG is a non-invasive technique to record spontaneous electrical activity of the brain by measuring the voltage fluctuations resulting from ionic current flows within the neurons of the brain [12]. That is, EEG signals represent the temporal profile of the change in the potential difference between two electrodes placed on the scalp.…”