title: 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 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 (18)FDG 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.
authors.affiliation: School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen, United Kingdom. b.platt@abdn.ac.uk
authors.forename: Bettina
authors.initials: B
authors.lastname: Platt
authors.forename: Benjamin
authors.initials: B
authors.lastname: Drever
authors.forename: David
authors.initials: D
authors.lastname: Koss
authors.forename: Sandra
authors.initials: S
authors.lastname: Stoppelkamp
authors.forename: Amar
authors.initials: A
authors.lastname: Jyoti
authors.forename: Andrea
authors.initials: A
authors.lastname: Plano
authors.forename: Aneli
authors.initials: A
authors.lastname: Utan
authors.forename: Georgina
authors.initials: G
authors.lastname: Merrick
authors.forename: Duncan
authors.initials: D
authors.lastname: Ryan
authors.forename: Valeria
authors.initials: V
authors.lastname: Melis
authors.forename: Hong
authors.initials: H
authors.lastname: Wan
authors.forename: Marco
authors.initials: M
authors.lastname: Mingarelli
authors.forename: Emanuele
authors.initials: E
authors.lastname: Porcu
authors.forename: Louise
authors.initials: L
authors.lastname: Scrocchi
authors.forename: Andy
authors.initials: A
authors.lastname: Welch
authors.forename: Gernot
authors.initials: G
authors.lastname: Riedel
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000502:physiology; D003071:Cognition / Q000502:physiology*; D004569:Electroencephalography; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012890:Sleep / Q000235:genetics / Q000502:physiology*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins
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