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Gernot RiedelTranslational studies using PLB1 - the first knock-in triple transgenic AD mouse’

Abstract :


Alzheimer’s disease (AD) is diagnosed as abnormal cognitive decay, and key histopathological hallmarks comprise progressive brain atrophy, accumulation of β-amyloid (plaques) and hyperphosphorylated tau (tangles).
Recent advances in brain imaging and EEG recordings indicate a unique AD-related signature, proposed as reliable indicators for prodrom-to-dementia conversion and treatment efficacy. Since these endophenotypes have not been matched in transgenic animals there is an unmet need for the establishment of experimental models with physiologically relevant early disease markers. We addressed this by creating a novel mouse overexpressing human mutated amyloid precursor protein and tau transgenes through single-copy knock-in into the safe Hprt locus under the forebrain- and neuron-specific CaMKIIα promoter. Crossed with an existing presenilin 1 (PS1) line, this created PLB1Triple mice. Stable gene expression and age-related pathology of intra-neuronal amyloid and hyperphosphorylated tau accumulation was confirmed in hippocampus and cortex from 6 months of age. At this early stage, pre-clinical PET/CT imaging identified a prefrontal 18F-deoxyglucose hypermetabolism alongside a parieto-occipital hypometabolism, while quantitative EEG from corresponding locations yielded heightened delta power during wakefulness and rapid eye movement (REM) sleep. Simultaneously, wakefulness increased at the expense of non-REM sleep. These anomalies emerged together with impairments in long-term and short-term hippocampal plasticity and preceded cognitive deficits in recognition memory, spatial learning, and sleep fragmentation that emerged at 12-13 months. Therefore, the onset and progression of symptoms in PLB1Triple mice putatively reiterate the time course of AD in a manner reminiscent of the transition from prodromal to full dementia.

Selected publications

Abnormal cognition, sleep, EEG and brain metabolism in a novel knock-in Alzheimer mouse, PLB1.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.PLoS One. 2011;6(11):e27068. Epub 2011 Nov 11.

Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ(9)-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour.Deiana S, Watanabe A, Yamasaki Y, Amada N, Arthur M, Fleming S, Woodcock H, Dorward P, Pigliacampo B, Close S, Platt B, Riedel G.Psychopharmacology (Berl). 2011 Jul 28.


FDG-PET imaging, EEG and sleep phenotypes as translational biomarkers for research in Alzheimer's disease.Platt B, Welch A, Riedel G.Biochem Soc Trans. 2011 Aug;39(4):874-80. Review.

 


Scientific focus :

Short bio

Career and Esteem: GR currently hold a Chair in Systems Neuroscience at Aberdeen University, Scotland, UK. He studied Biology/Zoology in Germany (Darmstadt and Mainz – PhD), worked as a post-doctoral Research Fellow in Magdeburg (Germany), York (England) and Edinburgh (Scotland) before accepting a post in Aberdeen. In addition, he also is honorary Professor at Wake Forest University in Winston-Salem, North Carolina - USA, and the Nencki Institute, Warsaw – Poland, and member of editorial boards of Behavioural Brain Research, Frontiers in Neuroscience, and Neuroscience and Neuroeconomics. GR has edited numerous special issues for neuroscience journals and has contributed to and organised symposia at meetings nationally and internationally.
Science: As a student in Biology, he developed an early interest in brain function and studied behaviour from lower vertebrates to mammals. To date, the central research focus concerns mechanisms for memory formation in their broadest sense (episodic, motor, habit), and how this knowledge can be translated to human disease. Consequently, the research group has established novel genetic and pharmacological models of major neurodegenerative and psychiatric disorders with cognitive dysfunction (Alzheimer, Parkinson, schizophrenia, depression, autism, Rett, obsessive-compulsive) and these are investigated using behavioural, cellular, biochemical, physiological and imaging endpoints in vivo and in vitro. A recent addition to this portfolio is the development of innovative wireless EEG devices for mice and the examination of sleep and sleep anomalies as biomarkers for neurological diseases.

Jacques Micheau.