Gernot Riedel

• Prof in Systems Neuroscience
• University of Aberdeen

Tauopathies are a heterogeneous mixture of neurodegenerative disorders, including Alzheimer's disease and frontotemporal dementia (FTD), characterised by the accumulation of tau filaments in brain tissue. Tau protein aggregation is inhibited by hydromethylthionine (HMT), an effect that appeared to be prevented in clinical trials for subjects alread...

The European Quality In Preclinical Data (EQIPD) consortium was born from the fact that publications report challenges with the robustness, rigor, and/or validity of research data, which may impact decisions about whether to proceed with further preclinical testing or to advance to clinical testing, as well as draw conclusions on the predictability...

Background Recent advances in blood-based biomarker discovery are paving the way for simpler, more accessible diagnostic tools that can detect early signs of Alzheimer’s disease (AD). Recent successes in the development of amyloid-targeting immunotherapy approaches mark an important advancement in providing new options for the treatment of AD. We h...

Genetic associations with macroscopic brain networks can provide insights into healthy and aberrant cortical connectivity in disease. However, associations specific to dynamic functional connectivity in Alzheimer's disease are still largely unexplored. Understanding the association between gene expression in the brain and functional networks may pr...

One aspect of reproducibility in preclinical research that is frequently overlooked is the physical condition in which physiological, pharmacological, or behavioural recordings are conducted. In this study, the physical conditions of mice were altered through the attachments of wireless electrophysiological recording devices (Neural Activity Tracke...

and it is clear that AI-analysis is taking off in our field. Whilst large language models like ChatGPT have taken the world by storm in the last year, specialized applications like computer-vision based techniques to track the behaviors of animals have gone from straightforward location tracking a few years ago to the detailed and deep insights int...

One aspect of reproducibility in preclinical research that is frequently overlooked is the physical condition in which physiological, pharmacological or behavioural recordings are conducted. In this study, the physical conditions of mice were altered through the attachments of wireless electrophysiological recording devices (Neural Activity Tracker...

One aspect of reproducibility in preclinical research that is frequently overlooked is the physical condition in which physiological, pharmacological, or behavioural recordings are conducted. In this study, the physical conditions of mice were altered through the attachments of wireless electrophysiological recording devices (Neural Activity Tracke...

Basal forebrain cholinergic dysfunction, most likely linked with tau protein aggregation, is a characteristic feature of Alzheimer’s disease (AD). Recent evidence suggests that tau protein is a putative target for the treatment of dementia, and the tau aggregation inhibitor, hydromethylthionine mesylate (HMTM), has emerged as a potential disease-mo...

The accumulation of α-synuclein (α-Syn) into Lewy bodies is a hallmark of synucleinopathies, a group of neurological disorders that include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Small oligomers as well as larger fibrils of α-Syn have been suggested to induce cell toxicity leading to a degenerative loss of neurones. A richer...

Metabolic disorders such as diabetes and obesity are linked to neurodegenerative diseases, with evidence of decreased brain glucose metabolism and insulin resistance in patients with dementia. Given the rising prevalence of age-related diseases, lifestyle adjustments and nutritional interventions are gaining interest. Dietary methionine restriction...

Background Apathy is the most common behavioural and psychological symptom in neurodegenerative diseases like Alzheimer’s disease (AD), frontotemporal dementia (FTD) or Parkinson’s disease (PD). Apathy typically includes a loss of motivation, initiative and interest, listlessness and indifference, flattening of emotions, absence of drive and passio...

Background Alzheimer disease (AD) has attracted considerable interest in novel therapies. Two Phase III trials by TauRx Pharmaceuticals (TRx‐005, TRx‐015) failed to attain their endpoints. A significant number of recruits, however, remained on symptomatic treatment and a post‐hoc analysis confirmed this sub‐cohort was selectively resilient against...

Background Alzheimer’s Disease (AD) is a common neurodegenerative disorder for which tau pathology is implicated. Abnormal forms of tau, which trigger neuronal dysfunction, can offer a therapeutic target. The main purpose of this study was to determine the effect of two new tau aggregation inhibitors here termed A and B, synthesised by TauRx Therap...

Background A key aspect of synaptic dysfunction in Alzheimer’s disease (AD) is loss of synaptic proteins. Previous publications showed that the presynaptic machinery is more strongly affected than postsynaptic proteins. However, it has also been reported that presynaptic protein loss is highly variable and shows region- and protein-specificity. Ob...

Background: ANY-Maze and EthoVision XT are two commonly used automated animal tracking systems employed to produce reliable and consistent results in behavioural paradigms. Data obtained with both tracking systems have presented differences, particularly when varying laboratory lighting conditions and contrasts of mice coat colour against the aren...

Genetic associations with macroscopic brain networks can provide insights into healthy and aberrant cortical connectivity in disease. However, associations specific to dynamic functional connectivity in Alzheimer's disease are still largely unexplored. Understanding the association between gene expression in the brain and functional connectivity ma...

Tau protein aggregations are important contributors to the etiology of Alzheimer's disease (AD). Hydromethylthionine (HMT) is a potent inhibitor of tau aggregation in vitro and in vivo and is being developed as a possible anti-dementia medication. HMT was also shown to affect the cholinergic system and to interact with mitochondria. Here, we used t...

In recent years, the use of insufficiently characterised control subjects has been a contributing factor to increasing irreproducibility in different areas of biomedical research including neuroscience and metabolism. There is now a growing awareness of phenotypic differences between the metabolic profiles of C57BL/6 substrains which are commonly u...

Parkinson's disease (PD) is a heterogeneous multi‐systemic disorder unique to humans characterized by motor and non‐motor symptoms. Preclinical experimental models of PD present limitations and inconsistent neurochemical, histological, and behavioral readouts. The 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of PD is the most com...

The EQIPD framework for rigor in animal experiments aims to unify current recommendations based on evidence behind their rationale and was prospectively tested for feasibility in multicenter animal experiments.

The accumulation of alpha-synuclein (α-Syn) into Lewy bodies in cortical and subcortical regions has been linked to the pathogenesis of synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). While there is a strong link between synuclein aggregates and the reduction in dopamine function in the emergence of PD, less...

The tau protein aggregation inhibitor hydromethylthionine mesylate (HMTM) was shown recently to have concentration-dependent pharmacological activity in delaying cognitive decline and brain atrophy in phase 3 Alzheimer’s disease (AD) clinical trials; the activity was reduced in patients receiving symptomatic therapies. The methylthionine (MT) moiet...

The prevention of tau protein aggregations is a therapeutic goal for the treatment of Alzheimer's disease (AD), and hydromethylthionine (HMT) (also known as leucomethylthioninium‐mesylate [LMTM]), is a potent inhibitor of tau aggregation in vitro and in vivo. In two Phase 3 clinical trials in AD, HMT had greater pharmacological activity on clinical...

Background The prevalence of Alzheimer’s disease (AD) is greater in women compared to men, but the reasons for this remain unknown. This sex difference has been widely neglected in experimental studies using transgenic mouse models of AD. Objective Here, we studied behavior and molecular pathology of 5-month-old 5XFAD mice, which express mutated h...

Laboratory workflows and preclinical models have become increasingly diverse and complex. Confronted with the dilemma of a multitude of information with ambiguous relevance for their specific experiments, scientists run the risk of overlooking critical factors that can influence the planning, conduct and results of studies and that should have been...

The reproducibility crisis (or replication crisis) in biomedical research is a particularly existential and under-addressed issue in the field of behavioral neuroscience, where, in spite of efforts to standardize testing and assay protocols, several known and unknown sources of confounding environmental factors add to variance. Human interference i...

Abnormal aggregation of tau is the pathological hallmark of tauopathies including frontotemporal dementia (FTD). We have generated tau-transgenic mice that express the aggregation-prone P301S human tau (line 66). These mice present with early-onset, high tau load in brain and FTD-like behavioural deficiencies. Several of these behavioural phenotype...

Laboratory workflows and preclinical models have become increasingly diverse and complex. Confronted with the dilemma of assessing a multitude of information with ambiguous relevance for their specific experiments, scientists run the risk of overlooking critical factors that can influence the planning, conduct and results of studies and that should...

Introduction to the EQIPD quality system

While high risk of failure is an inherent part of developing innovative therapies, it can be reduced by adherence to evidence-based rigorous research practices. Numerous analyses conducted to date have clearly identified measures that need to be taken to improve research rigor. Supported through the European Union's Innovative Medicines Initiative,...

Background: The prevalence of Alzheimers Disease (AD) is greater in women compared to men, but the reasons for this remain unknown. This sex difference has been widely neglected in experimental studies using transgenic mouse models of AD. Objective: Here, we studied behaviour and molecular pathology of 5-month-old 5XFAD mice, which express mutated...

Aim The β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) has been identified as the central initiator of amyloid β (Aβ) generation in the brain, the key hallmark of Alzheimer's disease (AD). However, recent studies provided evidence that BACE1 also plays a crucial role in metabolic regulation, and we have shown that neuronal human B...

Background Basal forebrain cholinergic dysfunction, likely linked to tau aggregation pathology, is a characteristic feature of AD. Cholinergic neurons contain choline acetyltransferase (ChAT) and high‐affinity tropomyosin‐related kinase A (TrkA) and send efferents to cortex and hippocampus where they release acetylcholine (ACh). The vesicular acety...

Purkinje cells are the only output cell of the cerebellar cortex. Their spatiotemporal activity is controlled by molecular layer interneurons (MLIs) through GABAA receptor-mediated inhibition. Recently, it has been reported that the cerebellar cortex is required for consolidation of conditioned fear responses during fear memory formation. Although...

Synapse loss is associated with motor and cognitive decline in multiple neurodegenerative disorders, and the cellular redistribution of tau is related to synaptic impairment in tauopathies, such as Alzheimer’s disease and frontotemporal dementia. Here, we examined the cellular distribution of tau protein species in human tau overexpressing line 66...

This is volume 1 of the Measuring Behavior 2020-21 Conference. Volume 2 will follow when the conference takes place in October 2021. www.measuringbehavior.org.

Mental disorders represent a significant public health burden worldwide due to their high prevalence, chronically disabling nature, and substantial impact on quality of life. Despite growing knowledge of the pathological mechanisms that underlie the development of these disorders, a high percentage of patients do not respond to first-line clinical...

While high risk of failure is an inherent part of developing innovative therapies, it can be reduced by adherence to evidence-based rigorous research practices. Numerous analyses conducted to date have clearly identified measures that need to be taken to improve research rigor. Supported through the European Union’s Innovative Medicines Initiative,...

Novel object and social interaction tasks allow assessments of rodent cognition and social behavior. Here, we combined these tasks and defined unequivocal locations of interest. Our procedure, termed OF-NO-SI, comprised habituation to the open field (OF), novel object (NO) and social interaction (SI) stages. Habituation was measured within- and bet...

Background Hydromethylthionine is a potent inhibitor of pathological aggregation of tau and TDP-43 proteins. Objective To compare hydromethylthionine treatment effects at two doses and to determine how drug exposure is related to treatment response in bvFTD. Methods We undertook a 52-week Phase III study in 220 bvFTD patients randomized to compar...

An early and sizeable loss of basal forebrain cholinergic neurons is a well characterised feature associated with measurable deficits in spatial learning and cognitive impairment in Alzheimer’s disease patients. In addition, pro-inflammatory glial cells such as astrocytes and microglia may also play a key role in the neurodegenerative cascade of Al...

Background Symptomatic treatments of Alzheimer’s disease (AD) with cholinesterase inhibitors and/or memantine are relatively ineffective and there is a need for new treatments targeting the underlying pathology of AD. In most of the failed disease-modifying trials, patients have been allowed to continue taking symptomatic treatments at stable doses...

The primeval function of the mammalian hippocampus (HPC) remains uncertain. Implicated in learning and memory, spatial navigation, and neuropsychological disorders, evolutionary theory suggests that the HPC evolved from a primeval chemosensory epithelium. Deficits in sensing of internal body status ('interoception') in patients with HPC lesions arg...

Background Although hydromethylthionine is a potent tau aggregation inhibitor, no difference was found in either of two Phase III trials in mild to moderate Alzheimer’s disease (AD) comparing doses in the range 150–250 mg/day with 8 mg/day intended as a control. Objective To determine how drug exposure is related to treatment response. Methods A...

The primeval function of the mammalian hippocampus (HPC) remains uncertain. Implicated in learning and memory, spatial navigation, and neuropsychological disorders, evolutionary theory suggests that the HPC evolved from a primeval chemosensory epithelium. Internal sensing deficits in patients with HPC lesions argue that internal sensing may be cons...

Pathological accumulation of misfolded α-synuclein (α-syn) in the brain plays a key role in the pathogenesis of Parkinson’s disease, leading to neuronal dysfunction and motor disorders. The underlying mechanisms linking α-Syn aggregations with neurotransmitter disturbance in Parkinson’s brains are not well characterized. In the present study, we in...

Behavioural flexibility is the ability to switch between tasks and strategies following a change in rules, and involves intact functioning of the medial prefrontal cortex. Impairments of behavioural flexibility have frequently been reported in patients with schizophrenia and rodents with disruption/dysfunction of the prefrontal cortex. The discover...

Gene mutations within amyloid precursor protein (APP or AβPP) and/or presenilin 1 (PS1) genes are determinants of familial Alzheimer’s disease (fAD) and remain fundamental for experimental models. Here, we generated a neuronal knock-in mouse (PLB2APP) with mutated human APP Swe/Lon and investigated histopathology and behavioral phenotypes. Addition...

Background: Rodent electroencephalography (EEG) in preclinical research is frequently conducted in behaving animals. EEG analysis is complicated by a number of confounds, particularly 1. The close relationship between EEG power and movement speed must be controlled for prior to further analysis. 2. The difficulty inherent in identifying EEG epochs...

Electroencephalography (EEG) records fast-changing neuronal signalling and communication and thus can offer a deep understanding of cognitive processes. However, traditional data analyses which employ the Fast-Fourier Transform (FFT) have been of limited use as they do not allow time- and frequency-resolved tracking of brain activity and detection...

α-Synuclein (α-Syn) aggregation is a pathological feature of synucleinopathies, neurodegenerative disorders that include Parkinson’s disease (PD). We have tested whether N,N,N′,N′-tetramethyl-10H-phenothiazine-3,7-diaminium bis(hydromethanesulfonate) (leuco-methylthioninium bis(hydromethanesulfonate); LMTM), a tau aggregation inhibitor, affects α-S...

Understanding the contribution of transmitter systems in behavioural pharmacology has a long tradition. Multiple techniques such as transmitter-specific lesions, and also localized administration of pharmacological toxins including agonists and antagonists of selected receptors have been applied. More recently, modern genetic tools have permitted c...

Background: Reproducibility of behavioural findings between laboratories is difficult due to behaviour being sensitive to environmental factors and interactions with genetics. The objective of this study was to investigate reproducibility of behavioural data between laboratories using the PhenoTyper home cage observation system and within laborato...

Background LMTM is being developed as a treatment for AD based on inhibition of tau aggregation. Objectives To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial in mild AD. Methods Mild AD patients (n = 800) were randomly assigned to 100 mg twice a day or 4 mg...

Alpha-Synuclein (α-Syn) accumulation is considered a major risk factor for the development of synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies. We have generated mice overexpressing full-length human α-Syn fused to a membrane-targeting signal sequence under the control of the mouse Thy1-promotor. Three separate lines...

In rodents, detection and quantification of motor impairments is difficult. The traction test (inverted grid with mice clinging to the underside) currently has no objective rating system. We here developed and validated the semi-automatic MATLAB script TracMouse for unbiased detection of video-recorded movement patterns. High precision videos were...

Aims: β-Secretase 1 (BACE1) is a key enzyme in Alzheimer's disease pathogenesis that catalyses the amyloidogenic cleavage of amyloid precursor protein (APP). Recently, global Bace1 deletion was shown to protect against diet-induced obesity and diabetes, suggesting that BACE1 is a potential regulator of glucose homeostasis. Here, we investigated wh...

These proceedings contain the papers presented at Measuring Behavior 2016, the 10th International Conference on Methods and Techniques in Behavioral Research. The conference was organised by Dublin City University in cooperation with the University of Aberdeen and Noldus. The conference was held during May 25-27, 2016 in Dublin, Ireland. We greeted...

The brain endocannabinoid system is a potential target for the treatment of psychiatric and metabolic conditions. Here, a novel CB 1 receptor antagonist (ABD459) was synthesized and assayed for pharmacological efficacy in vitro and for modulation of food consumption, vigilance staging and cortical electroencephalography in the mouse. ABD459 com...

Models of Tau pathology related to frontotemporal dementia (FTD) are essential to determine underlying neurodegenerative pathologies and resulting Tauopathy relevant behavioural changes. However, existing models are often limited in their translational value due to Tau overexpression, and the frequent occurrence of motor deficits which prevent comp...

High-mobility group box 1 (HMGB1) is a nuclear and cytosolic protein that is released during tissue damage from immune and non-immune cells — including microglia and neurons. HMGB1 can contribute to progression of numerous chronic inflammatory and autoimmune diseases which is mediated in part by interaction with the receptor for advanced glycation...

Dysfunction of parvalbumin (PV)-positive GABAergic interneurons (PVIs) within the prefrontal cortex (PFC) has been implicated in schizophrenia pathology. It is however unclear, how impaired signaling of these neurons may contribute to PFC dysfunction. To identify how PVIs contribute to PFC-dependent behaviors we inactivated PVIs in the PFC in mice...

Coefficient of variation (CV) and coefficient of error of the mean (CE) for stereological assessment of TH-positive neurons in the substantia nigra.

Coefficient of variation (CV) and coefficient of error of the mean (CE) for stereological assessment of TH-positive neurons in the substantia nigra.

Coefficient of variation (CV) and coefficient of error of the mean (CE) for stereological assessment of TH-positive neurons in the substantia nigra.

Parkinson's disease (PD) is the second most common neurodegenerative disease and results from the loss of dopaminergic neurons of the nigrostriatal pathway. The pathogenesis of PD is poorly understood, but inflammatory processes have been implicated. Indeed increases in the number of major histocompatibility complex II (MHC II) reactive cells have...

Neuronal β-secretase 1 (BACE1) is associated with pathogenesis of Alzheimer’s disease (AD) due to its role in amyloid production exerted via amyloid precursor protein (APP) cleavage. However, growing evidence suggests that BACE1 has multiple substrates other than APP, and its diverse actions may be involved in maintenance of glucose and insulin hom...

Deficiencies in social activities are hallmarks of numerous brain disorders. With respect to schizophrenia, social withdrawal belongs to the category of negative symptoms and is associated with deficits in the cognitive domain. Here, we used the N-methyl-D-aspartate receptor antagonist dizocilpine (MK-801) for induction of social withdrawal in rats...