Sleep architecture changes in the APP23 mouse model manifest at onset of cognitive deficits

Alzheimer's disease (AD), which accounts for most of the dementia cases, is, aside from cognitive deterioration, often characterized by the presence of non-cognitive symptoms such as activity and sleep disturbances. AD patients typically experience increased sleep fragmentation, excessive daytime sleepiness and night-time insomnia. Here, we sought to investigate the link between sleep architecture, cognition and amyloid pathology in the APP23 amyloidosis mouse model for AD. By means of polysomnographic recordings the sleep-wake cycle of freely-moving APP23 and wild-type (WT) littermates of 3, 6 and 12 months of age was examined. In addition, ambulatory cage activity was assessed by interruption of infrared beams surrounding the home cage. To assess visuo-spatial learning and memory a hidden-platform Morris-type Water Maze (MWM) experiment was performed. We found that sleep architecture is only slightly altered at early stages of pathology, but significantly deteriorates from 12 months of age, when amyloid plaques become diffusely present. APP23 mice of 12 months old had quantitative reductions of NREM and REM sleep and were more awake during the dark phase compared to WT littermates. These findings were confirmed by increased ambulatory cage activity during that phase of the light-dark cycle. No quantitative differences in sleep parameters were observed during the light phase. However, during this light phase, the sleep pattern of APP23 mice was more fragmented from 6 months of age, the point at which also cognitive abilities started to be affected in the MWM. Sleep time also positively correlated with MWM performance. We also found that spectral components in the EEG started to alter at the age of 6 months. To conclude, our results indicate that sleep architectural changes arise around the time the first amyloid plaques start to form and cognitive deterioration becomes apparent. These changes start subtle, but gradually worsen with age, adequately mimicking the clinical condition

Pentylenetetrazole-induced Seizure Susceptibility in the Tau58/4 Transgenic Mouse Model of Tauopathy

In several tauopathies such as Alzheimer's disease (AD), an increased incidence of seizures is observed. Tau, one of the major proteins implicated in AD pathology, is an important regulator of neural network excitability and might participate in the underlying epileptic cascade. However, the mechanisms underlying this relationship are not fully elucidated. We aim to investigate this mechanism by analyzing seizure susceptibility to the convulsant pentylenetetrazole (PTZ) in a novel rodent tauopathy model. A single dose of PTZ was systemically injected in Tau58/4 transgenic mice. To investigate whether young and aged heterozygous (HET) mice exhibit a higher susceptibility to seizures in comparison with wild-type (WT) littermates, video electroencephalography (EEG) in combination with behavioral scoring according to a modified Racine scale was used. The employment of different dosage groups enabled us to characterize the dose range reliably inducing seizures. Here, we report an increased seizure susceptibility in young but not in old HET Tau58/4 mice. Young HET animals displayed more severe seizures and had a reduced latency to the first seizure compared to WTs. Also, age-related differences in susceptibility could be demonstrated for both genotypes. Identification and targeting of secondary diseases such as epilepsy, which aggravate dementia and lead to earlier institutionalization, is key. This study finds that tau pathology itself is sufficient to alter seizure susceptibility in a rodent model, indicating that the disease process is crucial in the emergence of epilepsy in patients with tauopathy

Software for the frontiers of quantum chemistry:An overview of developments in the Q-Chem 5 package

This article summarizes technical advances contained in the fifth major release of the Q-Chem quantum chemistry program package, covering developments since 2015. A comprehensive library of exchange–correlation functionals, along with a suite of correlated many-body methods, continues to be a hallmark of the Q-Chem software. The many-body methods include novel variants of both coupled-cluster and configuration-interaction approaches along with methods based on the algebraic diagrammatic construction and variational reduced density-matrix methods. Methods highlighted in Q-Chem 5 include a suite of tools for modeling core-level spectroscopy, methods for describing metastable resonances, methods for computing vibronic spectra, the nuclear–electronic orbital method, and several different energy decomposition analysis techniques. High-performance capabilities including multithreaded parallelism and support for calculations on graphics processing units are described. Q-Chem boasts a community of well over 100 active academic developers, and the continuing evolution of the software is supported by an “open teamware” model and an increasingly modular design

PTZ-induced seizures in mice require a revised Racine scale

Seizure severity in experimental models of epilepsy is often evaluated by means of the Racine scale, in spite of the use of seizure induction methods that are different from those of the original paper by Racine in 1972. In such cases, the use of this scale is not always justified because some seizure behaviors are significantly different from those originally described or not present at all. Correspondingly, the pentylenetetrazole (PTZ) model, which is frequently used for antiepileptic drug research, lacked an adequate assessment tool to measure seizure severity. In 2009, an adapted intensity scale for PTZ-induced seizures was already designed for rats. Here, we evaluated electroencephalographic (EEG) and behavioral parameters after a single PTZ injection, to determine whether this scale is also suitable for use in mouse studies. We found that the scale designed for rats is quite robust and can thus be applied to score seizure severity in mice. Yet, certain convulsive behaviors and EEG characteristics were distinct between species. Therefore, a species-specific scale was designed, which included the concomitant EEG characteristic next to the behavioral expressions we observed, in order to establish a user-friendly scoring scale for PTZ-induced seizures in mice. To evaluate applicability, we utilized the scale in a seizure susceptibility study of a transgenic mouse model. We demonstrated that the maximum severity scores obtained with the newly revised Racine scale highly correlated with the administered dose. Hence, the revised scale differentiates well between different classes of seizure severity. (C) 2019 The Authors. Published by Elsevier Inc

Sleep and Alzheimer's disease:A pivotal role for the suprachiasmatic nucleus

Alzheimer's disease (AD), which accounts for most of the dementia cases, is, aside from cognitive deterioration, often characterized by the presence of non-cognitive symptoms. Society is desperately in need for interventions that alleviate the economic and social burden related to AD. Circadian dysrhythmia, one of these symptoms in particular, immensely decreases the self-care ability of AD patients and is one of the main reasons of caregiver exhaustion. Studies suggest that these circadian disturbances form the root of sleep-wake problems, diagnosed in more than half of AD patients. Sleep abnormalities have generally been considered merely a consequence of AD pathology. Recent evidence suggests that a bidirectional relationship exists between sleep and AD, and that poor sleep might negatively impact amyloid burden, as well as cognition. The suprachiasmatic nucleus (SCN), the main circadian pacemaker, is subjected to several alterations during the course of the disease. Its functional deterioration might fulfill a crucial role in the relation between AD pathophysiology and the development of sleep abnormalities. This review aims to give a concise overview of the anatomy and physiology of the SCN, address how AD pathology precisely impacts the SCN and to what degree these alterations can contribute to the progression of the disease. (C) 2017 Elsevier Ltd. All rights reserved

Alzheimer's disease : neurotransmitters of the sleep-wake cycle

With aging, our sleeping pattern alters. Elderly often wake unrested because their sleep time and sleep efficacy is reduced. In Alzheimer's disease (AD) patients, these alterations are even more pronounced and may further aggravate cognitive decline. Therefore, sleep disturbances greatly impact self-care ability, caregiver exhaustion and institutionalization rate. Reestablishing an effective sleep-wake cycle in these patients still remains an unresolved challenge, partly because sleep physiology is quite complex and multiple neurotransmitter systems contribute to a single process. Gaining a better understanding of sleep physiology will be crucial for further research. Conjointly, animal models, along with a multidisciplinary approach, will be of great value to establish a common ground between AD and sleep disturbances and work towards a potential therapeutic application