REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer’s Disease

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Early Onset of Hypersynchronous Network Activity and Expression of a Marker of Chronic Seizures in the Tg2576 Mouse Model of Alzheimer’s Disease

Cortical and hippocampal hypersynchrony of neuronal networks seems to be an early event in Alzheimer’s disease pathogenesis. Many mouse models of the disease also present neuronal network hypersynchrony, as evidenced by higher susceptibility to pharmacologically-induced seizures, electroencephalographic seizures accompanied by spontaneous interictal spikes and expression of markers of chronic seizures such as neuropeptide Y ectopic expression in mossy fibers. This network hypersynchrony is thought to contribute to memory deficits, but whether it precedes the onset of memory deficits or not in mouse models remains unknown. The earliest memory impairments in the Tg2576 mouse model of Alzheimer’s disease have been observed at 3 months of age. We thus assessed network hypersynchrony in Tg2576 and non-transgenic male mice at 1.5, 3 and 6 months of age. As soon as 1.5 months of age, Tg2576 mice presented higher seizure susceptibility to systemic injection of a GABA_A receptor antagonist. They also displayed spontaneous interictal spikes on EEG recordings. Some Tg2576 mice presented hippocampal ectopic expression of neuropeptide Y which incidence seems to increase with age among the Tg2576 population. Our data reveal that network hypersynchrony appears very early in Tg2576 mice, before any demonstrated memory impairments.     

Intra-Individual Variability of Physical Activity in Older Adults With and Without Mild Alzheimer’s Disease

Physical activity shows promise for protection against cognitive decline in older adults with and without Alzheimer’s disease (AD). To better understand barriers to adoption of physical activity in this population, a clear understanding of daily and weekly activity patterns is needed. Most accelerometry studies report average physical activity over an entire wear period without considering the potential importance of the variability of physical activity. This study evaluated individual differences in the amount and intra-individual variability of physical activity and determined whether these differences could be predicted by AD status, day of wear, age, gender, education, and cardiorespiratory capacity. Physical activity was measured via accelerometry (Actigraph GT3X+) over one week in 86 older adults with and without AD (n = 33 and n = 53, respectively). Mixed-effects location-scale models were estimated to evaluate and predict individual differences in the amount and intra-individual variability of physical activity. Results indicated that compared to controls, participants with AD averaged 21% less activity, but averaged non-significantly greater intra-individual variability. Women and men averaged similar amounts of physical activity, but women were significantly less variable. The amount of physical activity differed significantly across days of wear. Increased cardiorespiratory capacity was associated with greater average amounts of physical activity. Investigation of individual differences in the amount and intra-individual variability of physical activity provided insight into differences by AD status, days of monitor wear, gender, and cardiovascular capacity. All individuals regardless of AD status were equally consistent in their physical activity, which may have been due to a highly sedentary sample and/or the early disease stage of those participants with AD. These results highlight the value of considering individual differences in both the amount and intra-individual variability of physical activity.     

Deterministic chaоs and the problem of predictability in population dynamics

The studies of the processes that can significantly influence the predictability in population dynamics are reviewed and the results of mathematical simulations of population dynamics are compared to the time series obtained in field observations. Considerable attention is given to the chaotic changes in population abundance. Some methods of numerical analysis of chaoticity and predictability of the time series are considered. The importance of comparing the results of mathematical simulation and observation data is tightly linked to problems in detecting chaos in the dynamics of natural populations and estimating the prevalence of chaotic regimes in nature. Insight into these problems can allow identification of the functional role of chaotic regimes in population dynamics.     

Mechanisms of Neural and Behavioral Dysfunction in Alzheimer’s Disease

This review critically examines progress in understanding the link between Alzheimer’s disease (AD) molecular pathogenesis and behavior, with an emphasis on the impact of amyloid-β. We present the argument that the AD research field requires more multifaceted analyses into the impacts of Alzheimer’s pathogenesis which combine simultaneous molecular-, circuit-, and behavior-level approaches. Supporting this argument is a review of particular research utilizing similar, “systems-level” methods in mouse models of AD. Related to this, a critique of common physiological and behavioral models is made—highlighting the likely usefulness of more refined and specific tools in understanding the relationship between candidate molecular pathologies and behavioral dysfunction. Finally, we propose challenges for future research which, if met, may greatly extend our current understanding of how AD molecular pathology impacts neural network function and behavior and possibly may lead to refinements in disease therapeutics.     

Features of ceruloplasmin in the cerebrospinal fluid of Alzheimer’s disease patients

The level of the apo-form of the copper enzyme ceruloplasmin (CP) is an established peripheral marker in diseases associated with copper imbalance. In view of the proposal that disturbances of copper homeostasis may contribute to neurodegeneration associated with Alzheimer’s disease (AD), the present work investigates, by Western blot and non-reducing SDS-PAGE followed by activity staining, the features of CP protein, and the copper/CP relationship in cerebrospinal fluid (CSF) and serum of AD patients. Results show that only a fraction of total copper is associated with CP in the CSF, at variance with serum, both in affected and in healthy individuals. Furthermore, a conspicuous amount of apo-ceruloplasmin and a decrease of CP oxidase activity characterize the CSF of the affected individuals, and confirm that an impairment of copper metabolism occurs in their central nervous system. In the CSF of AD patients the decrease of active CP, associated with the increase in the pool of copper not sequestered by this protein, may play a role in the neurodegenerative process.     

Geographical Variability of the Craniological Characters in Eversmann’s Hamsters and the Taxonomic Structure of the Genus Allocricetulus (Cricetidae)

Biology Bulletin - The genus Allocricetulus at presently includes three taxa. The taxonomic status of two of them, A. eversmanni (Eversmann’s hamster) and A. curtatus (Mongolian...     

Is the Periodic “Spontaneous” Activity of Animals Determined by a Quasi-Rhythmic Factor of the External Environment?

Doklady Biological Sciences - We have studied the dynamics of the singing of garden bunting (Emberiza hortulana) and the dispersal of a flock of starlings (Sturnus vulgaris) for the night rest. The...     

It’s a Lipid’s World: Bioactive Lipid Metabolism and Signaling in Neural Stem Cell Differentiation

Lipids are often considered membrane components whose function is to embed proteins into cell membranes. In the last two decades, studies on brain lipids have unequivocally demonstrated that many lipids have critical cell signaling functions; they are called “bioactive lipids”. Pioneering work in Dr. Robert Ledeen’s laboratory has shown that two bioactive brain sphingolipids, sphingomyelin and the ganglioside GM1 are major signaling lipids in the nuclear envelope. In addition to derivatives of the sphingolipid ceramide, the bioactive lipids discussed here belong to the classes of terpenoids and steroids, eicosanoids, and lysophospholipids. These lipids act mainly through two mechanisms: (1) direct interaction between the bioactive lipid and a specific protein binding partner such as a lipid receptor, protein kinase or phosphatase, ion exchanger, or other cell signaling protein; and (2) formation of lipid microdomains or rafts that regulate the activity of a group of raft-associated cell signaling proteins. In recent years, a third mechanism has emerged, which invokes lipid second messengers as a regulator for the energy and redox balance of differentiating neural stem cells (NSCs). Interestingly, developmental niches such as the stem cell niche for adult NSC differentiation may also be metabolic compartments that respond to a distinct combination of bioactive lipids. The biological function of these lipids as regulators of NSC differentiation will be reviewed and their application in stem cell therapy discussed.     

A Validated Smartphone-Based Assessment of Gait and Gait Variability in Parkinson’s Disease

Background

A well-established connection exists between increased gait variability and greater fall likelihood in Parkinson’s disease (PD); however, a portable, validated means of quantifying gait variability (and testing the efficacy of any intervention) remains lacking. Furthermore, although rhythmic auditory cueing continues to receive attention as a promising gait therapy for PD, its widespread delivery remains bottlenecked. The present paper describes a smartphone-based mobile application (“SmartMOVE”) to address both needs.

Methods

The accuracy of smartphone-based gait analysis (utilizing the smartphone’s built-in tri-axial accelerometer and gyroscope to calculate successive step times and step lengths) was validated against two heel contact–based measurement devices: heel-mounted footswitch sensors (to capture step times) and an instrumented pressure sensor mat (to capture step lengths). 12 PD patients and 12 age-matched healthy controls walked along a 26-m path during self-paced and metronome-cued conditions, with all three devices recording simultaneously.

Results

Four outcome measures of gait and gait variability were calculated. Mixed-factorial analysis of variance revealed several instances in which between-group differences (e.g., increased gait variability in PD patients relative to healthy controls) yielded medium-to-large effect sizes (eta-squared values), and cueing-mediated changes (e.g., decreased gait variability when PD patients walked with auditory cues) yielded small-to-medium effect sizes—while at the same time, device-related measurement error yielded small-to-negligible effect sizes.

Conclusion

These findings highlight specific opportunities for smartphone-based gait analysis to serve as an alternative to conventional gait analysis methods (e.g., footswitch systems or sensor-embedded walkways), particularly when those methods are cost-prohibitive, cumbersome, or inconvenient.     

Neuronal Activity of the Subthalamic Nucleus in Patients with Parkinson’s Disease

The discharge activity of 637 neurons of the human subthalamic nucleus (STN), which were extracellularly recorded during twelve stereotactic surgeries in patients with Parkinson’s disease, has been analyzed. On the basis of the parameters of interspike intervals (ISIs), we have distinguished three major patterns of spontaneous neuronal activity: bursting neurons, regular tonic and irregular tonic neurons. Parametric analysis has enabled us to determine the values of basic parameters in the activity of these three distinguished types of neurons. It has been shown that the representativeness and the activity parameters of three different patterns change in the dorsoventral direction of the STN from the motor to the associative regions. The results will allow researchers to perform targeted search of pathological neuronal activity patterns associated with the motor symptoms of Parkinsonism.     

Variability of Stepping during a Virtual Reality Paradigm in Parkinson’s Disease Patients with and without Freezing of Gait

Background

Freezing of gait is a common and debilitating symptom affecting many patients with advanced Parkinson’s disease. Although the pathophysiology of freezing of gait is not fully understood, a number of observations regarding the pattern of gait in patients with this symptom have been made. Increased ‘Stride Time Variability’ has been one of the most robust of these features. In this study we sought to identify whether patients with freezing of gait demonstrated similar fluctuations in their stepping rhythm whilst performing a seated virtual reality gait task that has recently been used to demonstrate the neural correlate of the freezing phenomenon.

Methods

Seventeen patients with freezing and eleven non-freezers performed the virtual reality task twice, once whilst ‘On’ their regular Parkinsonian medication and once in their practically defined ‘Off’ state.

Results

All patients displayed greater step time variability during their ‘Off’ state assessment compared to when medicated. Additionally, in the ‘Off’ state, patients with freezing of gait had greater step time variability compared to non-freezers. The five steps leading up to a freezing episode in the virtual reality environment showed a significant increase in step time variability although the final three steps preceding the freeze were not characterized by a progressive shortening of latency.

Conclusions

The results of this study suggest that characteristic features of gait disturbance observed in patients with freezing of gait can also be demonstrated with a virtual reality paradigm. These findings suggest that virtual reality may offer the potential to further explore the freezing phenomenon in Parkinson’s disease.     

Is Modulation of the Rate of Proton Pumping a Key Event in Osmoregulation?

The net uptake of 3-O-methylglucose into leaf segments obtained from Senecio mikanioides Otto, and net proton efflux from the segments, were both promoted when the osmotic potential of the medium was decreased by addition of mannitol, sorbitol, or polyethylene glycol (optimal osmolarity, 0.3 Osmolar for mannitol and sorbitol). The effect was not due to promotion of `aging', since the antibiotic cerulenin suppressed aging without reducing the size of the mannitol stimulation; further, mannitol did not accelerate aging. Neither was the effect ascribable to diminished efflux (i.e. reduced `leak' because: first, visualization of the unidirectional sugar fluxes by double labeling indicated that the effect of added osmoticum was to promote influx rather than to reduce efflux; second, compartment analysis did not suggest any effect of mannitol on the rate constants for efflux from either the slowly equilibrating or more rapidly equilibrating compartment. The effect was not specific to poly-ols since it was also obtained with betaine and choline chloride. Since methyl glucose is not taken up into the phloem it could not be ascribed to a turgor effect on phloem loading. We conclude that the effect may reflect osmoregulation. As the sugar flux is probably driven by protonmotive force, it is likely that the effects on proton flux and on sugar flux are related. We suggest that the plasmalemma-sited proton pump is sensitive to the hydrostatic pressure gradient across the plasmalemma-cell wall complex, and functions both as detector and as effector in osmoregulation.     

Boron — Key element in the actions of phytochrome and gravity?

Hypocotyl sections from dark-grown mung bean (Vigna radiata (L.) Wilczek) seedlings grown without boron exhibit little or no increase in the translocation of fluorescein in phloem cells following gravitational stimulation or red irradiation. In contrast, pretreatment of the hypocotyl sections with low concentrations of boric acid before red irradiation or gravitational stimulation results in a rapid increase in fluorescein movement. Mung bean root tips without boron fail to remain attached to a negativelycharged glass surface after several minutes of red irradiation. A low boron concentration in the solution induces tip attachment. The suggestion is made that boron is required to stabilize a positive electrostatic charge in the plasma membrane that is generated by the actions of phytochrome and gravity.     

Movement Preparation and Bilateral Modulation of Beta Activity in Aging and Parkinson’s Disease

In previous studies of young subjects performing a reaction-time reaching task, we found that faster reaction times are associated with increased suppression of beta power over primary sensorimotor areas just before target presentation. Here we ascertain whether such beta decrease similarly occurs in normally aging subjects and also in patients with Parkinson’s disease (PD), where deficits in movement execution and abnormalities of beta power are usually present. We found that in both groups, beta power decreased during the motor task in the electrodes over the two primary sensorimotor areas. However, before target presentation, beta decreases in PD were significantly smaller over the right than over the left areas, while they were symmetrical in controls. In both groups, functional connectivity between the two regions, measured with imaginary coherence, increased before the target appearance; however, in PD, it decreased immediately after, while in controls, it remained elevated throughout motor planning. As in previous studies with young subjects, the degree of beta power before target appearance correlated with reaction time. The values of coherence during motor planning, instead, correlated with movement time, peak velocity and acceleration. We conclude that planning of prompt and fast movements partially depends on coordinated beta activity of both sensorimotor areas, already at the time of target presentation. The delayed onset of beta decreases over the right region observed in PD is possibly related to a decreased functional connectivity between the two areas, and this might account for deficits in force programming, movement duration and velocity modulation.