The involvement of cell cycle events in the pathogenesis of Alzheimer's disease

Most neurons undergo their last cell division within the first 1 to 2% of the lifespan of an organism. This has been interpreted to mean that adult neurons are permanently postmitotic, but Alzheimer's disease (AD) is an example of a late-onset neurodegenerative disease that challenges this concept. In AD, neurons in populations at risk for death reactivate their cell cycle and replicate their genome - but rather than complete the cycle with mitosis and cytokinesis, the neurons die. While opening new perspectives on the etiology of AD dementia, the simple linear model suggested by this description gains in complexity with the maturation of the adult brain. This complexity makes the full understanding of the relationship between cell division and cell death more difficult to achieve. The quest for understanding is worthwhile, however, as fresh avenues for therapeutic intervention are the prizes for success

Alzheimer's disease and the axon initial segment: a powerful new disease model

The dominant hypothesis of Alzheimer's disease initiation and progression is known as the amyloid cascade hypothesis. The core of this hypothesis is that the amyloid precursor protein (APP) is cleaved by two proteases (the b- and g-secretases) to produce a small peptide known as b-amyloid, which aggregates and serves as a disease causing agent. One of the strongest arguments supporting the amyloid cascade hypothesis is that mutations in either APP or the g-secretase are fully penetrant disease genes that lead to aggressive, early-onset forms of Alzheimer's disease. While the genetics identify APP, not b-amyloid per se, the field has nonetheless accepted the amyloid connection. We have preliminary evidence that offers a much more direct connection to APP that does not involve b-amyloid. We propose a cross-disciplinary set of experiments to test one aspect of this new idea. Specifically, we find that APP interacts with the two main structural proteins of the axon initial segment (AIS) – bIV-spectrin and AnkyrinG. The AIS is the specialized part of the axon where voltage sensitive ion channels are concentrated, allowing the generation of an action potential, the unit of neuronal activity. When APP levels rise the AIS is shifted away from the cell body and shortens, thus reducing neuronal excitability, potentially mimicking the condition of the AD brain. We propose to use state of the art network analysis hardware and software to analyse the functioning of neural networks in dissociated cortical cell cultures. We will then transfect APP-expressing plasmids into the cells of the culture and monitor the changing network dynamics. This will allow the altered AIS geometry to be directly linked to altered network function. With these preliminary data in hand we will be in a strong position to submit and R01 application to the NIH for enhanced funding

The study of personality preschool children in modern foreign research

The article deals with the problem of studying and describing the personality of the child in the preschool age. Provides the review of modern foreign studies on this issue. Grounded the importance of age characteristics for describing the structure of the child's personality.В статье рассматривается проблема изучения и описания личности ребенка в дошкольном возрасте. Представлен обзор современных зарубежных исследований, посвященных данному вопросу. Обосновывается важность возрастных характеристик для описания структуры личности ребенка

Viewing garden scenes: Interaction between gaze behavior and physiological responses

Previous research has shown that exposure to Japanese gardens reduces physiological measures of stress, e.g. heart rate, in both healthy subjects and dementia patients. However, the correlation between subjects’ physiological responses and their visual behavior while viewing the garden has not yet been investigated. To address this, we developed a system to collect simultaneous measurements of eye gaze and three physiological indicators of autonomic nervous system activity: electrocardiogram, blood volume pulse, and galvanic skin response. We recorded healthy subjects’ physiological/behavioral responses when they viewed two environments (an empty courtyard and a Japanese garden) in two ways (directly or as a projected 2D photograph). Similar to past work, we found that differences in subject’s physiological responses to the two environments when viewed directly, but not as a photograph. We also found differences in their behavioral responses. We quantified subject’s behavioral responses using several gaze metrics commonly considered to be measures of engagement of focus: average fixation duration, saccade amplitude, spatial entropy and gaze transition entropy. We found decrease in gaze transition entropy, the only metric that accounts for both the spatial and temporal properties of gaze, to have a weak positive correlation with decrease in heart rate. This suggests a relationship between engagement/focus and relaxation. Finally, we found gender differences: females’ gaze patterns were more spatially distributed and had higher transition entropy than males

Re-cycling paradigms: cell cycle regulation in adult hippocampal neurogenesis and implications for depression

Since adult neurogenesis became a widely accepted phenomenon, much effort has been put in trying to understand the mechanisms involved in its regulation. In addition, the pathophysiology of several neuropsychiatric disorders, such as depression, has been associated with imbalances in adult hippocampal neurogenesis. These imbalances may ultimately reflect alterations at the cell cycle level, as a common mechanism through which intrinsic and extrinsic stimuli interact with the neurogenic niche properties. Thus, the comprehension of these regulatory mechanisms has become of major importance to disclose novel therapeutic targets. In this review, we first present a comprehensive view on the cell cycle components and mechanisms that were identified in the context of the homeostatic adult hippocampal neurogenic niche. Then, we focus on recent work regarding the cell cycle changes and signaling pathways that are responsible for the neurogenesis imbalances observed in neuropathological conditions, with a particular emphasis on depression

The International Human Epigenome Consortium: A Blueprint for Scientific Collaboration and Discovery

The International Human Epigenome Consortium (IHEC) coordinates the generation of a catalog of high-resolution reference epigenomes of major primary human cell types. The studies now presented (see the Cell Press IHEC web portal at http://www.cell.com/consortium/IHEC) highlight the coordinated achievements of IHEC teams to gather and interpret comprehensive epigenomic datasets to gain insights in the epigenetic control of cell states relevant for human health and disease

DNA damage and cell cycle events implicate cerebellar dentate nucleus neurons as targets of Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Although the cerebellum is considered to be predominantly involved in fine motor control, emerging evidence documents its participation in language, impulsive behavior and higher cognitive functions. While the specific connections of the cerebellar deep nuclei (CDN) that are responsible for these functions are still being worked out, their deficiency has been termed "cerebellar cognitive affective syndrome" - a syndrome that bears a striking similarity to many of the symptoms of Alzheimer's disease (AD). Using ectopic cell cycle events and DNA damage markers as indexes of cellular distress, we have explored the neuropathological involvement of the CDN in human AD.</p> <p>Results</p> <p>We examined the human cerebellar dentate nucleus in 22 AD cases and 19 controls for the presence of neuronal cell cycle events and DNA damage using immunohistochemistry and fluorescence in situ hybridization. Both techniques revealed several instances of highly significant correlations. By contrast, neither amyloid plaque nor neurofibrillary tangle pathology was detected in this region, consistent with previous reports of human cerebellar pathology. Five cases of early stage AD were examined and while cell cycle and DNA damage markers were well advanced in the hippocampus of all five, few indicators of either cell cycle events (1 case) or a DNA damage response (1 case) were found in CDN. This implies that CDN neurons are most likely affected later in the course of AD. Clinical-pathological correlations revealed that cases with moderate to high levels of cell cycle activity in their CDN are highly likely to show deficits in unorthodox cerebellar functions including speech, language and motor planning.</p> <p>Conclusion</p> <p>Our results reveal that the CDN neurons are under cellular stress in AD and suggest that some of the non-motor symptoms found in patients with AD may be partly cerebellar in origin.</p