Chronic stresses such as loss of a spouse or sleep deprivation, may cause memory impairments and increase susceptibility to AD. Experimental models of stress demonstrate impairments in spatial memory, contextual memory and object recognition in response to psychosocial or environmental stress. Yet, it remains to be determined if and how environmental stress modifies the cellular and molecular alterations that result in cognitive deficits in normal aging and in AD. We are employing mouse models to test the hypothesis that chronic psychosocial stress and sleep deprivation will accelerate the development of cognitive impairment in normal aging and in AD. Using the triple-transgenic AD mouse model (3xTgAD mice) we are determining the effects of chronic stress on amyloidogenes, tau pathology, synaptic dysfunction and learning and memory impairment. We are testing the hypothesis that aging and AD compromise adaptive cellular stress response pathways resulting in increased oxidative stress associated with reduced expression of neuroprotective proteins such as brain-derived neurotrophic factor (BDNF) and antioxidant enzymes. In related studies we have found that, in a model of type 2 diabetes, overeating results in hyperactivation of the neuroendocrine stress system, and that elevated levels of adrenal glucocorticoids impair hippocampal synaptic plasticity and neurogenesis, and that these stress-related alterations are associated with a deficit in cognitive function. Interestingly, regular exercise and dietary energy restriction can counteract the adverse effects of diabetes on hippocampal plasticity by a mechanism involving up-regulation of the expression of the neurotrophic factor BDNF. Chronic stress may be a risk factor for developing Alzheimer's disease (AD), but most studies of the effects of stress in models of AD utilize acute adverse stressors of questionable clinical relevance. We therefore undertook a study to determine how chronic psychosocial stress affects behavioral and pathological outcomes in an animal model of AD, and to elucidate underlying mechanisms. A triple-transgenic mouse model of AD (3xTgAD mice) and nontransgenic control mice were used to test for an affect of chronic mild social stress on blood glucose, plasma glucocorticoids, plasma insulin, anxiety, and hippocampal amyloid, phosphorylated tau (ptau), and brain-derived neurotrophic factor (BDNF) levels. Despite the fact that both control and 3xTgAD mice experienced rises in corticosterone during episodes of mild social stress, at the end of the 6-week stress period 3xTgAD mice displayed increased anxiety, elevated levels of amyloid;oligomers and intraneuronal amyloid;, and decreased brain-derived neurotrophic factor levels, whereas control mice did not. Our findings suggest 3xTgAD mice are more vulnerable than control mice to chronic psychosocial stress, and that such chronic stress exacerbates amyloid;accumulation and impairs neurotrophic signaling. Parkinson's disease (PD) patients often exhibit impaired regulation of heart rate by the autonomic nervous system (ANS) that may precede motor symptoms in many cases. Results of autopsy studies suggest that brainstem pathology, including the accumulation of -synuclein, precedes damage to dopaminergic neurons in the substantia nigra in PD. However, the molecular and cellular mechanisms responsible for the early dysfunction of brainstem autonomic neurons are unknown. Here we report that mice expressing a mutant form of -synuclein that causes familial PD exhibit aberrant autonomic control of the heart characterized by elevated resting heart rate and an impaired cardiovascular stress response, associated with reduced parasympathetic activity and accumulation of -synuclein in the brainstem. These ANS abnormalities occur early in the disease process. Adverse effects of -synuclein on the control of heart rate are exacerbated by a high energy diet and ameliorated by intermittent energy restriction. Our findings establish a mouse model of early dysregulation of brainstem control of the cardiovascular system in PD, and further suggest the potential for energy restriction to attenuate ANS dysfunction, particularly in overweight individuals. Age-associated dysregulation of sleep can be worsened by Alzheimer's disease (AD). AD and sleep restriction both impair cognition, yet it is unknown if mild chronic sleep restriction modifies the proteopathic processes involved in AD. The goal of this work was to test the hypothesis that sleep restriction worsens memory impairments, and amyloid β-peptide (Aβ) and pTau accumulations in the brain in a mouse model of AD, with a focus on a role for circulating glucocorticoids (GC). Male 3xTgAD mice were subjected to sleep restriction (SR) for 6h/day for 6 weeks using the modified multiple platform technique, and behavioral (Morris water maze, fear conditioning, open field) and biochemical (immunoblot) outcomes were compared to mice undergoing daily cage transfers (large cage control;LCC) as well as control mice that remained in their home cage (control;CTL). At one week, both LCC and SR mice displayed significant elevations in plasma corticosterone compared to CTL (p<0.002). By four weeks, SR mice displayed a two-fold increase in circulating corticosterone levels compared to CTL. Behavioral data indicated deficits in contextual and cued memory in SR mice that were not present for LCC or CTL (p<0.04). Both Aβand pTau levels increased in the cortex of SR mice compared to CTL and LCC;however these changes were not noted in the hippocampus. Significant positive correlations between cortical Aβand pTau levels and circulating corticosterone indicate a potential role for GCs in mediating behavioral and biochemical changes observed after sleep restriction in a mouse model of AD. The ability to control impulses varies greatly, and difficulty with impulse control can have severe consequences;in the extreme, it is the defining feature of many psychiatric disorders. Evidence from disparate lines of research suggests that uric acid is elevated in psychiatric disorders characterized by high impulsivity, such as attention-deficit/hyperactivity disorder and bipolar disorder. The present research tests the hypothesis that impulsivity is associated with higher uric acid in humans and mice. Using two longitudinal, nonclinical community samples (total n = 6883), we tested whether there is an association between uric acid and normal variation in trait impulsivity measured with the Revised NEO Personality Inventory. We also examined the effect of uric acid on behavior by comparing wild-type mice, which naturally have low levels of uric acid, with mice genetically modified to accumulate high levels of uric acid. In both human samples, the emotional aspects of trait impulsivity, specifically impulsiveness and excitement seeking, were associated with higher levels of uric acid concurrently and when uric acid was measured 3 to 5 years later. Consistent with the human data, the genetically modified mice displayed significantly more exploratory and novelty-seeking behavior than the wild-type mice. Higher uric acid was associated with impulsivity in both humans and mice. The identification of biological markers of impulsivity may lead to a better understanding of the physiological mechanisms involved in impulsivity and may suggest potential targets for therapeutic intervention. Studying the progressive change in miRNAs modulation during aging of 3xTgAD mice, we identified miRNAs that were regulated in earlier stages of AD, suggesting them as potential AD biomarkers. We characterized AD- and EE-related effects in the mouse hippocampus on tomosyn, an inhibitor of the synaptic transmission machinery. While EE reduced tomosyn levels, tomosyn levels were increased in old mice.
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