Temporal and spatially controlled APP transgene expression using Cre-dependent alleles.

Although a large number of mouse models have been made to study Alzheimer's disease, only a handful allow experimental control over the location or timing of the protein being used to drive pathology. Other fields have used the Cre and the tamoxifen-inducible CreER driver lines to achieve precise spatial and temporal control over gene deletion and transgene expression, yet these tools have not been widely used in studies of neurodegeneration. Here, we describe two strategies for harnessing the wide range of Cre and CreER driver lines to control expression of disease-associated amyloid precursor protein (APP) in modeling Alzheimer's amyloid pathology. We show that CreER-based spatial and temporal control over APP expression can be achieved with existing lines by combining a Cre driver with a tetracycline-transactivator (tTA)-dependent APP responder using a Cre-to-tTA converter line. We then describe a new mouse line that places APP expression under direct control of Cre recombinase using an intervening lox-stop-lox cassette. Mating this allele with a CreER driver allows both spatial and temporal control over APP expression, and with it, amyloid onset. This article has an associated First Person interview with the first author of the paper.

The clock modulator Nobiletin mitigates astrogliosis-associated neuroinflammation and disease hallmarks in an Alzheimer's disease model.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder, and there is a pressing need to identify disease-modifying factors and devise interventional strategies. The circadian clock, our intrinsic biological timer, orchestrates various cellular and physiological processes including gene expression, sleep, and neuroinflammation; conversely, circadian dysfunctions are closely associated with and/or contribute to AD hallmarks. We previously reported that the natural compound Nobiletin (NOB) is a clock-enhancing modulator that promotes physiological health and healthy aging. In the current study, we treated the double transgenic AD model mice, APP/PS1, with NOB-containing diets. NOB significantly alleviated ß-amyloid burden in both the hippocampus and the cortex, and exhibited a trend to improve cognitive function in these mice. While several systemic parameters for circadian wheel-running activity, sleep, and metabolism were unchanged, NOB treatment showed a marked effect on the expression of clock and clock-controlled AD gene expression in the cortex. In accordance, cortical proteomic profiling demonstrated circadian time-dependent restoration of the protein landscape in APP/PS1 mice treated with NOB. More importantly, we found a potent efficacy of NOB to inhibit proinflammatory cytokine gene expression and inflammasome formation in the cortex, and immunostaining further revealed a specific effect to diminish astrogliosis, but not microgliosis, by NOB in APP/PS1 mice. Together, these results underscore beneficial effects of a clock modulator to mitigate pathological and cognitive hallmarks of AD, and suggest a possible mechanism via suppressing astrogliosis-associated neuroinflammation.

Inflammation increases the development of depression behaviors in male rats after spinal cord injury.

Following spinal cord injury, 18-26% of patients are diagnosed with depressive disorders, compared to 8-12% in the general population. As increased inflammation strongly correlates with depression in both animal and human studies, we hypothesized that the immune activation inherent to SCI could increase depression-like behavior. Thus, we proposed that reducing immune activation with minocycline, a microglial inhibitor, would decrease depression-like behavior following injury. Male Sprague-Dawley rats were given minocycline in their drinking water for 14 days following a moderate, mid-thoracic (T12) spinal contusion. An array of depression-like behaviors (social activity, sucrose preference, forced swim, open field activity) were examined prior to injury as well as on days 9-10, 19-20, and 29-30 post-injury. Peripheral cytokine levels were analyzed in serum collected prior to injury and 10 days post-injury. Hierarchical cluster analysis divided subjects into two groups based on behavior: depressed and not-depressed. Depressed subjects displayed lower levels of open field activity and social interaction relative to their not-depressed counterparts. Depressed subjects also showed significantly greater expression of pro-inflammatory cytokines both before and after injury and displayed lower levels of hippocampal neurogenesis than not-depressed subjects. Intriguingly, subjects who later showed depressive behaviors had higher baseline levels of the pro-inflammatory cytokine IL-6, which persisted throughout the duration of the experiment. Minocycline, however, did not affect serum cytokine levels and did not block the development of depression; equal numbers of minocycline versus vehicle-treated subjects appeared in both phenotypic groups. Despite this, these data overall suggest that molecular correlates of inflammation prior to injury could predict the development of depression after a physical stressor.

Effects of the Clock Modulator Nobiletin on Circadian Rhythms and Pathophysiology in Female Mice of an Alzheimer's Disease Model.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder and the most common cause of dementia. Various pathogenic mechanisms have been proposed to contribute to disease progression, and recent research provided evidence linking dysregulated circadian rhythms/sleep and energy metabolism with AD. Previously, we found that the natural compound Nobiletin (NOB) can directly activate circadian cellular oscillators to promote metabolic health in disease models and healthy aging in naturally aged mice. In the current study, using the amyloid-ß AD model APP/PS1, we investigated circadian, metabolic and amyloid characteristics of female mice and the effects of NOB. Female APP/PS1 mice showed reduced sleep bout duration, and NOB treatment exhibited a trend to improve it. While glucose tolerance was unchanged, female APP/PS1 mice displayed exaggerated oxygen consumption and CO2 production, which was mitigated by NOB. Likewise, cold tolerance in APP/PS1 was impaired relative to WT, and interestingly was markedly enhanced in NOB-treated APP/PS1 mice. Although circadian behavioral rhythms were largely unchanged, real-time qPCR analysis revealed altered expression of several core clock genes by NOB in the cerebral cortex, notably Bmal1, Npas2, and Rora. Moreover, NOB was also able to activate various clock-controlled metabolic genes involved in insulin signaling and mitochondrial function, including Igf1, Glut1, Insr, Irs1, Ucp2, and Ucp4. Finally, we observed that NOB attenuated the expression of several AD related genes including App, Bace1, and ApoE, reduced APP protein levels, and strongly ameliorated Aß pathology in the cortex. Collectively, these results reveal novel genotype differences and importantly beneficial effects of a natural clock-enhancing compound in biological rhythms and related pathophysiology, suggesting the circadian clock as a modifiable target for AD.

Aged Cattle Brain Displays Alzheimer's Disease-Like Pathology and Promotes Brain Amyloidosis in a Transgenic Animal Model.

Alzheimer's disease (AD) is one of the leading causes of dementia in late life. Although the cause of AD neurodegenerative changes is not fully understood, extensive evidence suggests that the misfolding, aggregation and cerebral accumulation of amyloid beta (Aß) and tau proteins are hallmark events. Recent reports have shown that protein misfolding and aggregation can be induced by administration of small quantities of preformed aggregates, following a similar principle by which prion diseases can be transmitted by infection. In the past few years, many of the typical properties that characterize prions as infectious agents were also shown in Aß aggregates. Interestingly, prion diseases affect not only humans, but also various species of mammals, and it has been demonstrated that infectious prions present in animal tissues, particularly cattle affected by bovine spongiform encephalopathy (BSE), can infect humans. It has been reported that protein deposits resembling Aß amyloid plaques are present in the brain of several aged non-human mammals, including monkeys, bears, dogs, and cheetahs. In this study, we investigated the presence of Aß aggregates in the brain of aged cattle, their similarities with the protein deposits observed in AD patients, and their capability to promote AD pathological features when intracerebrally inoculated into transgenic animal models of AD. Our data show that aged cattle can develop AD-like neuropathological abnormalities, including amyloid plaques, as studied histologically. Importantly, cow-derived aggregates accelerate Aß amyloid deposition in the brain of AD transgenic animals. Surprisingly, the rate of induction produced by administration of the cattle material was substantially higher than induction produced by injection of similar amounts of human AD material. Our findings demonstrate that cows develop seeding-competent Aß aggregates, similarly as observed in AD patients.

Modifiable Risk Factors for Alzheimer's Disease.

Since first described in the early 1900s, Alzheimer's disease (AD) has risen exponentially in prevalence and concern. Research still drives to understand the etiology and pathogenesis of this disease and what risk factors can attribute to AD. With a majority of AD cases being of sporadic origin, the increasing exponential growth of an aged population and a lack of treatment, it is imperative to discover an easy accessible preventative method for AD. Some risk factors can increase the propensity of AD such as aging, sex, and genetics. Moreover, there are also modifiable risk factors-in terms of treatable medical conditions and lifestyle choices-that play a role in developing AD. These risk factors have their own biological mechanisms that may contribute to AD etiology and pathological consequences. In this review article, we will discuss modifiable risk factors and discuss the current literature of how each of these factors interplay into AD development and progression and if strategically analyzed and treated, could aid in protection against this neurodegenerative disease.

Spirometric changes in fire-eating subjects in Mexico City.

BACKGROUND: Fire-eating is an activity mainly carried out by inner-city poorest subjects as a way to obtain money. Scant information has been reported concerning the consequences of this activity on lung function. METHODS: This study was accomplished in the streets of Mexico City by performing spirometric studies on 30 fire-eaters prior to and after their daily activity; in 16 of these subjects these studies were also conducted after salbutamol inhalation. RESULTS: All fire-eaters were males, 27.9 +/- 1.1 years of age (mean +/- standard error of the mean). Up to two thirds showed abnormalities in baseline spirometry (11 with an obstructive pattern and 9 with mixed pattern) not related to a smoking habit or drug abuse. Number of years in the fire-eating activity was inversely correlated with FEF50 (r=-0.46, p<0.01) and FEF75 (r=-0.33, p<0.05). Likewise, body mass index was inversely correlated with FEF25 and FEF50. These results were corroborated with multiple regression analysis. At the end of daily fire-eating activity, further diminution of FEF75 was observed (-7.6 +/- 1.4%, p<0.01). Aerosolized salbutamol caused statistically significant increment (p<0.05 to p<0.01) in nearly all spirometric variables, although on an individual basis only 10 of 16 (63%) had positive bronchodilation response. CONCLUSIONS: Fire-eaters showed a mild decrease of airflows, which partially correlated with number of years spent in this activity. After a 1-day fire-eating activity, further airflow limitation increased. Up to 63% of subjects tested improved some spirometric airflow value after salbutamol inhalation.