David Cheng

Deletion of Abca7 increases cerebral amyloid-β accumulation in the J20 mouse model of Alzheimer's disease

ATP-binding cassette transporter A7 (ABCA7) is expressed in the brain and has been detected in macrophages, microglia, and neurons. ABCA7 promotes efflux of lipids from cells to apolipoproteins and can also regulate phagocytosis and modulate processing of amyloid precursor protein (APP) to generate the Alzheimers disease (AD) amyloid-β (Aβ) peptide. Genome-wide association studies have indicated that ABCA7 single nucleotide polymorphisms confer increased risk for late-onset AD; however, the role that ABCA7 plays in the brain in the AD context is unknown. In the present study, we crossed ABCA7-deficient (A7−/−) mice with J20 amyloidogenic mice to address this issue. We show that ABCA7 loss doubled insoluble Aβ levels and thioflavine-S–positive plaques in the brain. This was not related to changes in APP processing (assessed by analysis of full-length APP and the APP β C-terminal fragment). Apolipoprotein E regulates cerebral Aβ homeostasis and plaque load; however, the apolipoprotein E concentration was not altered by ABCA7 loss. Spatial reference memory was significantly impaired in both J20 and J20/A7−/− mice compared with wild-type mice; however, there were no cognitive differences between J20 and J20/A7−/− mice. There were also no major differences detected in hippocampal or plaque-associated microglial/macrophage markers between J20 and J20/A7−/− mice, whereas the capacity for bone marrow-derived macrophages derived from A7−/− mice to take up oligomeric Aβ was reduced by 51% compared with wild-type mice. Our results suggest that ABCA7 plays a role in the regulation of Aβ homeostasis in the brain and that this may be related to altered phagocyte function.

Role of abca7 in mouse behaviours relevant to neurodegenerative diseases

ATP-binding cassette transporters of the subfamily A (ABCA) are responsible for the translocation of lipids including cholesterol, which is crucial for neurological function. Recent studies suggest that the ABC transporter ABCA7 may play a role in the development of brain disorders such as schizophrenia and Alzheimer’s disease. However, Abca7’s role in cognition and other behaviours has not been investigated. Therefore, we characterised homozygous Abca7 knockout mice in a battery of tests for baseline behaviours (i.e. physical exam, baseline locomotion and anxiety) and behaviours relevant to schizophrenia (i.e. prepulse inhibition and locomotor response to psychotropic drugs) and Alzheimer’s disease (i.e. cognitive domains). Knockout mice had normal motor functions and sensory abilities and performed the same as wild type-like animals in anxiety tasks. Short-term spatial memory and fear-associated learning was also intact in Abca7 knockout mice. However, male knockout mice exhibited significantly impaired novel object recognition memory. Task acquisition was unaffected in the cheeseboard task. Female mice exhibited impaired spatial reference memory. This phenomenon was more pronounced in female Abca7 null mice. Acoustic startle response, sensorimotor gating and baseline locomotion was unaltered in Abca7 knockout mice. Female knockouts showed a moderately increased motor response to MK-801 than control mice. In conclusion, Abca7 appears to play only a minor role in behavioural domains with a subtle sex-specific impact on particular cognitive domains.

Long-term cannabidiol treatment prevents the development of social recognition memory deficits in Alzheimer's disease transgenic mice

Impairments in cognitive ability and widespread pathophysiological changes caused by neurotoxicity, neuroinflammation, oxidative damage, and altered cholesterol homeostasis are associated with Alzheimers disease (AD). Cannabidiol (CBD) has been shown to reverse cognitive deficits of AD transgenic mice and to exert neuroprotective, anti-oxidative, and anti-inflammatory properties in vitro and in vivo. Here we evaluate the preventative properties of long-term CBD treatment in male AβPPSwe/PS1ΔE9 (AβPP × PS1) mice, a transgenic model of AD. Control and AD transgenic mice were treated orally from 2.5 months of age with CBD (20 mg/kg) daily for 8 months. Mice were then assessed in the social preference test, elevated plus maze, and fear conditioning paradigms, before cortical and hippocampal tissues were analyzed for amyloid load, oxidative damage, cholesterol, phytosterols, and inflammation. We found that AβPP × PS1 mice developed a social recognition deficit, which was prevented by CBD treatment. CBD had no impact on anxiety or associative learning. The prevention of the social recognition deficit was not associated with any changes in amyloid load or oxidative damage. However, the study revealed a subtle impact of CBD on neuroinflammation, cholesterol, and dietary phytosterol retention, which deserves further investigation. This study is the first to demonstrate CBDs ability to prevent the development of a social recognition deficit in AD transgenic mice. Our findings provide the first evidence that CBD may have potential as a preventative treatment for AD with a particular relevance for symptoms of social withdrawal and facial recognition.

Novel behavioural characteristics of the APPSwe/PS1ΔE9 transgenic mouse model of Alzheimer's disease

In order to better understand animal models of Alzheimers disease, novel phenotyping strategies have been established for transgenic mouse models. In line with this, the current study characterised male APPxPS1 transgenic mice on mixed C57BL/6JxC3H/HeJ background for the first time for social recognition memory, sensorimotor gating, and spatial memory using the cheeseboard test as an alternative to the Morris water maze. Furthermore, locomotion, anxiety, and fear conditioning were evaluated in transgenic and wild type-like animals. APPxPS1 males displayed task-dependent hyperlocomotion and anxiety behaviours and exhibited social recognition memory impairments compared to wild type-like littermates. Spatial learning and memory, fear conditioning, and sensorimotor gating were unaffected in APPxPS1 transgenic mice. In conclusion, this study describes for the first time social recognition memory deficits in male APPxPS1 mice and suggests that spatial learning and memory deficits reported in earlier studies are dependent on the sex and genetic background of the APPxPS1 mouse line used. Furthermore, particular test conditions of anxiety and spatial memory paradigms appear to impact on the behavioural response of this transgenic mouse model for Alzheimers disease.

Novel behavioural characteristics of female APPSwe/PS1ΔE9 double transgenic mice

Murine models are commonly used to evaluate progression of Alzheimers disease. APPSwe/PS1ΔE9 (APPxPS1) mice have previously been reported to demonstrate impaired learning and memory in the Morris water maze test. However, this paradigm introduces a variety of behaviours that may confound performance of the mice, thus an alternative was sought. A battery of behavioural tests (light-dark test, elevated plus maze, novel object recognition task, social recognition test, cheeseboard task and prepulse inhibition) was used to investigate various behavioural and cognitive domains with relevance to Alzheimers disease. We found 9-month old female APPxPS1 mice exhibited impaired spatial memory in the reversal cheeseboard task. In addition, task-dependent hyperlocomotion and anxiolytic-like behaviours were observed in the light-dark test. Female APPxPS1 demonstrated intact object recognition memory and sensorimotor gating was not significantly decreased compared to control mice except for one particular interstimulus interval. The social recognition test failed to detect preference for social novelty in control females. In conclusion, this is the first study to describe a memory deficit in female APPxPS1 mice in the hidden cheeseboard task. Transgenic females also exhibited task-dependent reduction in anxiety behaviours and hyperlocomotion. These novel findings enhance our understanding of the behavioural phenotype of APPxPS1 females and present the cheeseboard as a valid alternative to other established spatial memory tests. Furthermore, the task-dependency of some of our findings suggests that behavioural profiling of APPxPS1 transgenic mice should be assessed using a variety of behavioural paradigms.

Feeling positive and productive: role of supervisor–worker relationship in predicting construction workers’ performance in the Philippines

AbstractGiven the complex and dynamic nature of construction work, workers rely heavily on their supervisors for task allocation and ongoing guidance and support. Their relationships with superviso...

The therapeutic potential of the phytocannabinoid cannabidiol for Alzheimer's disease.

Alzheimers disease (AD) is the most common neurodegenerative disorder, characterized by progressive loss of cognition. Over 35 million individuals currently have AD worldwide. Unfortunately, current therapies are limited to very modest symptomatic relief. The brains of AD patients are characterized by the deposition of amyloid-β and hyperphosphorylated forms of tau protein. AD brains also show neurodegeneration and high levels of oxidative stress and inflammation. The phytocannabinoid cannabidiol (CBD) possesses neuroprotective, antioxidant and anti-inflammatory properties and reduces amyloid-β production and tau hyperphosphorylation in vitro. CBD has also been shown to be effective in vivo making the phytocannabinoid an interesting candidate for novel therapeutic interventions in AD, especially as it lacks psychoactive or cognition-impairing properties. CBD treatment would be in line with preventative, multimodal drug strategies targeting a combination of pathological symptoms, which might be ideal for AD therapy. Thus, this review will present a brief introduction to AD biology and current treatment options before outlining comprehensively CBD biology and pharmacology, followed by in-vitro and in-vivo evidence for the therapeutic potential of CBD. We will also discuss the role of the endocannabinioid system in AD before commenting on the potential future of CBD for AD therapy (including safety aspects).

The perils of dating your boss: The role of hierarchical workplace romance and sex on evaluators’ career advancement decisions for lower status romance participants

Engaging in romantic relationships at work, especially with one’s superiors (i.e., hierarchical workplace romance; [HWR]), has generally been shown to negatively impact the participants involved. However, less attention has focused on its impact on the career advancement of lower status romance participants and when such an impact is exacerbated. Two experiments show that third-party evaluators were less likely to promote (Study 1) and select lower status HWR participants for training opportunities (Study 2) than their counterparts not in an HWR. Moreover, the negative career ramification of an HWR was stronger for men romantically involved with their female superiors than women with their male superiors (Study 2). This research highlights the need for organizational members to be aware of biases associated with HWR and gender role–based status expectations because past achievements may be discounted for lower status HWR participants, especially men.

Does laughing at yourself help you work? Self-deprecating humor and performance

Many believe that the ability to laugh at oneself is beneficial in the workplace with many consultants and business journalists often prescribing its use. However, limited scholarly research exists to support these prescriptions. This paper examines the use of self- deprecating humour and its effect on performance. Self-deprecating humour is prevalent in the United Kingdom, Australia and New Zealand and is often seen as part of the culture. Findings from an experimental study (N=84) and a field study (N=165) show that laughing at oneself can be used to increase performance. However, laughing at oneself frequently may not lead to performance benefits and may actually lead to a decrease in work performance.