Kelley Bromley‐Brits

The Morris Water Maze (MWM) was first established by neuroscientist Richard G. Morris in 1981 in order to test hippocampal-dependent learning, including acquisition of spatial memory and long-term spatial memory. The MWM is a relatively simple procedure typically consisting of six day trials, the main advantage being the differentiation between the spatial (hidden-platform) and non-spatial (visible platform) conditions. In addition, the MWM testing environment reduces odor trail interference. This has led the task to be used extensively in the study of the neurobiology and neuropharmacology of spatial learning and memory. The MWM plays an important role in the validation of rodent models for neurocognitive disorders such as Alzheimer's Disease. In this protocol we discussed the typical procedure of MWM for testing learning and memory and data analysis commonly used in Alzheimer's disease transgenic model mice.

Alzheimer's disease (AD) is the most common neurodegenerative disorder leading to dementia. Neuritic plaques are the hallmark neuropathology in AD brains. Proteolytic processing of amyloid-β precursor protein at the β site by beta-site amyloid-β precursor protein-cleaving enzyme 1 (BACE1) is essential to generate Aβ, a central component of the neuritic plaques. BACE1 is increased in some sporadic AD brains, and dysregulation of BACE1 gene expression plays an important role in AD pathogenesis. This review will focus on the regulation of BACE1 gene expression at the transcriptional, post-transcriptional, translation initiation, translational and post-translational levels, and its role in AD pathogenesis. Further studies on BACE1 gene expression regulation will greatly contribute to our understanding of AD pathogenesis and reveal potential novel approaches for AD prevention and drug development.

The Morris Water Maze (MWM) was first established by neuroscientist Richard G. Morris in 1981 in order to test hippocampal-dependent learning, including acquisition of spatial memoryand long-term spatial memory 1. The MWM is a relatively simple procedure typically consisting of six day trials, the main advantage being the differentiation between the spatial (hidden-platform) and non-spatial (visible platform) conditions 2-4. In addition, the MWM testing environment reduces odor trail interference 5. This has led the task to be used extensively in the study of the neurobiology and neuropharmacology of spatial learning and memory. The MWM plays an important role in the validation of rodent models for neurocognitive disorders such as Alzheimer’s Disease 6, 7. In this protocol we discussed the typical procedure of MWM for testing learning and memory and data analysis commonly used in Alzheimer’s disease transgenic model mice.

The presenilin-associated complex regulates two independent intramembranous cleavage activities, i.e. gamma-secretase and epsilon-secretase activity. The gamma-secretase complex requires four critical components for its activity: presenilin 1, anterior pharynx-defective 1, nicastrin 1 and presenilin enhancer 2, all of which are degraded through the ubiquitin-proteasome pathway. Recently, TMP21, a type I transmembrane protein involved in endoplasmic reticulum/Golgi transport, was identified as a member of the presenilin complex. Knockdown of TMP21 selectively regulated pathogenic gamma-secretase activity, resulting in increased amyloid beta protein 40 and 42, without affecting the epsilon-cleavage of Notch. A further understanding of TMP21 degradation is required to examine the biological consequences of TMP21 protein level aberrations and their potential role in the pathogenesis of Alzheimer's disease and drug development. Here we show that human TMP21 has a short half-life of approximately 3 h. Treatment with proteasomal inhibitors can increase TMP21 protein levels in both a time- and dose-dependent manner, and both co-immunoprecipitation and immunofluorescent staining show that TMP21 is ubiquitinated. Inhibition of the lysosomal pathway failed to show a dose-dependent increase in TMP21 protein levels. Taken together, these results indicate that the degradation of TMP21, as with the other presenilin-associated gamma-secretase complex members, is mediated by the ubiquitin-proteasome pathway.

Cannabinoids have been shown to increase neurogenesis in adult brain, as well as protect neurons from excitotoxicity, calcium influx, inflammation, and ischemia. Recent studies have shown that synthetic cannabinoids can alleviate water maze impairments in rats treated with intracranial amyloid beta protein (Abeta); however it is unknown whether this effect is due to the cannabinoids' anti-inflammatory properties or whether it affects Abeta processing. Here we investigate whether cannabinoids have any effect on Alzheimer's disease in vivo. We found that HU210, a potent synthetic cannabinoid, did not improve water maze performance or a contextual fear conditioning task in an APP23/PS45 double transgenic mouse model of AD. HU210 had no effect on APP processing and Abeta generation, as well as neuritic plaque formation in the brains of AD transgenic mice. Our study showed that synthetic cannabinoid HU210 had no beneficial effects on AD neuropathology and behavioral deficits of AD model mice, which advises caution of such drug's application in AD therapies.