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Inhibition of the cyclic‐AMP degrading enzyme phosphodiesterase type 4 (PDE4) in the brains of animal models is protective in Alzheimer's disease (AD). We show for the first time that enzymes from the subfamily PDE4D not only colocalize with beta‐amyloid (Aβ) plaques in a mouse model of AD but that Aβ directly associates with the catalytic machinery of the enzyme. Peptide mapping suggests that PDE4D is the preferential PDE4 subfamily for Aβ as it possesses a unique binding site. Intriguingly, exogenous addition of Aβ to cells overexpressing the PDE4D5 longform caused PDE4 activation and a decrease in cAMP. We suggest a novel mechanism where PDE4 longforms can be activated by Aβ, resulting in the attenuation of cAMP signalling to promote loss of cognitive function in AD. [ABSTRACT FROM AUTHOR]

Microglia activity can drive excessive synaptic loss during the prodromal phase of Alzheimer's disease (AD) and is associated with lowered cyclic adenosine monophosphate (cAMP) due to cAMP phosphodiesterase 4B (PDE4B). This study aimed to investigate whether long-term inhibition of PDE4B by A33 (3 mg/kg/day) can prevent synapse loss and its associated cognitive decline in APPswe/PS1dE9 mice. This model is characterized by a chimeric mouse/human APP with the Swedish mutation and human PSEN1 lacking exon 9 (dE9), both under the control of the mouse prion protein promoter. The effects on cognitive function of prolonged A33 treatment from 20 days to 4 months of age, was assessed at 7–8 months. PDE4B inhibition significantly improved both the working and spatial memory of APPswe/PSdE9 mice after treatment ended. At the cellular level, in vitro inhibition of PDE4B induced microglial filopodia formation, suggesting that regulation of PDE4B activity can counteract microglia activation. Further research is needed to investigate if this could prevent microglia from adopting their 'disease-associated microglia (DAM)' phenotype in vivo. These findings support the possibility that PDE4B is a potential target in combating AD pathology and that early intervention using A33 may be a promising treatment strategy for AD. [ABSTRACT FROM AUTHOR]

Sphingosine‐1‐phosphate receptor (S1PR) modulators are clinically used to treat relapse‐remitting multiple sclerosis (MS) and the early phase of progressive MS when inflammation still prevails. In the periphery, S1PR modulators prevent lymphocyte egress from lymph nodes, hence hampering neuroinflammation. Recent findings suggest a role for S1PR modulation in remyelination. As the Giα‐coupled S1P1 subtype is the most prominently expressed S1PR in oligodendrocyte precursor cells (OPCs), selective modulation (functional antagonism) of S1P1 may have direct effects on OPC functionality. We hypothesized that functional antagonism of S1P1 by ponesimod induces remyelination by boosting OPC differentiation. In the cuprizone mouse model of demyelination, we found ponesimod to decrease the latency time of visual evoked potentials compared to vehicle conditions, which is indicative of functional remyelination. In addition, the Y maze spontaneous alternations test revealed that ponesimod reversed cuprizone‐induced working memory deficits. Myelin basic protein (MBP) immunohistochemistry and transmission electron microscopy of the corpus callosum revealed an increase in myelination upon ponesimod treatment. Moreover, treatment with ponesimod alone or in combination with A971432, an S1P5 monoselective modulator, significantly increased primary mouse OPC differentiation based on O4 immunocytochemistry. In conclusion, S1P1 functional antagonism by ponesimod increases remyelination in the cuprizone model of demyelination and significantly increases OPC differentiation in vitro. [ABSTRACT FROM AUTHOR]

Background: Current treatment options for Alzheimer's disease (AD) are limited, inefficient, and often have serious side effects. Oxytocin is a neuropeptide implicated in a variety of central processes, such as social and reproductive behaviors. Among others, it has garnered attention in various domains of psychiatric research, while its role in the development and course of neurodegenerative disorders like AD is rather unknown. Objective: This study aimed to investigate the role of exogenous oxytocin administration on memory, specifically in view of AD, as a potential novel treatment option. Methods: We describe a novel treatment approach by using a relatively low dose of long-term intranasal oxytocin treatment, to restore memory deficits in female APPswePS1dE9 mice. Results: Female APPswePS1dE9 mice treated with oxytocin showed increased spatial memory performance in the object location task and improved working memory in the Y-Maze, while indicating decreased sociability. Conclusions: These results indicate that oxytocin is able to reverse acquired cognitive deficits in female APPswePS1dE9 mice. [ABSTRACT FROM AUTHOR]

Educational contracts define the parameters of teacher obligations to students, parents, and other stakeholders freeing teachers to design and implement instruction rather than trying to fulfill roles (counselor, social worker, parent) best filled by other stakeholders. Describes analogous contracts used in the business world and provides examples of prototype contracts for middle school students. (PEN)

Leptospirosis is a water borne zoonotic disease of global significance that is caused by pathogenic species of the genus Leptospira. Pathogenic leptospires live in the kidneys of reservoir or infected animals and are shed in their urine contaminating water, soil, etc. Rodents are considered the primary reservoir of leptospirosis, but little is known about the role of herpetofauna (non‐avian reptiles and amphibians) in the epidemiology of the disease. To address this, various species of amphibians and reptiles in the Cumberland Gap Region of the Central Appalachia were screened for the presence of Leptospira spp. Kidneys harvested from of a total of 116 amphibians and reptiles belonging to seven species of snakes, seven species of salamanders, seven species of frogs/toads, seven species of turtles and one species of lizards were tested using a highly specific TaqMan based qPCR that targets lipl32 gene of pathogenic Leptospira spp. Overall, 15 of the tested 116 amphibians and reptiles were positive (12.9%; 95% CI: 7.4%–20.4%). Of the 101 amphibians, 11 were positive (10.9%; 95% CI: 5.6%–18.7%), and 4 of the 15 reptiles tested positive (26.7%; 95% CI: 7.8%–55.1%). The amplified gene fragments of lipl32 from qPCR positive kidneys were sequenced and found to be identical with known pathogenic Leptospira spp. These results suggest that although the proportion of reptiles and amphibians transmitting pathogenic Leptospira spp. within the environment may be low as compared to rodents, they pose a risk to other susceptible hosts that share their habitats and may have role in maintaining a baseline infection in the environment. [ABSTRACT FROM AUTHOR]