Amyloid reduction by amyloid-beta vaccination also reduces mouse tau pathology and protects from neuron loss in two mouse models of Alzheimer's disease.

Shown to lower amyloid deposits and improve cognition in APP transgenic mouse models, immunotherapy appears to be a promising approach for the treatment of Alzheimer's disease (AD). Due to limitations in available animal models, however, it has been unclear whether targeting amyloid is sufficient to reduce the other pathological hallmarks of AD-namely, accumulation of pathological, nonmutated tau and neuronal loss. We have now developed two transgenic mouse models (APPSw/NOS2(-/-) and APPSwDI/NOS2(-/-)) that more closely model AD. These mice show amyloid pathology, hyperphosphorylated and aggregated normal mouse tau, significant neuron loss, and cognitive deficits. A beta(1-42) or KLH vaccinations were started in these animals at 12 months, when disease progression and cognitive decline are well underway, and continued for 4 months. Vaccinated APPSwDI/NOS2(-/-) mice, which have predominantly vascular amyloid pathology, showed a 30% decrease in brain A beta and a 35-45% reduction in hyperphosphorylated tau. Neuron loss and cognitive deficits were partially reduced. In APPSw/NOS2(-/-) vaccinated mice, brain A beta was reduced by 65-85% and hyperphosphorylated tau by 50-60%. Furthermore, neurons were completely protected, and memory deficits were fully reversed. Microhemorrhage was observed in all vaccinated APPSw/NOS2(-/-) mice and remains a significant adverse event associated with immunotherapy. Nevertheless, by providing evidence that reducing amyloid pathology also reduces nonmutant tau pathology and blocks neuron loss, these data support the development of amyloid-lowering therapies for disease-modifying treatment of AD.

Human apolipoprotein E redistributes fibrillar amyloid deposition in Tg-SwDI mice.

Human apolipoprotein (ApoE) genotype influences the development of Alzheimer's disease and cerebral amyloid angiopathy (CAA). Specific mutations within the amyloid-beta protein (Abeta) peptide have been identified that cause familial forms of CAA. However, the effect of APOE genotype on accumulation of CAA mutant Abeta in brain is not well understood. In the present study, we determined how human ApoE3 or ApoE4 influence cerebral Abeta accumulation in transgenic mice (Tg-SwDI) that accumulate human Dutch/Iowa (E22Q/D23N) CAA mutant Abeta in brain, primarily in the form of fibrillar cerebral microvascular amyloid. Using Tg-SwDI mice bred onto a human APOE3/3 or human APOE4/4 background, we found that both human ApoE3 and ApoE4 proteins led to a strong reduction in the amount of cerebral microvascular amyloid with an unexpected concomitant appearance of extensive fibrillar parenchymal plaque amyloid. There was strong colocalization of all ApoE proteins with fibrillar amyloid deposits in the mice. In Tg-SwDI/hAPOE3/3 and Tg-SwDI/hAPOE4/4 mice, there was no change in the levels of total Abeta(40) and Abeta(42) or in the amounts of soluble and insoluble Abeta in brain compared with Tg-SwDI mice on the endogenous mouse APOE background. The shift from primarily cerebral microvascular amyloid to parenchymal plaque amyloid in Tg-SwDI/hAPOE3/3 and Tg-SwDI/hAPOE4/4 mice resulted in a parallel shift in the association of activated microglia. These findings indicate that human ApoE has a strong influence on the spatial development of human Dutch/Iowa CAA mutant amyloid accumulation in mouse brain and that microglial activation is in response to the spatial accumulation of fibrillar amyloid.

Progression of amyloid pathology to Alzheimer's disease pathology in an amyloid precursor protein transgenic mouse model by removal of nitric oxide synthase 2.

Alzheimer's disease (AD) is characterized by three primary pathologies in the brain: amyloid plaques, neurofibrillary tangles, and neuron loss. Mouse models have been useful for studying components of AD but are limited in their ability to fully recapitulate all pathologies. We crossed the APPSwDI transgenic mouse, which develops amyloid beta (Abeta)-protein deposits only, with a nitric oxide synthase 2 (NOS2) knock-out mouse, which develops no AD-like pathology. APPSwDI/NOS2(-/-) mice displayed impaired spatial memory compared with the APPSwDI mice, yet they have unaltered levels of Abeta. APPSwDI mice do not show tau pathology, whereas APPSwDI/NOS2(-/-) mice displayed extensive tau pathology associated with regions of dense microvascular amyloid deposition. Also, APPSwDI mice do not have any neuron loss, whereas the APPSwDI/NOS2(-/-) mice have significant neuron loss in the hippocampus and subiculum. Neuropeptide Y neurons have been shown to be particularly vulnerable in AD. These neurons appear to be particularly vulnerable in the APPSwDI/NOS2(-/-) mice as we observe a dramatic reduction in the number of NPY neurons in the hippocampus and subiculum. These data show that removal of NOS2 from an APP transgenic mouse results in development of a much greater spectrum of AD-like pathology and behavioral impairments.

The impact of blended learning on student performance in a cardiovascular pharmacotherapy course.

OBJECTIVE: To examine student engagement with, perception of, and performance resulting from blended learning for venous thromboembolism in a required cardiovascular pharmacotherapy course for second-year students. DESIGN: In 2013, key foundational content was packaged into an interactive online module for students to access prior to coming to class; class time was dedicated to active-learning exercises. ASSESSMENT: Students who accessed all online module segments participated in more in class clicker questions (p=0.043) and performed better on the examination (p=0.023). There was no difference in clicker participation or examination performance based on time of module access (prior to or after class). The majority of participants agreed or strongly agreed that foundational content learned prior to class, applied activities during class, and content-related questions in the online module greatly enhanced learning. CONCLUSION: This study highlights the importance of integrating online modules with classroom learning and the role of blended learning in improving academic performance.

The flipped classroom: a course redesign to foster learning and engagement in a health professions school.

Recent calls for educational reform highlight ongoing concerns about the ability of current curricula to equip aspiring health care professionals with the skills for success. Whereas a wide range of proposed solutions attempt to address apparent deficiencies in current educational models, a growing body of literature consistently points to the need to rethink the traditional in-class, lecture-based course model. One such proposal is the flipped classroom, in which content is offloaded for students to learn on their own, and class time is dedicated to engaging students in student-centered learning activities, like problem-based learning and inquiry-oriented strategies. In 2012, the authors flipped a required first-year pharmaceutics course at the University of North Carolina Eshelman School of Pharmacy. They offloaded all lectures to self-paced online videos and used class time to engage students in active learning exercises. In this article, the authors describe the philosophy and methodology used to redesign the Basic Pharmaceutics II course and outline the research they conducted to investigate the resulting outcomes. This article is intended to serve as a guide to instructors and educational programs seeking to develop, implement, and evaluate innovative and practical strategies to transform students' learning experience. As class attendance, students' learning, and the perceived value of this model all increased following participation in the flipped classroom, the authors conclude that this approach warrants careful consideration as educators aim to enhance learning, improve outcomes, and fully equip students to address 21st-century health care needs.

Pharmacy student engagement, performance, and perception in a flipped satellite classroom.

OBJECTIVE: To determine whether "flipping" a traditional basic pharmaceutics course delivered synchronously to 2 satellite campuses would improve student academic performance, engagement, and perception. DESIGN: In 2012, the basic pharmaceutics course was flipped and delivered to 22 satellite students on 2 different campuses. Twenty-five condensed, recorded course lectures were placed on the course Web site for students to watch prior to class. Scheduled class periods were dedicated to participating in active-learning exercises. Students also completed 2 course projects, 3 midterm examinations, 8 graded quizzes, and a cumulative and comprehensive final examination. ASSESSMENT: Results of a survey administered at the beginning and end of the flipped course in 2012 revealed an increase in students' support for learning content prior to class and using class time for more applied learning (p=0.01) and in the belief that learning key foundational content prior to coming to class greatly enhanced in-class learning (p=0.001). Significantly more students preferred the flipped classroom format after completing the course (89.5%) than before completing the course (34.6%). Course evaluation responses and final examination performance did not differ significantly for 2011 when the course was taught using a traditional format and the 2012 flipped-course format. Qualitative findings suggested that the flipped classroom promoted student empowerment, development, and engagement. CONCLUSION: The flipped pharmacy classroom can enhance the quality of satellite students' experiences in a basic pharmaceutics course through thoughtful course design, enriched dialogue, and promotion of learner autonomy.