POTENTIAL MECHANISMS OF HIPPOCAMPAL RESILIENCE TO ALZHEIMER’S DISEASE PATHOLOGY

Alzheimer’s disease (AD) is an age-related, progressive neurodegenerative proteinopathy with few treatments and no cure. Accumulation of beta amyloid and tau proteins are associated with disease symptoms including cognitive dysfunction and impaired spatial learning and memory. New therapeutic strategies are vital to address disease etiology and symptoms, but recent clinical failures have underscored the importance of mechanistic studies that search for new resilience factors in the context of disease progression. We define two possible mechanisms of neural resilience to AD symptoms and pathophysiology in the hippocampus, a nexus of spatial learning and memory and a critical site of synergy for amyloid and tau pathophysiology. These studies describe the interaction of two critical inhibitory neuron populations in the process of spatial learning and memory and detect early signs of dysfunction in a mouse model of AD. This work also identifies novel inhibitory circuit remodeling associated with stabilization of hippocampal activity alterations and indicates that inhibitory circuit fiber outgrowth in the hippocampus confers resilience to AD pathophysiology. Our results also establish disease relevance for an understudied innate waste clearance of the brain in both human AD patients and mouse models. This reserve waste clearance system relies on astrocytes to encase deleterious proteins and cellular organelles in dense, carbohydrate-rich structures termed corpora amylacea and periodic acid-Schiff granules in humans and mice, respectively. Our results indicate that tau can localize to these waste containers in the human and mouse hippocampus and that their generation is associated with increased astrocytic reactivity. We further describe the bimodal trajectory of hippocampal CA density in relation to advancing tau pathology (Braak 06) stage in AD patients and decreased hippocampal CA density in demented patients when compared to cognitively normal controls. Furthermore, we established relationships with CA density and advancing biological age, amyloid score, and APOE allele variant at select AD progression stages. These results indicate that loss of CA as a reserve waste clearance system is associated with poor cognitive outcomes and advanced Braak stage in a cohort of human AD patients. Overall, our studies highlight two possible resilience mechanisms for future targeted therapies in AD.Doctor of Philosoph

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least 4 m. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the 6.5 m James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 yr, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit