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BackgroundApolipoprotein E ε4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). A recent case report identified a rare variant in APOE, APOE3-R136S (Christchurch), proposed to confer resistance to autosomal dominant Alzheimer's Disease (AD). However, it remains unclear whether and how this variant exerts its protective effects.MethodsWe introduced the R136S variant into mouse Apoe (ApoeCh) and investigated its effect on the development of AD-related pathology using the 5xFAD model of amyloidosis and the PS19 model of tauopathy. We used immunohistochemical and biochemical analysis along with single-cell spatial omics and bulk proteomics to explore the impact of the ApoeCh variant on AD pathological development and the brain's response to plaques and tau.ResultsIn 5xFAD mice, ApoeCh enhances a Disease-Associated Microglia (DAM) phenotype in microglia surrounding plaques, and reduces plaque load, dystrophic neurites, and plasma neurofilament light chain. By contrast, in PS19 mice, ApoeCh suppresses the microglial and astrocytic responses to tau-laden neurons and does not reduce tau accumulation or phosphorylation, but partially rescues tau-induced synaptic and myelin loss. We compared how microglia responses differ between the two mouse models to elucidate the distinct DAM signatures induced by ApoeCh. We identified upregulation of antigen presentation-related genes in the DAM response in a PS19 compared to a 5xFAD background, suggesting a differential response to amyloid versus tau pathology that is modulated by the presence of ApoeCh. Bulk proteomics show upregulated mitochondrial protein abundance with ApoeCh in 5xFAD mice, but reductions in mitochondrial and translation associated proteins in PS19 mice.ConclusionsThese findings highlight the ability of the ApoeCh variant to modulate microglial responses based on the type of pathology, enhancing DAM reactivity in amyloid models and dampening neuroinflammation to promote protection in tau models. This suggests that the Christchurch variant's protective effects likely involve multiple mechanisms, including changes in receptor binding and microglial programming.

The Covid-19 pandemic challenged health care delivery systems worldwide. Many acute care hospitals in communities that experienced surges in cases and hospitalizations had to make decisions such as rationing scarce resources. Hospitals serving low-income communities, communities of color, and those in other historically marginalized or vulnerable groups reported the greatest operational impacts of surges. However, cross-institutional collaborations within jurisdictions offer unique opportunities to prevent or mitigate health disparities in resource utilization and access to care. In January 2020, in response to the emerging coronavirus epidemic, the San Francisco Department of Public Health (SFDPH) and local hospital and health systems partners convened to align and coordinate medical surge planning and response. Adopting a governance structure of mutual accountability and transparency, the San Francisco Health Systems Collaborative guided local medical and public health response in the areas of medical surge, vaccination administration, testing, and therapeutics. Four principles guided the collaborative response: (1) shared priorities, (2) clear governance and accountability, (3) data transparency, and (4) operational coordination. High-level priorities established included protecting vulnerable people, protecting health care workers, and maintaining health system capacity. The governance structure consisted of three layers: local hospital and health systems CEOs coordinating with SFDPH executives; hospital chief medical and nursing officers coordinating high-level surge capacity assessments and mitigation plans; and local clinical operational managers working with public health response operational leaders to coordinate scarce resource utilization. Fluctuating with the tempo of the disease indicators and medical surge, governance and coordination were maintained through a tiered meeting and reporting system. Data visibility and transparency were key principles facilitating operational decision-making and executive-level coordination of resources, including identifying additional surge bed capacity for use systemwide, as well as ensuring efficient and equitable vaccine distribution through implementation of five mass-vaccination sites with prioritized access for vulnerable communities. Applying these four principles of shared priorities, accountability, transparency, and operational coordination and pragmatism helped the public health and individual hospital systems make contributions to the overall response that were aligned with their unique strengths and resources. Publication here represents the first official public use of the name San Francisco Health Systems Collaborative (which had served as the term used internally to refer to the group) and the first time codifying this structure. Through this coordination, San Francisco achieved one of the lowest Covid-19 death rates and had one of the highest vaccination and booster rates, compared with rates across California or the United States. Similar principles and implementation methods can be adopted by other health jurisdictions for future emergency outbreak response.

IntroductionEmerging evidence links changes in the gut microbiome to late-onset Alzheimer's disease (LOAD), necessitating examination of AD mouse models with consideration of the microbiome.MethodsWe used shotgun metagenomics and untargeted metabolomics to study the human amyloid beta knock-in (hAβ-KI) murine model for LOAD compared to both wild-type (WT) mice and a model for early-onset AD (3xTg-AD).ResultsEighteen-month female (but not male) hAβ-KI microbiomes were distinct from WT microbiomes, with AD genotype accounting for 18% of the variance by permutational multivariate analysis of variance (PERMANOVA). Metabolomic diversity differences were observed in females, however no individual metabolites were differentially abundant. hAβ-KI mice microbiomes were distinguishable from 3xTg-AD animals (81% accuracy by random forest modeling), with separation primarily driven by Romboutsia ilealis and Turicibacter species. Microbiomes were highly cage specific, with cage assignment accounting for more than 40% of the PERMANOVA variance between the groups.DiscussionThese findings highlight a sex-dependent variation in the microbiomes of hAβ-KI mice and underscore the importance of considering the microbiome when designing studies that use murine models for AD.HighlightsMicrobial diversity and the abundance of several species differed in human amyloid beta knock-in (hAβ-KI) females but not males. Correlations to Alzheimer's disease (AD) genotype were stronger for the microbiome than the metabolome. Microbiomes from hAβ-KI mice were distinct from 3xTg-AD mice. Cage effects accounted for most of the variance in the microbiome and metabolome.

BackgroundVariants in ABCA7, a member of the ABC transporter superfamily, have been associated with increased risk for developing late onset Alzheimer's disease (LOAD).MethodsCRISPR-Cas9 was used to generate an Abca7V1613M variant in mice, modeling the homologous human ABCA7V1599M variant, and extensive characterization was performed.ResultsAbca7V1613M microglia show differential gene expression profiles upon lipopolysaccharide challenge and increased phagocytic capacity. Homozygous Abca7V1613M mice display elevated circulating cholesterol and altered brain lipid composition. When crossed with 5xFAD mice, homozygous Abca7V1613M mice display fewer Thioflavin S-positive plaques, decreased amyloid beta (Aβ) peptides, and altered amyloid precursor protein processing and trafficking. They also exhibit reduced Aβ-associated inflammation, gliosis, and neuronal damage.DiscussionOverall, homozygosity for the Abca7V1613M variant influences phagocytosis, response to inflammation, lipid metabolism, Aβ pathology, and neuronal damage in mice. This variant may confer a gain of function and offer a protective effect against Alzheimer's disease-related pathology.HighlightsABCA7 recognized as a top 10 risk gene for developing Alzheimer's disease. Loss of function mutations result in increased risk for LOAD. V1613M variant reduces amyloid beta plaque burden in 5xFAD mice. V1613M variant modulates APP processing and trafficking in 5xFAD mice. V1613M variant reduces amyloid beta-associated damage in 5xFAD mice.

Emergency care systems (ECS) are undergoing a period of rapid development on the African continent. What were formerly large intake zones are now being shaped into dedicated emergency units. Emergency care providers are being trained via certificate and even residency programs. However, significant challenges still exist. Resource limitations, staffing, and other system inputs are often the easiest issues to identify, but they only account for part of the problem. There are other prominent barriers to the delivery of high quality emergency care including lack of governmental leadership, poor system and facility organization, lack of provider training, and community misunderstanding of ECS functions. Released in May 2019, World Health Assembly (WHA) 72 resolution 12.9 “Emergency care systems for universal health coverage: ensuring timely care for the acutely ill and injured” has squarely placed ECS strengthening as a priority item to member state governments. Moving forward, it will be important to ensure that these systems are set up for success, as high-quality emergency care systems have the potential to avert half of all deaths in low- and middle-income countries (LMIC). With momentum building from the recent WHA amendment and the health systems community more focused than ever on the consideration of quality in health systems design, it is of the utmost importance that ECS planners dovetail these interests such that these nascent systems are designed while 1) applying a systems thinking lens and 2) maintaining a focus on quality. This article helps to accomplish this by breaking down ECS into five major categories for evaluation as defined by the WHO Emergency Care Systems Assessment tool, providing an understanding of the functions of each, and identifying which indicators might be used to gauge performance. We also reinforce the notion that these indicators must dive deeper than system inputs and health outcomes, they must be patient centered in order to truly be reflective of success.

IntroductionAlzheimer's disease (AD) is a neurodegenerative disorder with multifactorial etiology, including genetic factors that play a significant role in disease risk and resilience. However, the role of genetic diversity in preclinical AD studies has received limited attention.MethodsWe crossed five Collaborative Cross strains with 5xFAD C57BL/6J female mice to generate F1 mice with and without the 5xFAD transgene. Amyloid plaque pathology, microglial and astrocytic responses, neurofilament light chain levels, and gene expression were assessed at various ages.ResultsGenetic diversity significantly impacts AD-related pathology. Hybrid strains showed resistance to amyloid plaque formation and neuronal damage. Transcriptome diversity was maintained across ages and sexes, with observable strain-specific variations in AD-related phenotypes. Comparative gene expression analysis indicated correlations between mouse strains and human AD.DiscussionIncreasing genetic diversity promotes resilience to AD-related pathogenesis, relative to an inbred C57BL/6J background, reinforcing the importance of genetic diversity in uncovering resilience in the development of AD.HighlightsGenetic diversity's impact on AD in mice was explored. Diverse F1 mouse strains were used for AD study, via the Collaborative Cross. Strain-specific variations in AD pathology, glia, and transcription were found. Strains resilient to plaque formation and plasma neurofilament light chain (NfL) increases were identified. Correlations with human AD transcriptomics were observed.

IntroductionThe BIN1 coding variant rs138047593 (K358R) is linked to Late-Onset Alzheimer's Disease (LOAD) via targeted exome sequencing.MethodsTo elucidate the functional consequences of this rare coding variant on brain amyloidosis and neuroinflammation, we generated BIN1K358R knock-in mice using CRISPR/Cas9 technology. These mice were subsequently bred with 5xFAD transgenic mice, which serve as a model for Alzheimer's pathology.ResultsThe presence of the BIN1K358R variant leads to increased cerebral amyloid deposition, with a dampened response of astrocytes and oligodendrocytes, but not microglia, at both the cellular and transcriptional levels. This correlates with decreased neurofilament light chain in both plasma and brain tissue. Synaptic densities are significantly increased in both wild-type and 5xFAD backgrounds homozygous for the BIN1K358R variant.DiscussionThe BIN1 K358R variant modulates amyloid pathology in 5xFAD mice, attenuates the astrocytic and oligodendrocytic responses to amyloid plaques, decreases damage markers, and elevates synaptic densities.HighlightsBIN1 rs138047593 (K358R) coding variant is associated with increased risk of LOAD. BIN1 K358R variant increases amyloid plaque load in 12-month-old 5xFAD mice. BIN1 K358R variant dampens astrocytic and oligodendrocytic response to plaques. BIN1 K358R variant decreases neuronal damage in 5xFAD mice. BIN1 K358R upregulates synaptic densities and modulates synaptic transmission.

IntroductionSynaptic loss is a hallmark of Alzheimer's disease (AD) that correlates with cognitive decline in AD patients. Complement-mediated synaptic pruning has been associated with this excessive loss of synapses in AD. Here, we investigated the effect of C5aR1 inhibition on microglial and astroglial synaptic pruning in two mouse models of AD.MethodsA combination of super-resolution and confocal and tridimensional image reconstruction was used to assess the effect of genetic ablation or pharmacological inhibition of C5aR1 on the Arctic48 and Tg2576 models of AD.ResultsGenetic ablation or pharmacological inhibition of C5aR1 partially rescues excessive pre-synaptic pruning and synaptic loss in an age and region-dependent fashion in two mouse models of AD, which correlates with improved long-term potentiation (LTP).DiscussionReduction of excessive synaptic pruning is an additional beneficial outcome of the suppression of C5a-C5aR1 signaling, further supporting its potential as an effective targeted therapy to treat AD.HighlightsC5aR1 ablation restores long-term potentiation in the Arctic model of AD. C5aR1 ablation rescues region specific excessive pre-synaptic loss. C5aR1 antagonist, PMX205, rescues VGlut1 loss in the Tg2576 model of AD. C1q tagging is not sufficient to induce VGlut1 microglial ingestion. Astrocytes contribute to excessive pre-synaptic loss at late stages of the disease.

San Francisco implemented one of the most intensive, comprehensive, multipronged COVID-19 pandemic responses in the United States using 4 core strategies: (1) aggressive mitigation measures to protect populations at risk for severe disease, (2) prioritization of resources in neighborhoods highly affected by COVID-19, (3) timely and adaptive data-driven policy making, and (4) leveraging of partnerships and public trust. We collected data to describe programmatic and population-level outcomes. The excess all-cause mortality rate in 2020 in San Francisco was half that seen in 2019 in California as a whole (8% vs 16%). In almost all age and race and ethnicity groups, excess mortality from COVID-19 was lower in San Francisco than in California overall, with markedly diminished excess mortality among people aged >65 years. The COVID-19 response in San Francisco highlights crucial lessons, particularly the importance of community responsiveness, joint planning, and collective action, to inform future pandemic response and advance health equity.

The nanoscale organization of enzymes associated with the dynamics of second messengers is critical for ensuring compartmentation and localization of signaling molecules in cells. Specifically, the spatiotemporal orchestration of cAMP and Ca2+ oscillations is critical for many cellular functions. Previous experimental studies have shown that the formation of nanodomains of A-kinase anchoring protein 79/150 (AKAP150) and adenylyl cyclase 8 (AC8) on the surface of pancreatic MIN6 β cells modulates the phase of Ca2+-cAMP oscillations from out-of-phase to in-phase. In this work, we develop computational models of the Ca2+/cAMP pathway and AKAP/AC nanodomain formation that give rise to the two important predictions: instead of an arbitrary phase difference, the out-of-phase Ca2+/cAMP oscillation reaches Ca2+ trough and cAMP peak simultaneously, which is defined as inversely out-of-phase; the in-phase and inversely out-of-phase oscillations associated with Ca2+-cAMP dynamics on and away from the nanodomains can be explained by an incoherent feedforward loop. Factors such as cellular surface-to-volume ratio, compartment size, and distance between nanodomains do not affect the existence of in-phase or inversely out-of-phase Ca2+/cAMP oscillation, but cellular surface-to-volume ratio and compartment size can affect the time delay for the inversely out-of-phase Ca2+/cAMP oscillation while the distance between two nanodomains does not. Finally, we predict that both the Turing pattern-generated nanodomains and experimentally measured nanodomains demonstrate the existence of in-phase and inversely out-of-phase Ca2+/cAMP oscillation when the AC8 is at a low level, consistent with the behavior of an incoherent feedforward loop. These findings unveil the key circuit motif that governs cAMP and Ca2+ oscillations and advance our understanding of how nanodomains can lead to spatial compartmentation of second messengers.