Biology subjects

Western, D.

Publications and source records attributed to Western, D..

3 recordsLinked to original sources

bioRxiv2025

Ms4a4a deficiency ameliorates plaque pathology in a mouse model of amyloid accumulation

Genome-wide association studies for Alzheimer disease (AD) risk have identified a number of genes enriched in microglia, including MS4A4A. Common variants in MS4A4A influence AD risk, MS4A4A expression, TREM2 signaling, and a specific microglial transcriptional state, though the exact role of MS4A4A in AD remains unclear. Using a mouse model of amyloid beta (A{beta}) accumulation (5xFAD), we examined the impact of Ms4a4a loss on A{beta} pathology. Before A{beta} accumulation, Ms4a4a loss reduces steady-state A{beta} levels and shortens A{beta} half-life in brain interstitial fluid. In aged 5xFAD Ms4a4a-deficient mice, plaques are more compact with reduced overall plaque burden. Microglia lacking Ms4a4a are more pro-inflammatory and produce more MMP-9, which may promote degradation of A{beta} and A{beta} fibrils. Human subjects that carry a variant near MS4A4A (rs1582763) that confers resilience to AD also exhibit significantly elevated levels of MMP-9 in their cerebrospinal fluid. Together, our results suggest that loss of Ms4a4a improves A{beta} pathology by altering A{beta} clearance, offering insights for therapeutic interventions in AD.

neuroscience↗

bioRxiv2024

Synapse protein signatures in cerebrospinal fluid and plasma predict cognitive maintenance versus decline in Alzheimers disease

Rates of cognitive decline in Alzheimers disease (AD) are extremely heterogeneous, with ages of symptom onset ranging from age 40-100 years and conversion from mild cognitive impairment to AD dementia taking 2-20 years. Development of biomarkers for amyloid-beta (A{beta}) and tau protein aggregates, the hallmark pathologies of AD, have improved patient monitoring/stratification and drug development, but they still only explain 20-40% of the variance in cognitive impairment (CI) in AD. To discover additional molecular drivers and biomarkers of AD dementia, we perform cerebrospinal fluid (CSF) proteomics on 3,416 individuals from six deeply phenotyped prospective AD case-control cohorts. We identify synapse proteins as the strongest correlates of CI, independent of A{beta} and tau. Using machine learning we derive the CSF YWHAG:NPTX2 synapse protein ratio, a robust correlate of CI, which explains 27% of the variance in CI beyond CSF PTau181:A{beta}42, 10% beyond tau PET, and 50% beyond CSF NfL in A{beta} positive individuals. We find YWHAG:NPTX2 also increases with normal aging as early as age 20 and increases at a faster rate in APOE4 carriers and autosomal dominant-AD mutation carriers. Most notably, YWHAG:NPTX2+ individuals (top 25th percentile) are 15-times (HR=15.4 [10.6-22.2]) more likely to experience cognitive decline over 15 years compared to YWHAG:NPTX2- individuals (bottom 25th percentile), and this rises to 19-times (HR=18.9 [10.83-32.9]) with additional stratification by A{beta} and phosphorylated tau status. Lastly, we perform plasma proteomics on 4,245 individuals to develop a plasma-based signature of CI which partly recapitulates CSF YWHAG:NPTX2. Overall, our findings underscore CSF YWHAG:NPTX2 and the corresponding plasma signature as robust prognostic biomarkers for AD onset and progression beyond gold-standard biomarkers of A{beta}, tau, and neurodegeneration and implicate synapse dysfunction as a core driver of AD dementia.

neuroscience↗

bioRxiv2021

Cascading effects of elephant-human interactions in a savanna ecosystem and the implications for ecology and conservation

Our study monitored the changes in elephant numbers, distribution and ecological impact over a fifty-year period as the free-ranging intermingled movements of wildlife and traditional subsistence pastoralists across the Amboseli ecosystem were disrupted by a national park, livestock ranches, farms, settlements and changing lifestyles and economies. Elephants compressed into the national park by poaching and settlement turned woodlands to grassland and shrublands and swamps into short grazing lawns, causing a reduction of plant and herbivore diversity and resilience to extreme events. The results echo the ecological findings of high-density elephant populations in protected areas across eastern and southern Africa. The impact has led to the view of elephants in parks being incompatible with biodiversity and to population control measures. In contrast to Amboseli National Park, we found woody vegetation grew and plant diversity fell in areas abandoned by elephants. We therefore used naturalist and exclosure experiments to determine the density-dependent response of vegetation to elephants. We found plant richness to peak at the park boundary where elephants and livestock jostled spatially, setting up a creative browsing-grazing tension and a patchwork of habitats explaining the plant richness. A review of prehistorical and historical literature lends support to the Amboseli findings that elephants and people, the two dominant keystone species in the savannas, have been intimately entangled prior to the global ivory trade and colonialism. The findings point to the inadequacy of parks for conserving mega herbivores and as ecological baselines. The Amboseli study underlines the significance of space and mobility in expressing the keystone role of elephants, and to community-based conservation as a way to win space and mobility for elephants, alleviate the ecological disruption of compressed populations and minimize population management.

ecology↗