TREM2 is exclusively expressed by microglia in the brain and is strongly linked to the risk for Alzheimer’s disease (AD). As microglial responses modulated by TREM2 are central to AD pathogenesis, enhancing TREM2 signaling has been explored as an AD therapeutic strategy. However, the effective therapeutic window targeting TREM2 is unclear. Here, by using microglia-specific inducible mouse models overexpressing human wild-type TREM2 (TREM2-WT) or R47H risk variant (TREM2-R47H), we show that TREM2-WT expression reduces amyloid deposition and neuritic dystrophy only during the early amyloid seeding stage, whereas TREM2-R47H exacerbates amyloid burden during the middle amyloid rapid growth stage. Single-cell RNA sequencing reveals suppressed disease-associated microglia (DAM) signature and reduced DAM population upon TREM2-WT expression in the early stage, whereas upregulated antigen presentation pathway is detected with TREM2-R47H expression in the middle stage. Together, our findings highlight the dynamic effects of TREM2 in modulating AD pathogenesis and emphasize the beneficial effect of enhancing TREM2 function in the early stage of AD development.
Summary. Results obtained in the sheep cell‐rosette test for identification of human T lymphocytes are strongly dependant on the origin of the sheep erythrocytes. Other factors which influence rosette formation are the duration of incubation of the lymphocyte erythrocyte mixture and the concentration of serum used. The most reproducible results, giving a range of 55–75% RFC among the peripheral blood lymphocytes of healthy adults, are obtained by leaving the cell mixture overnight at room temperature in the presence of 10–25% serum.The spontaneous sheepcell rosette test appears to be a useful means of identifying human T lymphocytes (Jondal et al, 1972; Papamichail et al, 1972; Wortis et al, 1973; Yata et al, 1973); there are, however, striking discrepancies in the percentage of rosette‐forming cells (RFC) reported among the peripheral blood lymphocytes of healthy donors for the figures quoted range from under 5% (Bach et al, 1969) to almost 80% (Bentwich et al, 1973). There are many points of variation between the techniques employed (Bach et al, 1969; Coombs et al. 1970; Brain et al, 1970; Lay et al, 1971; Jondal et al, 1972; Papamichail et al, 1972; Wybran et al, 1973; Yata et al, 1973; Bentwich et al, 1973) but the importance of such technical variations is largely unknown (Urbaniak et al, 1973). In the present study, several of the points of variance between published techniques have been analysed.
Objective: Alzheimers disease (AD) has several known genetic determinants, yet the mechanisms through which they lead to disease onset remain poorly understood. This study aims to estimate the effects of genetic liability to AD on plasma metabolites measured at seven different stages across the life course.
Methods: Genetic and metabolomic data from 5,648 offspring from the Avon Longitudinal Study of Parents and Children birth cohort were used. Linear regression models examined the association between higher AD liability, as measured by a genetic risk score (GRS), and plasma metabolites measured at 8, 16, 18 and 25 years of age. Two hundred twenty-nine metabolites were studied, most relating to lipid/lipoprotein traits. Two-sample Mendelian randomization was performed using summary statistics from age-stratified genome-wide association studies (GWAS) of the same metabolites for 118,466 participants from the UK Biobank, to examine the persistence of any AD liability effects into late adulthood.
Results: The GRS including the APOE4 isoform demonstrated the strongest positive associations for cholesterol-related traits per doubling of genetic liability to AD, e.g., for low-density lipoprotein cholesterol (LDL-C) at age 25yrs (0.12 SD; 95% CI 0.09, 0.14), with similar magnitudes of association across age groups in ALSPAC. In the UK Biobank, the effect of AD liability decreased with age tertile for several lipid traits (e.g., LDL-C, youngest: 0.15 SD; 95% CI 0.07, 0.23, intermediate: 0.13 SD; 95% CI 0.07, 0.20, oldest: 0.10 SD; 95% CI 0.05, 0.16). Across both cohorts, the effect of AD liability on high-density lipoprotein cholesterol (HDL-C) attenuated as age increased. Fatty acid metabolites also demonstrated positive associations in both cohorts, though smaller in magnitude compared with lipid traits. Sensitivity analyses indicated that these effects were driven by the APOE4 isoform.
Conclusions: These results support a profound influence of the APOE4 isoform on circulating lipids and fatty acids from early life to later adulthood. Such lipid and fatty acid traits may be implicated in early AD pathogenesis and warrant further investigation as potential targets for preventing the onset of AD.
Background
Non-pharmaceutical interventions to reduce the spread of COVID-19 may have disproportionately affected already disadvantaged populations.
Methods
We analysed data from 2710 young adult participants of the Avon Longitudinal Study of Parents and Children. We assessed the associations of socioeconomic position (SEP) and Adverse Childhood Experiences (ACEs, e.g. abuse, neglect, measures of family dysfunction) with changes to health-related behaviours (meals, snacks, exercise, sleep, alcohol and smoking/vaping), and to financial and employment status during the first UK lockdown between March–June 2020.
Results
Experiencing 4+ ACEs was associated with reporting decreased sleep quantity during lockdown (OR 1.53, 95% CI: 1.07–2.18) and increased smoking and/or vaping (OR 1.85, 95% CI: 0.99–3.43); no other associations were seen between ACEs or SEP and health-related behaviour changes. Adverse financial and employment changes were more likely for people with low SEP and for people who had experienced multiple ACEs; e.g. a history of 4+ ACEs was associated with being furloughed or on other leave during lockdown (OR 1.92, 95% CI: 1.35–2.74).
Conclusions
In this sample of young adults, there was little evidence that lockdown worsened inequalities in health-related behaviours. However, adverse financial and employment consequences of lockdown were more likely to be experienced by people who have already experienced socioeconomic deprivation or childhood adversity, thereby widening social inequalities and demonstrating the need for support into adulthood for those with a history of ACEs.
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