Endothelial C3a receptor mediates vascular inflammation and blood-brain barrier permeability during aging

Dysfunction of immune and vascular systems has been implicated in aging and Alzheimer disease; however, their interrelatedness remains poorly understood. The complement pathway is a well-established regulator of innate immunity in the brain. Here, we report robust age-dependent increases in vascular inflammation, peripheral lymphocyte infiltration, and blood-brain barrier (BBB) permeability. These phenotypes were subdued by global inactivation and by endothelial cell–specific ablation of C3ar1. Using an in vitro model of the BBB, we identified intracellular Ca²⁺ as a downstream effector of C3a/C3aR signaling and a functional mediator of vascular endothelial cadherin junction and barrier integrity. Endothelial C3ar1 inactivation also dampened microglia reactivity and improved hippocampal and cortical volumes in the aging brain, demonstrating a crosstalk between brain vasculature dysfunction and immune cell activation and neurodegeneration. Further, prominent C3aR-dependent vascular inflammation was also observed in a tau-transgenic mouse model. Our studies suggest that heightened C3a/C3aR signaling through endothelial cells promotes vascular inflammation and BBB dysfunction and contributes to overall neuroinflammation in aging and neurodegenerative disease.     

Social determinants of ethno-racial inequalities in substance use: a decomposition of national survey data

Background

Similar to the US, mortality due to suicide and the use of opioids, alcohol, and other substances (so-called “Deaths of Despair”), is rising in Canada and has been disproportionately observed among Whites compared to other racial and ethnic groups. This study aimed to assess the determinants of the ethno-racial differences in the use of substances that underlie these deaths.

Methods

Using nationally representative data from the Canadian Community Health Survey (2003, 2015–2016, 2018 cycles), a decomposition analysis was performed to estimate the contribution of psychosocial determinants, including age, sex, marital status, immigration, education, income, rurality, and affective health on inequalities between White and non-White populations in illicit substance, opioid, and problematic alcohol use and combined use (≥ 2) of substances.

Results

Overall, White respondents reported higher levels (by 5% to 10%) of substance use than non-White peers. Over 30% of the ethno-racial inequalities in illicit substance, problematic alcohol, and polysubstance use are explained by the protective role of immigration among those who are not White, whose low levels of substance use lower the prevalence in the non-White population overall. Among those born in Canada, no ethno-racial differences in substance use were observed.

Conclusion

Social determinants, particularly immigrant status, explain a substantial proportion of ethno-racial inequalities in substance use in Canada. The jump in substance use between racialized populations who immigrated to Canada and those Canadian-born highlights the importance of exploring within-group variability in deaths of despair risk and considering how intersecting forces including systemic racism shape substance use patterns across generations.