Integrated source apportionment and risk assessment of metals is of great importance for contamination source control and remediation at the regional watershed scale. To identify metal sources and source-specific ecological risks, sediments were collected in the Wen-Rui Tang urban watershed for metal analysis. Risk assessment showed considerable and extremely high risk for Cu and Cd with large spatial variation. Positive matrix factorization model extracted three main sources with reasonable prediction efficacy for metal concentrations. Due to different toxicity coefficients for various metals, the low concentration contribution of source factor 2 (27.2%) contributed 83.7% of total risk, while a high concentration loading for factor 3 (40.8%) only contributed 4.6% to total risk. Predicted source-specific risk was similar to determined risk level for Cr, Ni and Pb; however, Cu and Cd were predicted with decreased risk, while Zn had increased risk. Triangular fuzzy number (TFN) coupled with stochastic simulation showed elevated trend in risk simulation for Cd and Cu when compared with determined risk. The uncertainties for risk evaluation appear to result from spatial variations in metal concentrations. Source apportionment and specific-risk assessment results suggest that different strategies may be required to address mitigation of elevated metal concentrations versus ecological risk.

The hemizygous R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). Using transcriptomic analysis of single nuclei from brain tissues of patients with AD carrying the R47H mutation or the common variant (CV)–TREM2, we found that R47H-associated microglial subpopulations had enhanced inflammatory signatures reminiscent of previously identified disease-associated microglia (DAM) and hyperactivation of AKT, one of the signaling pathways downstream of TREM2. We established a tauopathy mouse model with heterozygous knock-in of the human TREM2 with the R47H mutation or CV and found that R47H induced and exacerbated TAU-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had substantial overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of AKT signaling, and elevation of a subset of DAM signatures. Pharmacological AKT inhibition with MK-2206 largely reversed the enhanced inflammatory signatures in primary R47H microglia treated with TAU fibrils. In R47H heterozygous tauopathy mice, MK-2206 treatment abolished a tauopathy-dependent microglial subcluster and rescued tauopathy-induced synapse loss. By uncovering disease-enhancing mechanisms of the R47H mutation conserved in human and mouse, our study supports inhibitors of AKT signaling as a microglial modulating strategy to treat AD.