Highlights d The FTD-causing V337M tau mutation impairs axon initial segment (AIS) plasticity d The V337M tau mutation impairs activity homeostasis d The V337M tau mutation leads to accumulation of EB3 in the AIS d EB3 is critical for regulating AIS plasticity and activity homeostasis

Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer’s disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-κB activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-κB inactivation and further transformed by constitutive NF-κB activation. Our study establishes a role for microglial NF-κB signaling in mediating tau spreading and toxicity in tauopathy.

Background Cognitive impairment is common in hemodialysis patients and associated with significant morbidity. Limited information exists on whether cognitive impairment is associated with survival, and whether type of cognitive impairment is important. Study Design Longitudinal cohort. Setting & Participants Cognitive function was assessed at baseline and yearly using a comprehensive battery of cognitive tests in 292 prevalent hemodialysis patients. Predictor Using principal component analysis, individual test results were reduced into 2 domain scores, representing memory and executive function. By definition, each score carried a mean of 0 and SD of 1. Outcomes Association of each score with all-cause mortality was assessed using Cox proportional hazards models adjusted for demographics as well as dialysis and cardiovascular (CV) risk factors. Results Mean age of participants was 63 years, 53% were male, 23% were African American and 90% had at least a high school education. During median follow up of 2.1 (IQR, 1.1–3.7) years, 145 deaths occurred. Each 1-SD better executive function score was associated with 35% lower hazard of mortality (HR, 0.65; 95% CI, 0.55–0.76). In models adjusting for demographics and dialysis-related factors, this relationship was partially attenuated but remained significant (HR, 0.81; 95% CI, 0.67–0.98), while adjustment for CV disease and heart failure further attenuated it (HR, 0.87; 95% CI, 0.72–1.06). Use of time-dependent models showed a similar unadjusted association (HR, 0.62; 95% CI, 0.54–0.72), with the relationship remaining significant after adjustment for demographics, dialysis, and CV risk factors (HR, 0.79; 95% CI, 0.66–0.94). Better memory was associated with lower mortality in univariate analysis (HR per 1 SD, 0.82 [95% CI, 0.69–0.96]), but not when adjusting for demographics (HR, 1.00; 95% CI, 0.83–1.19). Limitations Patients with dementia were excluded from the full battery, perhaps underestimating strength of the association. Conclusions Worse executive function and memory are associated with increased risk of mortality. For memory, this association is explained by patient demographics, while for executive function this relationship may be partly explained by CV disease burden.

R47H- TREM2 mutation enhances AKT signaling in human AD microglia and mediates proinflammatory and synaptic toxicity in a tauopathy mouse model.