👤 Daniel D Callow

Cognitive resilience, the ability to maintain better than expected cognitive function despite neuropathological burden, is a key contributor to clinical outcomes in Alzheimer's disease (AD), though the underlying neurobiological mechanisms remain poorly understood. To determine whether hippocampal volume and microstructure moderate the relationship between early tau pathology and cognitive performance, thereby serving as potential markers of cognitive resilience. Cross-sectional observational study. Participant data was obtained from the longitudinal BIOCARD Study, a volunteer-based research cohort. The sample included 190 dementia-free adults (mean age = 68 years), comprising 176 cognitively unimpaired individuals and 14 with mild cognitive impairment (MCI). Hippocampal volume and microstructure (mean diffusivity (MD)) were measured using structural magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI), respectively. Tau pathology was measured using FMK-6240 tau PET imaging across Braak stages I-III. Cognitive performance was indexed using global and domain-specific composite scores. Regression models tested the interactions between hippocampal volume or MD and tau burden, adjusting for demographics, APOE genotype, amyloid status, and diagnostic status. Lower hippocampal MD (indicative of better microstructural integrity) attenuated the negative association between tau burden in Braak stages II-III and both global cognition and episodic memory (ps < 0.010). Logistic regression models indicated that lower hippocampal MD was associated with a weaker relationship between tau burden in Braak stages II-III and the likelihood of MCI diagnosis (ps < 0.050). In contrast, hippocampal volume did not moderate the relationship between tau and any cognitive outcome (ps > 0.250). Hippocampal MD may serve as a promising imaging marker of cognitive resilience to early tau pathology, with potential utility for risk stratification and as a target for preventive interventions in AD. Show less

Canonical Wnt signaling is controlled intracellularly by the level of β-catenin protein, which is dependent on Axin scaffolding of a complex that phosphorylates β-catenin to target it for ubiquitylation and proteasomal degradation. This function of Axin is counteracted through relocalization of Axin protein to the Wnt receptor complex to allow for ligand-activated Wnt signaling. AXIN1 and AXIN2 protein levels are regulated by tankyrase-mediated poly(ADP-ribosyl)ation (PARsylation), which destabilizes Axin and promotes signaling. Mechanistically, how tankyrase limits Axin protein accumulation, and how tankyrase levels and activity are regulated for this function, are currently under investigation. By RNAi screening, we identified the RNF146 RING-type ubiquitin E3 ligase as a positive regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins. RNF146 also destabilizes tankyrases TNKS1 and TNKS2 proteins and, in a reciprocal relationship, tankyrase activity reduces RNF146 protein levels. We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation. RNF146 is a cytoplasmic protein that also prevents tankyrase protein aggregation at a centrosomal location. Tankyrase auto-PARsylation and PARsylation of Axin is known to lead to proteasome-mediated degradation of these proteins, and we demonstrate that, through ubiquitylation, RNF146 mediates this process to regulate Wnt signaling. Show less