Frontotemporal dementia (FTD) is a major cause of early-onset neurodegeneration characterized by progressive behavioral, emotional, and cognitive decline. Progranulin haploinsufficiency, a leading genetic cause of familial FTD, disrupts lysosomal function, lipid metabolism, autophagy, and neuroimmune signaling across multiple cell types. Increasing evidence indicates that microglia are particularly sensitive to progranulin loss, exhibiting elevated complement activation that contributes to TDP-43 proteinopathy and neuronal dysfunction. Here, we investigate the biological role of restoring progranulin exclusively within microglia by transplanting human induced pluripotent stem cell-derived microglial progenitors into progranulin (Grn)-deficient mice. We find that engraftment of wild-type, but not Grn-deficient, human microglia restore brain-wide progranulin levels, normalize microglial transcriptional states, and ameliorate pathological, functional, and behavioral phenotypes associated with progranulin loss. Because human microglia are the only source of progranulin in this system, these findings demonstrate that microglial progranulin is sufficient to restore key aspects of cellular, circuit, and behavioral homeostasis in a progranulin-deficient FTD model. More broadly, this work highlights a central, microglia-intrinsic role for progranulin in maintaining brain function and provides a framework for dissecting microglia-specific mechanisms across FTD and related neurodegenerative disorders.
H. Davtyan, Sarah Naguib, Y. Voskobiynyk et al.· Molecular Neurodegeneration· 0 citations
This study aimed to compare subjective and objective circadian measures with a focus on sex differences and cognition in healthy older adults. A total of 126 participants (aged 65–90 years) completed the Horne & Ostberg Morning-Eveningness Questionnaire (MEQ) and the Circadian Type Inventory (CTI) to assess their morning-evening preference and four circadian traits: rigidity vs flexibility (CTI-FR) and languidity vs vigor (CTI-LV). These self-report measures were compared to actigraphy data from a sub-cohort of 63 individuals who wore wrist actigraphs for 24 hours a day over a 7-day period. Results showed that cognitively healthy older adults tend towards rigidity and vigor (on the CTI) and morningness (on the MEQ). Overall, the languid vs vigorous types and flexible vs rigid types displayed differences in MEQ scores. Sex moderated the association between the CTI-LV and MEQ with a steeper association in males than females (p = 0.012). Actigraphy data showed that males had less stable (interdaily stability, IS, p = 0.03) and more fragmented (interdaily variability, IV, p = 0.001) circadian rhythms than older females. Subjective MEQ scores were strongly predictive of acrophase time (p = 0.009) in males but not females. Using information processing speed (IPS) as a marker of cognitive function, we found that greater circadian rhythm fragmentation (IV) was linked to slower verbal IPS (p = 0.004) in males. Morning preference on the MEQ predicted faster spatial IPS in the overall sample (p < 0.001). These findings provide preliminary evidence of the relationship between subjective sleep preferences and objective circadian data in cognitively healthy older adults with notable sex differences in these relationships.
Natalie S Pandher, L. Yack, E. Li et al.· PLoS ONE· 0 citations
