The effect of work characteristics on advanced practice provider burnout: a secondary cross-sectional analysis.

Dysregulation in glucose metabolism has been implicated in Alzheimer’s disease (AD) risk and progression of cognitive decline [–]. Large-scale epidemiological studies support this mechanistic link, showing that even modest elevations in blood glucose are predictive of increased AD risk and accelerated cognitive decline with aging []. These observations implicate systemic metabolic dysfunction as a significant contributor to brain vulnerability in neurodegeneration. Impaired insulin signaling, as observed in diet-induced insulin resistance, has been linked to both metabolic and neurodegenerative disorders [–]. This phenomenon has sparked interest in insulin-modulating therapies, including GLP-1 receptor agonists and intranasal insulin for AD [–]. However, the cellular mechanisms linking systemic metabolic dysfunction to neurodegeneration remain poorly understood. To examine how diet-induced insulin resistance interacts with the pathological progression of AD, we employed a chronic high-fat, high-sugar (HFHS) diet [, ] to induce metabolic dysfunction in double knock-in (DKI) Alzheimer’s mice expressing human mutant APP and human wild-type (WT) tau [–]. Prior studies investigating metabolic dysfunction in AD models have relied on APP or tau overexpression systems or combined metabolic insults [, ]. These approaches, along with variability in genetic background, age, and induction paradigms for metabolic impairment, have produced inconsistent results, making it difficult to isolate the specific contributions of metabolic stress to AD-related phenotypes []. By applying a chronic dietary challenge to genetically defined knock-in models with pathophysiologically relevant mutations, we sought to determine how systemic metabolic stress is associated with the behavioral changes, glial activation states, and cellular transcriptional responses in the AD brain. To evaluate metabolic, behavioral, and cellular outcomes, we combined glucose and weight monitoring, spatial memory testing, histological analyses of glial reactivity and synaptic markers, and single-nucleus RNA sequencing (snRNA-seq) to resolve cell-type-specific transcriptional responses. Chronic HFHS-diet induced metabolic stress associated with insulin resistance in both WT and DKI mice. Spatial learning and memory deficits were pronounced only in HFHS-fed DKI mice, but not in lean-diet-fed DKI or HFHS-fed WT mice. Transcriptomic analyses identified glial cell populations and cortical inhibitory neurons as being particularly responsive to diet-induced metabolic stress. We identified and defined a distinct pan-glial transcriptional program, which we term the (MinD) state. In parallel, the transcription factor Meis2 was selectively upregulated in cortical Layer 2 (L2) inhibitory neurons, with diet-induced changes observed in WT mice that were further amplified in DKI mice. These coordinated glial and neuronal transcriptional changes occurred without detectable alterations in amyloid-β (Aβ) or tau deposition.