Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder primarily characterized by progressive cognitive dysfunction. Substantial loss of hippocampal neurons is closely associated with irreversible cognitive decline; however, the underlying mechanisms have not yet been fully elucidated. In this study, conditionally overexpressing adiponectin receptor 1 (AdipoR1) in the hippocampus of APP/PS1 transgenic AD mice, we found that it significantly improved learning and memory abilities and effectively mitigated the abnormal loss of hippocampal neurons and dendritic spines. AdipoR1 overexpression primarily maintained neuronal numbers through reducing neuronal death rather than promoting neurogenesis, and this protective effect is closely linked to the inhibition of the neuronal NLRP3 inflammasome, leading to a marked reduction in pyroptosis levels within the hippocampus. Our results demonstrated, for the first time, that AdipoR1 exerted a crucial neuroprotective role in AD pathology through modulating the NLRP3-mediated neuroinflammatory pathway, which might offer new insights into the mechanisms of neuronal loss in AD and suggest that the AdipoR1–NLRP3 signaling axis may serve as a potential therapeutic target for early intervention in AD.
Obesity is associated with an increased risk of psychiatric disorders and altered reward processing. Neuropeptide Y (NPY) links metabolic state, reward-driven behavior, and emotional processing. We therefore tested whether intranasal (i.n.) NPY modifies high-fat diet (HFD)-induced behavioral alterations. Male C57BL/6J mice were fed HFD (48% kcal fat) or control diet for 8 weeks and assessed for anxiety-like behavior using the light/dark box test (LDT), self-care behavior using the splash test, and sucrose-directed ingestive behavior using sucrose intake and sucrose preference (SP). A separate cohort of control- and HFD-fed mice received i.n. NPY or vehicle, followed by assessment of SP and ingestive behavior after 3, 24 and 48 h. Neuroendocrine and inflammatory parameters were measured in blood, brain, and colon. HFD reduced sucrose-directed ingestive behavior, reflected by reduced sucrose intake and SP, without significantly affecting anxiety-like behavior in the LDT or self-care behavior in the splash test. HFD reduced hypothalamic Npy mRNA and peptide levels as well as circulating corticosterone, while the evaluated inflammation-related markers remained unchanged. I.n. NPY had no effect after 24 or 48 h but reduced sucrose intake and SP, and increased circulating corticosterone 3 h after administration specifically in HFD-fed animals. In contrast, i.n. NPY reduced food intake and body weight after 3 h, independent of diet. Because these effects were consistent with neuropeptide Y receptor Y2 (NPY2R)-mediated actions, we tested i.n. NPY in HFD-fed Npy2r-deficient mice. In these mice, i.n. NPY did not affect sucrose intake, SP, food intake, or corticosterone, consistent with a potential involvement of NPY2R.
Defining how antipsychotic drugs acutely reshape neurochemical signaling across discrete brain regions is critical for understanding their central pharmacological actions. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) enables spatially resolved, untargeted molecular profiling directly in tissue and is well suited to investigate early drug-induced effects. Here, we applied MALDI-MSI to characterize acute neurochemical and metabolomic alterations and to explore trypsin-digested peptidomic changes in rat brain following single-dose exposure to the atypical antipsychotics risperidone and olanzapine. By using MALDI matrices optimized for neurotransmitters, small metabolites, and peptides, we achieved broad molecular coverage across cortical, striatal, and hippocampal regions. This approach revealed distinct, drug-specific spatial signatures encompassing monoamine-related metabolites, purine metabolism, and lipids. In the striatum, both compounds altered dopamine metabolism, as reflected by changes in 3-methoxytyramine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid. In cortical and hippocampal regions, risperidone selectively increased levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethyleneglycol sulfate, indicating a distinct noradrenergic signature. Pathway analysis identified purine metabolism as a major treatment-responsive pathway, consistent with altered nucleotide homeostasis and energy metabolism. Together, these findings provide spatially resolved insight into how atypical antipsychotics modulate brain chemistry, revealing region-specific neurochemical signatures underlying their pharmacological effects.
Alzheimer’s disease (AD) represents a progressive neurodegenerative disorder that predominantly impairs the central nervous system. This study integrated single-cell RNA sequencing (scRNA-seq) and Mendelian randomization (MR) analysis to explore AD therapeutic targets and characterize alterations in immune cell infiltration and function. We analyzed the subtypes, developmental trajectories and intercellular communication of peripheral blood T cells from AD scRNA-seq data. Cell clustering identified CD8+ T cells as the key immune subpopulation in AD, with two vital intercellular communication pathways (MIF-(CD74+CD44) and MIF-(CD74+CXCR4)) identified by trajectory analysis. The expression quantitative trait loci (eQTL) data retrieved from the IEU OpenGWAS database were utilized to perform MR and colocalization analysis to evaluate the association between target genes and AD. Six multiple-SNP and one single-SNP potential target genes were screened via differential expression and MR analysis. Among these, dual-specificity phosphatase 2 (DUSP2) showed a suggestive but weak association with AD, with a mild positive correlation observed in sensitivity analyses. No statistically significant shared genetic signals were detected via colocalization analysis. Additionally, significant differences in intercellular communication were observed between DUSP2+IM and DUSP2-IM cells, with distinct activity across various communication pathways. Gene expression levels in the AD group were significantly higher than in healthy individuals (P = 0.01). In conclusion, this study identified CD8+ T cells as crucial factors in AD pathogenesis, while DUSP2 emerged as a suggestive candidate gene requiring further validation, providing novel mechanistic insights and potential therapeutic targets for AD treatment.
Fatigue and sleep disturbances are common in Parkinson Disease (PD) and significantly reduce quality of life, yet effective pharmacological treatments are limited. Light therapy offers a promising non-pharmacologic approach, but most lighting interventions have focused on improving sleep. Using a novel and easily administered morning lighting intervention, we previously demonstrated improvement in sleep duration. We have now extended the prior study through the addition of 23 individuals to investigate the intervention's effect on fatigue and sleep. In this single-arm intervention study, participants received morning light for 4 consecutive weeks from table or floor luminaires designed to deliver circadian-effective ambient light at home. Objective sleep was measured with wrist-worn actigraphy and subjective sleep, fatigue and mood were assessed using standardized questionnaires. Analysis of pre and post intervention data for the current cohort was performed separately as well as in combination with the 20 participants from the previously reported pilot study. For the 23 current participants, fatigue on the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale improved by 3.9 ± 1.00 points (p = 0.0026). While sleep duration increased by mean 21.3 ± 14.4 min, it was not statistically significant (p = 0.082). When combined with the 20 participants from the prior pilot study, significant improvement in fatigue by 2.8 ± 0.85 points (p = 0.0033) was observed and sleep duration was also significantly increased by 24.7 ± 10.4 min (p = 0.012). These findings support morning light as a novel intervention for fatigue in PD.
