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Inflammation has emerged as a prominent feature of bipolar disorder (BD) pathophysiology, drawing attention to brain barriers known to regulate immune-brain interactions. While perturbation of the blood-brain barrier has been reported in BD, the blood-cerebrospinal fluid (CSF) barrier formed largely by the choroid plexus (ChP) remains underexamined. To address this gap in knowledge, we used a multiplex array to measure cytokine protein abundance in postmortem ChP tissue from individuals with BD and unaffected controls, revealing elevated levels of CCL2 and SPP1, factors associated with monocyte and macrophage recruitment and activation. In contrast, expression of cytokines involved in tissue homeostasis, trophic support, and immune signaling, including OSM, IGF-1, CX3CL1, TGFB3, GDNF, LIF, BDNF, SCF, and FGFs, was reduced. Several cytokines, including CCL2 and PLGF, exhibited condition-specific divergent age trajectories. Bulk RNA sequencing of the same cohort revealed a modest set of differentially expressed genes, including transcripts associated with oxidative stress, mitochondrial function, and immune regulation that were upregulated in BD. Notably, the BD CSF biomarker NELL2 was downregulated in the ChP. Gene set enrichment analysis highlighted activation of inflammatory and cellular stress pathways, as well as reduced expression of junction-related gene programs. These findings suggest a shift in ChP function in BD characterized by increased pro-inflammatory signaling and reduced trophic and barrier-supportive activity. Together, these data identify the ChP as an active site of immune dysregulation in BD and support the broader notion of brain barrier dysfunction in mood disorder pathology. Show less

Gestational intermittent hypoxia (GIH), which serves as a model for obstructive sleep apnea (OSA), is associated with adverse maternal and neonatal outcomes, especially cognitive impairments in offspring. Growing evidence supports that the anti-inflammatory actions of melatonin significantly influence the peripartum environment and contribute to the mitigation of neurodegeneration. However, the full impact of GIH on offspring cognition and the molecular mechanisms by which melatonin modulates these effects remain uncertain. Thus, in this study, we explored the neurobiological changes in GIH-exposed offspring and the mechanism underlying maternal melatonin supplementation in preventing these alterations using a murine model. C57BL/6J mice were exposed to GIH between gestational Days 15 and 21. Concurrently, dams received either vehicle or melatonin. The Morris water maze test was employed to evaluate offspring cognitive function, after which the offspring were euthanized at 2 months of age. The hippocampal levels of glial markers (ionized calcium-binding adapter molecule 1 [Iba-1], glial fibrillary acidic protein [GFAP]), NOD-like receptor thermal protein domain-associated protein 3 [NLRP3], nuclear factor-kappa B [NF-κB], tight-junction proteins (zonula occludens-1 [ZO-1], occludin), and synaptic plasticity-related proteins (brain-derived neurotrophic factor [BDNF], tropomyosin receptor kinase B [TrkB], postsynaptic density protein 95 [PSD-95], synaptophysin [SYN]) were quantified by enzyme-linked immunosorbent assay and western blot. Maternal melatonin supplementation significantly attenuated learning and memory impairments, reduced the protein levels of Iba-1 and GFAP by suppressing NLRP3/NF-κB signaling, and elevated those of ZO-1, occludin, BDNF, TrkB, PSD-95, and SYN. Additionally, melatonin mitigated inflammatory responses, glial cell activation, blood-brain barrier (BBB) leakage, and synaptic dysfunction induced by GIH in mice. Our results demonstrated that GIH-exposed mice exhibit cognitive deficits, alongside neuroinflammatory responses, leading to inflammasome activation, glial reactivity, BBB breakdown, and synaptic deficits. However, melatonin exerted significant protective effects against these deleterious effects. Show less

Efficient, spatially selective delivery of adeno-associated virus (AAV) therapeutics to deep brain structures remains a major challenge to gene therapy for Alzheimer's disease (AD), owing to limited transport across the blood-brain barrier (BBB) and poor penetration to target neurons. Here, we establish an integrated, noninvasive imaging and therapy platform that combines microbubble-enhanced focused ultrasound (MB-FUS) with positron emission tomography/computed tomography (PET/CT) to transiently modulate the BBB, enhance region-specific AAV delivery following systemic dosing, and longitudinally track transduction in vivo. Optimized MB-FUS achieved targeted hippocampal delivery of systemically administered AAV9 in healthy mice, resulting in a 10-fold enhancement of neuronal transduction as compared to non-FUS controls. Importantly, longitudinal PET reporter gene imaging in the 5xFAD AD model demonstrated robust brain AAV transduction that remained stable for at least seven months. Finally, to assess therapeutic impact, we used brain-derived neurotrophic factor (BDNF) as a test cargo. MB-FUS-facilitated delivery elevated BDNF expression in targeted regions and produced short-term improvements in synaptic signaling in 5xFAD mice. Collectively, these results highlight MB-FUS as a next-generation delivery platform to overcome barriers to AAV therapeutic delivery in Alzheimer's disease and position longitudinal PET assessment as a critical, translatable tool for monitoring and optimizing gene therapy. Show less

Alzheimer's disease (AD) is a common neurodegenerative disorder wherein reactive oxygen species (ROS) and Amyloid-β-protein (Aβ) play critical roles. Inspired by traditional Chinese charcoal drug and the anti-inflammatory properties of some carbon dots, we developed Radix Isatidis derived carbon dots (RI-CDs) via a hydrothermal method. The RI-CDs can cross the blood-brain barrier (BBB) and were thus evaluated for AD therapy. In vitro, RI-CDs scavenged ROS, inhibited Aβ Show less

Alzheimer's disease (AD) presents a critical therapeutic gap, necessitating novel multitarget strategies. Excitotoxicity via NMDA receptor overactivation and oxidative stress is a key driver of Tau hyperphosphorylation and neuronal loss. While the tripeptide Gly-Pro-Glu (GPE) derived from IGF-1 exhibits NMDA receptor antagonism, its clinical potential is limited by poor blood-brain barrier penetration and rapid hydrolysis. Herein, we rationally designed three novel GPE-derived oligopeptide conjugates (SAC-PE, SPE, and SAR-SPE) by replacing the N-terminal glycine with antioxidant moieties (( Show less

Hyposalivation affects cognitive function. However, its impact on hippocampus-dependent memory remains unclear. Saliva contains brain-derived neurotrophic factor (BDNF), which is also synthesized in the hippocampus and can pass through the blood-brain barrier (BBB) to influence hippocampal plasticity. Therefore, we hypothesized that hyposalivation reduces peripheral BDNF availability, leading to decreased hippocampal BDNF levels and cognitive impairment. In this study, this relationship was investigated using an in vivo model of sialadenectomy-induced hyposalivation. A total of 24 8-week-old male ddY mice were divided into control and extraction (EXT) groups. The EXT group underwent submandibular and sublingual salivary gland extractions, whereas the control group underwent a sham operation. Saliva was collected at baseline (0 weeks) and at 2- and 3-weeks postoperatively. Cognitive function was assessed using the Y-maze, fear conditioning (FC), novel object recognition (NOR), and object location tests (OLT). Anxiety-like behavior was evaluated using the open field test (OFT) and elevated plus-maze (EPM) tests. Hippocampi were collected at 3 weeks post-operation for BDNF quantification using enzyme-linked immunosorbent assay, and its concentration in subregions of the hippocampus was determined by semi-quantitative analysis. Hyposalivation significantly impaired spatial working memory in the Y-maze test and contextual fear memory in the FC, both of which are hippocampus-dependent. NOR showed only a transient deficit at 24 h during the 2-week period (no significant difference in 3-week post-operation), whereas long-term spatial memory measured by the OLT exhibited a persistent 24-h impairment at both 2 and 3 weeks, indicating reduced long-term spatial memory rather than accelerated decay. No significant differences were observed in anxiety-like behavior. Although sialoadenectomy significantly reduced salivary secretion and total salivary BDNF output, the concentration of BDNF in saliva in both groups remained unchanged at 2- and 3-weeks post-operation. However, hippocampal BDNF levels were significantly lower in the EXT group than in the control group. These findings suggest that hyposalivation may selectively impair hippocampus-related spatial memory without affecting recognition memory or anxiety-related behaviors. Show less

This study was designed to explore the effects of esketamine on cognitive deficits and blood-brain barrier (BBB) dysfunction in sepsis-associated encephalopathy (SAE). An in vivo SAE model was generated through the administration of lipopolysaccharide (LPS), and LPS-induced cognitive impairment in rats was evaluated using the Morris water maze (MWM) test. BBB disruption in vivo was assessed by measuring brain water content together with Evans blue dye penetration, while LPS-induced endothelial hyperpermeability in vitro was examined through FITC-dextran leakage. The protein expression of claudin-3 and ZO-1 was determined by western blotting. In addition, the levels of pro-inflammatory cytokines, cell apoptosis, autophagy, and the activity of the BDNF/TrkB pathway were examined. Rapamycin (Rap, an autophagy inducer) and K252a (a BDNF inhibitor) were used to determine whether the protective effects of esketamine were associated with autophagy and BDNF/TrkB signaling. Esketamine treatment significantly improved the LPS-induced cognitive dysfunction and neurological injury observed in vivo, and it also inhibited the production of pro-inflammatory cytokines and reduced cell apoptosis both in vivo and in LPS-treated hCMEC/D3 cells. Importantly, esketamine alleviated BBB hyperpermeability in vivo and prevented LPS-induced endothelial leakage in vitro. Moreover, esketamine suppressed LPS-induced autophagy, and the influence of esketamine on claudin-3 and ZO-1 expression was reversed when Rap was applied. Esketamine activated the BDNF/TrkB pathway, and the protective effects of esketamine on BBB integrity and autophagy in response to LPS were abolished by K252a. Taken together, these findings indicate that esketamine protects the BBB against SAE by activating the BDNF/TrkB pathway and inhibiting autophagy, providing a potential therapeutic strategy for SAE. Show less

This study aimed to investigate how pericyte degeneration contributes to BBB disruption in Alzheimer's disease, focusing on the roles of insulin signaling and the imbalance between matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of MMPs (TIMPs). We employed an in vitro BBB model by co-culturing brain-specific microvascular endothelial-like cells (iBMECs) differentiated from human induced pluripotent stem cells (hiPSCs) and primary human brain vasculature pericytes (hBVPs). Protein expression under solo- versus co-culture conditions was assessed by western blot. MMP enzymatic activity in the culture media was measured by fluorometric assay. Exosomes were isolated from conditioned media and brain derived neurotrophic growth factor (BDNF) concentrations were determined using ELISA assays. TIMP1 and collagen-IV expression was significantly increased in co-cultured BBB endothelial cells and pericytes compared to solo-cultures. However, a greater effect was observed in cells co-cultured for 2 days than 7 days. Elevated TIMP1 in co-culture media significantly inhibited MMP activity. The AKT and ERK pathways were activated in both cell types after 7 days of co-culture, and the ERK signaling mediated TIMP1 upregulation in endothelial cells. BDNF was significantly enriched in exosomes isolated from co-culture media on the abluminal side compared to the solo-cultures. Endothelial cells also protected pericytes from accumulation of toxic amyloid-beta 42 by downregulating low density lipoprotein receptor-related protein 1 (LRP1) expression. These findings provide mechanistic insights into BBB disruption due to pericyte degeneration and highlight the important role of BBB insulin resistance in causing cerebrovascular dysfunction in AD. Show less