Red light-induced localized release of carbon monoxide for alleviating postoperative cognitive dysfunction.

Inflammation within the central nervous system (CNS), which may be triggered by surgical trauma, has been implicated as a significant factor contributing to postoperative cognitive dysfunction (POCD). The relationship between mitigating inflammation at peripheral surgical sites and its potential to attenuate the CNS inflammatory response, thereby easing POCD symptoms, remains uncertain. Notably, carbon monoxide (CO), a gasotransmitter, exhibits pronounced anti-inflammatory effects. Herein, we have developed carbon monoxide-releasing micelles (CORMs), a nanoparticle that safely and locally liberates CO upon exposure to 650 nm light irradiation. In a POCD mouse model, treatment with CORMs activated by light (CORMs + hv) markedly reduced the concentrations of interleukin (IL)-6, IL-1ß, and tumor necrosis factor-alpha (TNF-α) in both the peripheral blood and the hippocampus, alongside a decrease in ionized calcium-binding adapter molecule 1 in the hippocampal CA1 region. Furthermore, CORMs + hv treatment diminished Evans blue extravasation, augmented the expression of tight junction proteins zonula occludens-1 and occludin, enhanced neurocognitive functions, and fostered fracture healing. Bioinformatics analysis and experimental validation has identified Htr1b and Trhr as potential key regulators in the neuroactive ligand-receptor interaction signaling pathway implicated in POCD. This work offers new perspectives on the mechanisms driving POCD and avenues for therapeutic intervention.

Highly BBB-permeable nanomedicine reverses neuroapoptosis and neuroinflammation to treat Alzheimer's disease.

The prevalence of Alzheimer's disease (AD) is increasing globally due to population aging. However, effective clinical treatment strategies for AD still remain elusive. The mechanisms underlying AD onset and the interplay between its pathological factors have so far been unclear. Evidence indicates that AD progression is ultimately driven by neuronal loss, which in turn is caused by neuroapoptosis and neuroinflammation. Therefore, the inhibition of neuroapoptosis and neuroinflammation could be a useful anti-AD strategy. Nonetheless, the delivery of active drug agents into the brain parenchyma is hindered by the blood-brain barrier (BBB). To address this challenge, we fabricated a black phosphorus nanosheet (BP)-based methylene blue (MB) delivery system (BP-MB) for AD therapy. After confirming the successful preparation of BP-MB, we proved that its BBB-crossing ability was enhanced under near-infrared light irradiation. In vitro pharmacodynamics analysis revealed that BP and MB could synergistically scavenge excessive reactive oxygen species (ROS) in okadaic acid (OA)-treated PC12 cells and lipopolysaccharide (LPS)-treated BV2 cells, thus efficiently reversing neuroapoptosis and neuroinflammation. To study in vivo pharmacodynamics, we established a mouse model of AD mice, and behavioral tests confirmed that BP-MB treatment could successfully improve cognitive function in these animals. Notably, the results of pathological evaluation were consistent with those of the in vitro assays. The findings demonstrated that BP-MB could scavenge excessive ROS and inhibit Tau hyperphosphorylation, thereby alleviating downstream neuroapoptosis and regulating the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Overall, this study highlights the therapeutic potential of a smart nanomedicine with the capability of reversing neuroapoptosis and neuroinflammation for AD treatment.

Nanotechnology approaches to drug delivery for the treatment of ischemic stroke.

Ischemic stroke is a major global public health concern that lacks effective treatment options. A significant challenge lies in delivering therapeutic agents to the brain due to the restrictive nature of the blood-brain barrier (BBB). The BBB's selectivity hampers the delivery of therapeutically relevant quantities of agents to the brain, resulting in a lack of FDA-approved pharmacotherapies for stroke. In this article, we review therapeutic agents that have been evaluated in clinical trials or are currently undergoing clinical trials. Subsequently, we survey strategies for synthesizing and engineering nanoparticles (NPs) for drug delivery to the ischemic brain. We then provide insights into the potential clinical translation of nanomedicine, offering a perspective on its transformative role in advancing stroke treatment strategies. In summary, existing literature suggests that drug delivery represents a major barrier for clinical translation of stroke pharmacotherapies. While nanotechnology has shown significant promise in addressing this challenge, further advancements aimed at improving delivery efficiency and simplifying formulations are necessary for successful clinical translation.

Omega-3 Polyunsaturated Fatty Acids and Blood-Brain Barrier Integrity in Major Depressive Disorder: Restoring Balance for Neuroinflammation and Neuroprotection.

Major depressive disorder (MDD), affecting over 264 million individuals globally, is associated with immune system dysregulation and chronic neuroinflammation, potentially linked to neurodegenerative processes. This review examines blood-brain barrier (BBB) dysfunction in MDD, focusing on key regulators like matrix metalloproteinase 9 (MMP9), aquaporin-4 (AQP4), and ATP-binding cassette subfamily B member 1 (ABCB1). We explore potential mechanisms by which compromised BBB integrity in MDD may contribute to neuroinflammation and discuss the therapeutic potential of omega-3 polyunsaturated fatty acids (n-3 PUFAs). n-3 PUFAs have demonstrated anti-inflammatory and neuroprotective effects, and potential ability to modulate MMP9, AQP4, and ABCB1, thereby restoring BBB integrity in MDD. This review aims to elucidate these potential mechanisms and evaluate the evidence for n-3 PUFAs as a strategy to mitigate BBB dysfunction and neuroinflammation in MDD.

Disruption of blood-brain barrier and endothelial-to-mesenchymal transition are attenuated by Astragalus polysaccharides mediated through upregulation of ETS1 expression in experimental autoimmune encephalomyelitis.

Blood-brain barrier (BBB) breakdown, an early hallmark of multiple sclerosis (MS), remains crucial for MS progression. Our previous works have confirmed that Astragalus polysaccharides (APS) can significantly ameliorate demyelination and disease progression in experimental autoimmune encephalomyelitis (EAE) mice. However, it remains unclear whether APS protects BBB and the potential mechanism. In this study, we found that APS effectively reduced BBB leakage in EAE mice, which was accompanied by a decreased level of endothelial-to-mesenchymal transition (EndoMT) in the central nervous system (CNS). We further induced EndoMT in the mouse brain endothelial cells (bEnd.3) by interleukin-1ß (IL-1ß) in vitro. The results showed that APS treatment could inhibit IL-1ß-induced EndoMT and endothelial cell dysfunction. In addition, the transcription factor ETS1 is a central regulator of EndoMT related to the compromise of BBB. We tested the regulation of APS on ETS1 and identified the expression of ETS1 was upregulated in both EAE mice and bEnd.3 cells by APS. ETS1 knockdown facilitated EndoMT and endothelial cell dysfunction, which completely abolished the regulatory effect of APS. Collectively, APS treatment could protect BBB integrity by inhibiting EndoMT, which might be associated with upregulating ETS1 expression. Our findings indicated that APS has potential value in the prevention of MS.

Association Between Blood-Brain Barrier Disruption and Stroke-Associated Pneumonia in Acute Ischemic Stroke Patients After Endovascular Therapy: A Retrospective Cohort Study.

Background: Stroke, particularly due to large vessel occlusion (LVO), is a major cause of mortality and disability globally. Endovascular therapy (ET) significantly improves outcomes for acute ischemic stroke (AIS) patients, but complications such as stroke-associated pneumonia (SAP) increase mortality and healthcare costs. This study investigates the association between blood-brain barrier (BBB) disruption and the increased risk of SAP and explores the relationship between BBB disruption and medium-term functional outcomes. Methods: The retrospective cohort study was performed on AIS patients enrolled between January 2019 to February 2023 who underwent ET. Patients were divided into two groups: BBB disruption and without BBB disruption. Multiple logistic regression model was conducted to measure the association between BBB disruption and SAP. Mediation analysis was used to estimate the potential mediation effects on the associations of BBB disruption with SAP. A restricted cubic spline (RCS) regression model was used to further outline the connection between the highest CT value of hyperattenuated lesions areas and the risk of SAP. Results: The study included 254 patients who underwent endovascular therapy, with 155 patients in the BBB disruption group (exposure) and 99 patients in the without BBB disruption group (control). Multiple logistic regression analysis revealed a significantly increased risk of SAP in patients with BBB disruption (OR = 2.337, 95% CI: 1.118-4.990, p = 0.025). Furthermore, mediation analysis suggested that this association may be partly due to malignant cerebral oedema and haemorrhagic transformation. The study found an inverse L-shaped dose-response relationship between the maximum CT values of BBB disruption areas and the incidence of SAP. SAP partially mediated the association between BBB disruption and 3-month poor functional outcome. Conclusion: BBB disruption are a potential risk factor for SAP. BBB disruption may affect short- and medium-term prognosis of patients after ET in part through SAP.

Ferroptosis and pathogenesis of neuritic plaques in Alzheimer's Disease.

Neuritic plaques are pathognomonic and terminal lesions of Alzheimer's Disease (AD). They embody AD pathogenesis because they harbor in one space critical pathologic features of the disease: amyloid deposits, neurofibrillary degeneration (NFD), neuroinflammation, iron accumulation. Neuritic plaques are thought to arise from the conversion of diffuse extracellular deposits of amyloid beta protein (Aß), and it is believed that during conversion amyloid toxicity creates the dystrophic neurites of neuritic plaques, as well as neurofibrillary tangles (NFTs). However, recent evidence from human post-mortem studies suggests a much different mechanism of neuritic plaque formation where the first step in their creation is neuronal degeneration driven by iron overload and ferroptosis. Similarly, NFTs represent corpses of iron-laden neurons that develop independent of Aß deposits. In this review, we will focus on the role of free redox-active iron in the development of typical AD pathology, as determined largely by evidence obtained in human temporal lobe during early, preclinical stages of AD. The findings have allowed construction of a scheme of AD pathogenesis where brain iron is center stage and is involved in every step of the sequence of events that produce characteristic AD pathology. We will discuss how the study of preclinical AD has produced a fresh and revised assessment of AD pathogenesis that may be important for reconsidering current therapeutic efforts and guiding future ones. Significance Statement This review offers a novel perspective on AD pathogenesis where elevated brain iron plays a central role and is involved throughout the development of lesions. We review arguments against the amyloid cascade theory and explain how recent findings in humans during early preclinical disease support iron-mediated cell death and endogenous iron containment mechanisms as critical components of neuritic plaque formation and the ensuing dementia.

Exploring chitosan nanoparticles for enhanced therapy in neurological disorders: a comprehensive review.

Chitosan nanoparticles have emerged as a promising therapeutic platform for treating neurological disorders due to their biocompatibility, biodegradability, and ease of functionalization. One of the significant challenges in treating neurological conditions is overcoming the blood-brain barrier (BBB), which restricts the effective delivery of therapeutic agents to the brain. Addressing this barrier is crucial for the successful treatment of various neurological diseases, including Alzheimer's disease, Parkinson's disease, epilepsy, migraine, psychotic disorders, and brain tumors. Chitosan nanoparticles offer several advantages: they enhance drug absorption, protect drugs from degradation, and enable targeted delivery. These properties open new possibilities for non-invasive therapies for neurological conditions. Numerous studies have highlighted the neuroprotective potential of chitosan nanoparticles, demonstrating improved outcomes in animal models of neurodegeneration and neuroinflammation. Additionally, surface modifications of these nanoparticles allow for the attachment of specific ligands or molecules, enhancing the precision of drug delivery to neuronal cells. Despite these advancements, several challenges persist in the clinical translation of chitosan nanoparticles. Issues such as large-scale production, regulatory hurdles, and the need for further research into long-term safety must be addressed. This review explores recent advancements in the use of chitosan nanoparticles for managing neurological disorders and outlines potential future directions in this rapidly evolving field of research.

Ulinastatin modulates NLRP3 inflammasome pathway in PTZ-induced epileptic mice: A potential mechanistic insight.

Objective: The NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome-driven immune-inflammatory response has been shown to play a critical role in epilepsy progression across multiple studies. While Ulinastatin (UTI), an immunomodulatory agent known to target the NLRP3 pathway in neurological disorders, its implications in epilepsy have not been extensively studied. This investigation aims to explore UTI's role and underlying mechanisms in epilepsy. Methods: To assess UTI's effects on epilepsy severity, neuroinflammation, and BBB integrity, a pentylenetetrazole (PTZ)-induced epilepsy model in mice and a co-culture system involving BV2 and HT22 cells stimulated by lipopolysaccharide (LPS) and ATP were employed. Techniques utilized included qPCR, Western blotting, ELISA, immunohistochemistry (IHC) staining, Evans Blue dye extravasation, glutamate assays, the Morris water maze, and Annexin V apoptosis assays. Results: In the PTZ model, UTI administration led to a substantial decrease in seizure intensity and susceptibility, inhibited NLRP3 inflammasome activation, reduced neuroinflammatory interactions, lowered hippocampal and systemic inflammatory mediator levels, and improved cognitive performance. Furthermore, UTI upregulated claudin-5 expression, a tight junction protein in the endothelium, and diminished Evans Blue dye leakage, indicating improved BBB integrity. In BV2 and HT22 cell co-culture models, UTI exerted neuroprotective effects by mitigating microglia-mediated neurotoxicity and fostering neuronal recovery. Conclusions: The findings demonstrate that UTI exerts transformative regulatory effects on the NLRP3 inflammasome in epilepsy models. This intervention effectively suppresses neuroinflammation, lessens seizure severity and susceptibility, and ameliorates epilepsy-related BBB dysfunction and cognitive impairments.

Sex-dependent temporal changes in astrocyte-vessel interactions following diffuse traumatic brain injury in rats.

Traumatic brain injury (TBI) is associated with diffuse axonal injury (DAI), a primary pathology linked to progressive neurodegeneration and neuroinflammation, including chronic astrogliosis, which influences long-term post-TBI recovery and morbidity. Sex-based differences in blood-brain barrier (BBB) permeability increases the risk of accelerated brain aging and early-onset neurodegeneration. However, few studies have evaluated chronic time course of astrocytic responses around cerebrovascular in the context of aging after TBI and sex dependence. We observed increased glial fibrillary acidic protein (GFAP)-labeled accessory processes branching near and connecting with GFAP-ensheathed cortical vessels, suggesting a critical nuance in astrocyte-vessel interactions after TBI. To quantify this observation, male and female Sprague Dawley rats (∼3 months old, n = 5-6/group) underwent either sham surgery or midline fluid percussion injury. Using immunohistochemical analysis, we quantified GFAP-labeled astrocyte primary and accessory processes that contacted GFAP-ensheathed vessels in the somatosensory barrel cortex at 7, 56, and 168 days post-injury (DPI). TBI significantly increased GFAP-positive primary processes at 7 DPI (P < 0.01) in both sexes. At 56 DPI, these vessel-process interactions remained significantly increased exclusively in males (P < 0.05). At 168 DPI, both sexes showed a significant reduction in vessel-process interactions compared to 7 DPI (P < 0.05); however, a modest but significant injury effect reemerged in females (P < 0.05). A similar sex-dependent pattern in the number of accessory processes provides novel evidence of long-term temporal changes in astrocyte-vessel interactions. TBI-induced changes in astrocyte-vessel interactions may indicate chronic BBB vulnerability and processes responsible for early onset vascular and neurodegenerative pathology.

From blood to brain: Exploring the role of fibrinogen in the pathophysiology of depression and other neurological disorders.

Recent findings indicate that fibrinogen, a protein involved in blood clotting, plays a significant role in neuroinflammation and mood disorders. Elevated fibrinogen levels are consistently observed in individuals with depression, potentially contributing to microglial activation. This could impair fibrinolysis and contribute to a pro-inflammatory environment in the brain. This neuroinflammatory response can impair neuroplasticity, a key process for learning, memory, and mood regulation. Fibrinogen may also indirectly influence neurotransmitters like serotonin, which play a vital role in mood regulation. Furthermore, fibrinogen's interaction with astrocytes may trigger a cascade of events leading to demyelination, a process where the protective sheath around nerve fibers deteriorates. This can disrupt communication within the nervous system and contribute to depression symptoms. Intriguingly, targeting fibrinogen or related pathways holds promise for therapeutic interventions. For instance, modulating PAI-1 (Plasminogen activator inhibitor-1) activity or inhibiting fibrinogen's interaction with brain cells could be potential strategies. This review explores the multifaceted relationship between fibrinogen and neurological disorders with a focus on depression highlighting its potential as a therapeutic target. Further research is necessary to fully elucidate the mechanisms underlying this association and develop effective therapeutic strategies targeting the fibrinolytic system for mood disorders.

First-line zorifertinib for EGFR-mutant non-small cell lung cancer with central nervous system metastases: The phase 3 EVEREST trial.

BACKGROUND: Zorifertinib (AZD3759), an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) with high blood-brain barrier penetration capability, demonstrated promising intracranial and systemic antitumor activity in phase 1 and 2 studies in central nervous system (CNS)-metastatic patients. METHODS: In this phase 3 EVEREST trial (ClinicalTrials.gov: NCT03653546), patients with EGFR-sensitizing mutations, advanced treatment-naive non-small cell lung cancer (NSCLC), and non-irradiated symptomatic or asymptomatic CNS metastases were randomized (1:1) to zorifertinib or first-generation EGFR-TKI (gefitinib or erlotinib; control). The primary endpoint was blinded independent central review (BICR)-assessed progression-free survival (PFS) per RECIST1.1. FINDINGS: Overall, 439 patients were randomized (zorifertinib n = 220; control n = 219). Most patients had the EGFR L858R mutation (55%) or >3 CNS lesions (54%). Median PFS was significantly longer with zorifertinib versus control (9.6 versus 6.9 months; hazard ratio [HR], 0.719; 95% confidence interval [CI], 0.580-0.893; p = 0.0024). Zorifertinib significantly prolonged intracranial PFS versus control (BICR per modified RECIST1.1: HR, 0.467; 95% CI, 0.352-0.619; investigator per RANO-BM: HR, 0.627; 95% CI, 0.466-0.844). Overall survival (OS) was immature; the estimated median OS was 37.3 months with zorifertinib and 31.8 months with control (HR, 0.833; 95% CI, 0.524-1.283) in patients subsequently treated with third-generation EGFR-TKIs. Safety profiles were consistent with previously reported data for zorifertinib. CONCLUSIONS: Zorifertinib significantly improved systemic and intracranial PFS versus first-generation EGFR-TKIs; adverse events were manageable. Sequential use of zorifertinib and third-generation EGFR-TKIs showed the potential to prolong patients' survival. The results favor zorifertinib as a novel, well-validated first-line option for CNS-metastatic patients with EGFR-mutant NSCLC. FUNDING: This work was funded by Alpha Biopharma (Jiangsu) Co., Ltd., China.

Hypoxia-Induced Inflammation in In Vitro Model of Human Blood-Brain Barrier: Modulatory Effects of the Olfactory Ensheathing Cell-Conditioned Medium.

Hypoxia compromises the integrity of the blood-brain barrier (BBB) and increases its permeability, thereby inducing inflammation. Olfactory ensheathing cells (OECs) garnered considerable interest due to their neuroregenerative and anti-inflammatory properties. Here, we aimed to investigate the potential modulatory effects of OEC-conditioned medium (OEC-CM) on the response of human brain microvascular endothelial cells (HBMECs), constituting the BBB, when exposed to hypoxia. HBMECs were utilized to establish the in vitro BBB model. OECs were isolated from mouse olfactory bulbs, and OEC-CM was collected after 48 h of culture. The effect of OEC-CM treatment on the HBMEC viability was evaluated under both normoxic and hypoxic conditions at 6 h, 24 h, and 30 h. Western blot and immunostaining techniques were employed to assess NF-κB/phospho-NF-κB expression. HIF-1α, VEGF-A, and cPLA2 mRNA expression levels were quantified using digital PCR. ELISA assays were performed to measure PGE2, VEGF-A, IL-8 secretion, and cPLA2 specific activity. The in vitro formation of HBMEC capillary-like structures was examined using a three-dimensional matrix system. OEC-CM attenuated pro-inflammatory responses and mitigated the HIF-1α/VEGFA signaling pathway activation in HBMECs under hypoxic condition. Hypoxia-induced damage of the BBB can be mitigated by novel therapeutic strategies harnessing OEC potential.

Blood-Brain Barrier-Penetrating Metal-Organic Framework Antioxidant Nanozymes for Targeted Ischemic Stroke Therapy.

Overproduction of reactive oxygen species (ROS) during reperfusion in ischemic stroke (IS) severely impedes neuronal survival and results in high rates of morbidity and disability. The effective blood-brain barrier (BBB) penetration and brain delivery of antioxidative agents remain the biggest challenge in treating ischemic reperfusion-induced cerebrovascular and neural injury. In this study, a metal-organic framework (MOF) nanozyme (MIL-101-NH2(Fe/Cu)) with ROS scavenging activities to encapsulate neuroprotective agent rapamycin is fabricated and decorating the exterior with BBB-targeting protein ligands (transferrin), thereby realizing enhanced drug retention and controlled release within ischemic lesions for the synergistic treatment of IS. Through the receptor-mediated transcellular pathway, the transferrin-coated MOF nanoparticles achieved efficient transport across the BBB and targeted accumulation at the cerebral ischemic injury site of mice with middle cerebral artery occlusion/reperfusion (MCAO/R), wherein the nanocarrier exhibited catalytic activities of ROS decomposition into O2 and H2O2-responsive rapamycin release. By its BBB-targeting, antioxidative, anti-inflammatory, and antiapoptotic properties, the MOF nanosystem addressed multiple pathological factors of IS and realized remarkable neuroprotective effects, leading to the substantial reduction of cerebral infarction volume and accelerated recovery of nerve functions in the MCAO/R mouse model. This MOF-based nanomedicine provides valuable design principles for effective IS therapy with multi-mechanism synergies.

Utilizing Multifaceted Approaches to Target Drug Delivery in the Brain: From Nanoparticles to Biological Therapies.

The blood-brain barrier (BBB) poses an important obstacle to treating neurological disorders because it limits the entry of therapeutic agents into the central nervous system (CNS). Surmounting this barrier is crucial for delivering drugs effectively and targeting precise areas of the brain affected by conditions like Parkinson's disease, Alzheimer's disease, and brain tumors. This review examines the diverse strategies employed to enhance brain targeting, including nanotechnology, viral vectors, and biological therapies. Nanoparticles, liposomes, and dendrimers offer promising approaches for encapsulating drugs and facilitating their transport across the BBB. Viral vectors, such as adeno-associated viruses, demonstrate high transfection efficiency for gene therapy applications in CNS diseases. Biological therapies, including stem cell transplantation and neuromodulation techniques, can potentially restore normal cellular function and treat genetic disorders. Challenges such as BBB permeability, safety concerns, and regulatory considerations are discussed, along with future perspectives on precision medicine, noninvasive delivery methods, and biomarker discovery. By addressing these challenges and embracing innovative approaches, the field of brain drug targeting aims to transfer the way that neurological illness is treated and improve patient outcomes.

Frontiers of Neurodegenerative Disease Treatment: Targeting Immune Cells in Brain Border Regions.

Neurodegenerative diseases (NDs) demonstrate a complex interaction with the immune system, challenging the traditional view of the brain as an "immune-privileged" organ. Microglia were once considered the sole guardians of the brain's immune response. However, recent research has revealed the critical role of peripheral immune cells located in key brain regions like the meninges, choroid plexus, and perivascular spaces. These previously overlooked cells are now recognized as contributors to the development and progression of NDs. This newfound understanding opens doors for pioneering therapeutic strategies. By targeting these peripheral immune cells, we may be able to modulate the brain's immune environment, offering an alternative approach to treat NDs and circumvent the challenges posed by the blood-brain barrier. This comprehensive review will scrutinize the latest findings on the complex interactions between these peripheral immune cells and NDs. It will also critically assess the prospects of targeting these cells as a ground-breaking therapeutic avenue for these debilitating disorders.

Single domain antibody-scFv conjugate targeting amyloid ß and TfR penetrates the blood-brain barrier and interacts with amyloid ß.

Neurodegenerative diseases such as Alzheimer's disease (AD) pose substantial challenges to patients and health-care systems, particularly in countries with aging populations. Immunotherapies, including the marketed antibodies lecanemab (Leqembi®) and donanemab (KisunlaTM), offer promise but face hurdles due to limited delivery across the blood-brain barrier (BBB). This limitation necessitates high doses, resulting in increased costs and a higher risk of side effects. This study explores transferrin receptor (TfR)-binding camelid single-domain antibodies (VHHs) for facilitated brain delivery. We developed and evaluated fusion proteins (FPs) combining VHHs with human IgG Fc domains or single-chain variable fragments (scFvs) of the anti-amyloid-beta (Aß) antibody 3D6. In vitro assessments showed varying affinities of the FPs for TfR. In vivo evaluations indicated that specific VHH-Fc and VHH-scFv fusions reached significant brain concentrations, emphasizing the importance of optimal TfR binding affinities. The VHH-scFv fusions were further investigated in mouse models with Aß pathology, showing higher retention compared to wild-type mice without Aß pathology. Our findings suggest that these novel VHH-based FPs hold potential for therapeutic and diagnostic applications in AD, providing a strategy to overcome BBB limitations and enhance brain targeting of antibody-based treatments. Furthermore, our results suggest that a given bispecific TfR-binding fusion format has a window of "optimal" affinity where parenchymal delivery is adequate, while blood pharmacokinetics aligns with the desired application of the fusion protein.

Association between risk of Alzheimer's disease and related dementias and angiotensin receptor â ¡ blockers treatment for individuals with hypertension in high-volume claims data.

BACKGROUND: Findings regarding the protective effect of Angiotensin II receptor blockers (ARBs) against Alzheimer's disease and related dementias (AD/ADRD) and cognitive decline have been inconclusive. METHODS: Individuals with hypertension who do not have any prior ADRD diagnosis were included in this retrospective cohort study from Optum's de-identified Clinformatics® Data Mart. We identified antihypertensive medication (AHM) drug classes and subclassified ARBs by blood-brain barrier (BBB) permeability. We compared baseline characteristics and used the Kaplan-Meier (KM) survival curve and adjusted Cox proportional hazards (PH) model for survival analyses. FINDINGS: From 6,390,826 individuals with hypertension, there were 1,839,176 ARB users, 3,366,841 non-ARB AHM users, and 1,184,809 AHM non-users. The unadjusted KM curve showed that ARB users had lower cumulative hazard than other AHM users or AHM non-users (P < 0.0001). In Cox PH analysis, ARB users showed a 20% lower adjusted hazard of developing ADRD compared to angiotensin-converting enzyme inhibitor (ACEI) users and a 29% and 18% reduced hazard when compared to non-ARB/ACEI AHM users and AHM non-users (all P < 0.0001). Consumption of BBB-crossing ARBs was linked to a lower hazard of ADRD development than non-BBB-crossing ARBs, undetermined ARBs, and non-consumption of AHMs by 11%, 25%, and 31% (all P < 0.0001). INTERPRETATION: This study suggests that ARBs are superior to ACEIs, non-ARB/ACEI AHMs, or non-use of AHMs in reducing the hazard of ADRD among patients with hypertension. Also, BBB-permeability in ARBs was associated with lower ADRD incidence. There is no cure for AD, ADRD, or vascular dementia; hence, these findings are significant in preventing those disorders in an inexpensive, convenient, and safe way. Limitations in claims data should be considered when interpreting our findings. FUNDING: This research was supported by the National Institute on Aging grants (R01AG084236, R01AG083039, RF1AG072799, R56AG074604).

Atomically precise Fluorescent Gold Nanocluster as a barrier-permeable and brain-specific imaging probe.

Photonic nanomaterials play a crucial role in facilitating the necessary signal for optical brain imaging, presenting a promising avenue for early diagnosis of brain-related disorders. However, the blood-brain barrier (BBB) presents a significant challenge, blocking the entry of most molecules or materials from the bloodstream into the brain. To overcome this, photonic nanocrystals in the form of gold clusters (LAuC) with size less than 3nm, have been developed, with Levodopa conjugated to LAuC (Dop@LAuC) for targeted brain imaging. Dop@LAuC crosses the BBB and emits in the near-infrared (NIR) wavelength, enabling real-time optical brain imaging. An in vitro BBB model using brain endothelial cells showed that 50% of Dop@LAuC crossed the barrier within 3 hours, compared to only 10% of LAuC, highlighting the enhanced ability of L-dopa-conjugated gold clusters to penetrate the BBB. In vivo optical imaging in healthy mice further confirmed the material's efficacy to cross BBB without compromising the barrier integrity.