Brain Accumulation Research Articles

18F]SF51, a novel 18F-labeled PET radioligand for translocator protein 18kDa (TSPO) in brain, works well in monkeys but fails in humans.

[18F]SF51 is a novel radioligand for imaging translocator protein 18 kDa (TSPO) that previously displayed excellent imaging properties in nonhuman primates. This study assessed its performance in human brain and its dosimetry. Seven healthy participants underwent brain PET imaging to measure TSPO binding using a two-tissue compartment model (2TCM) to calculate total distribution volume (VT). This cohort included two high-affinity binders (HABs), three mixed-affinity binders (MABs), and two low-affinity binders (LABs). Two other participants received whole-body scans to assess radiation exposure. Peak brain radioactivity reached a standardized uptake value (SUV) of 1.4 at 3 minutes post-injection, diminishing to 30% of peak by 120 minutes. The average VT for all genotype groups was notably low (<1 mL·cm-3), emphasizing the radioligand's poor binding in brain. [18F]SF51 remained sensitive to the TSPO polymorphism in vivo, as shown by a two-fold difference in VT between HABs and LABs. VT stabilization by 80 minutes post-injection suggested minimal radiometabolite accumulation in brain. The average effective dose was 13.8 ± 0.9 µSv/MBq. Contrary to previously published animal data, [18F]SF51 showed low binding to human TSPO, with uptake remaining influenced by the rs6971 polymorphism. These findings highlight the challenges of developing TSPO radioligands and underscore the significant species differences that may influence translational outcomes.ClinicalTrials.gov identifier: NCT05564429; registered 10/03/2022.

Dopamine-conjugated extracellular vesicles induce autophagy in Parkinson's disease.

The application of extracellular vesicles (EVs) as vehicles for anti-Parkinson's agents represents a significant advance, yet their clinical translation is hampered by challenges in efficient brain delivery and complex blood-brain barrier (BBB) targeting strategies. In this study, we engineered dopamine onto the surface of adipose-derived stem cell EVs (Dopa-EVs) utilizing a facile, two-step cross-linking approach. This engineering enhanced neuronal uptake of the EVs in primary neurons and neuroblastoma cells, a process shown to be competitively inhibited by dopamine pretreatment and dopamine receptor antibodies. Notably, Dopa-EVs demonstrated increased brain accumulation in mouse Parkinson's disease (PD) models. Therapeutically, Dopa-EVs administration led to the rescue of dopaminergic neuronal loss and amelioration of behavioural deficits in both 6-hydroxydopamine (6-OHDA) and α-Syn PFF-induced PD models. Furthermore, we observed that Dopa-EVs stimulated autophagy evidenced by the upregulation of Beclin-1 and LC3-II. These findings collectively indicate that surface modification of EVs with dopamine presents a potent strategy for targeting dopaminergic neurons in the brain. The remarkable therapeutic potential of Dopa-EVs, demonstrated in PD models, positions them as a highly promising candidate for PD treatment, offering a significant advance over current therapeutic modalities.

Maternal transfer and sex-differences in brain bioaccumulation for Northern bobwhite quail (Colinus virginianus) exposed to per- and poly-fluoroalkyl substances

Per- and poly-fluoroalkyl substances (PFAS) are highly persistent chemicals commonly found in surface protectants, and class B aqueous film forming foams (AFFF), and many other consumer and industrial products. As a result of their widespread application and use, PFAS are now found in environmental media across the globe. Research has revealed that exposure to environmentally relevant concentrations of PFAS can reduce reproductive success and have immunological effects in laboratory animals, including birds. Further, PFAS can be passed down from parents to offspring, posing a threat to sensitive life stages. PFAS may enter the brain by disrupting tight junctions or binding to transporters, but our overall understanding of the interactions and accumulation of PFAS in the avian brain is limited due to the lack of data. We obtained archived samples of male-female pairs of Northern bobwhite quail (NBWQ) from chronic toxicity studies where adults were exposed to either individual PFAS or binary mixtures through drinking water for at least 60 days. PFAS were detected in the brains of exposed adult quail, while brains from control birds had only occasional detections of PFAS; mostly perfluorooctane sulfonic acid (PFOS), likely because our source of birds was pen-raised animals and many PFAS are ubiquitous. Despite similar average daily intake (ADI) for both males and females, we observed higher concentrations of most PFAS in the brains of male birds compared to female birds, with the exception of perfluoroheptanoic acid (PFHpA). For the binary mixture exposures, PFOS appeared to reduce brain concentrations of perfluorohexane sulfonic acid (PFHxS) in both males and females to levels that could not be explained by ADI differences alone. Collectively, study results demonstrated that brain accumulation of short-chain PFAS in birds was not significantly affected by sex, however, long-chain PFAS exposure resulted in avian brain accumulation with generally higher PFAS concentrations in males compared to females. The findings of this study offer insights into the accumulation of PFAS in the avian brain and suggest that there may be sex differences in potential risks associated with exposure to these pervasive chemicals.

Retraction Note: Two Mn(II)-Organic Frameworks: Selective Detection of Fe3+ Ion and Treatment Activity on Alcohol-Induced Cerebellar Atrophy by Reducing ROS Accumulation in Brain

Retraction Note: Two Mn(II)-Organic Frameworks: Selective Detection of Fe3+ Ion and Treatment Activity on Alcohol-Induced Cerebellar Atrophy by Reducing ROS Accumulation in Brain

Thorase deficiency causes both Aβ accumulation and tau hyperphosphorylation in mouse brain.

The pathogenesis of two major pathogenic characters-amyloid beta (Aβ) accumulation and hyperphosphorylated tau protein-in the brains of patients with Alzheimer's disease (AD) remains unclear. Western blot and immunofluorescence staining were performed to detect the proteins in the brains of Thorase conditional knockout/transgenic mice and their littermates. A co-immunoprecipitation assay was applied to examine the Thorase-interacting proteins. Genetic deletion of Thorase resulted in tau hyperphosphorylation and promoted Aβ accumulation in the mouse brain. Conversely, Thorase overexpression alleviated the pathogenesis of AD. Thorase regulated the phosphorylation of tau by targeting specific kinases and theprotein phosphatase 2B (PP2B). Thorase deficiency also impaired microglial phagocytosis and induced neuroinflammation by the activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3)inflammasomes in microglia. Thorase may be a potential druggable target for developing therapeutic approaches to treat AD and other neurodegenerative diseases. Thorase deletion leads to elevated amyloid beta (Aβ) deposition and hyperphosphorylated tau accumulation in the brain. Thorase regulates the phosphorylation of tau protein via PP2B. Thorase deficiency impairs microglial phagocytosis and promotesNLRP3-mediated neuroinflammation. Overexpression of Thorase alleviates Aβ deposition and tau phosphorylation in the AD mouse model.

Limosilactobacillus Fermentun ZS09 Can Improve Antibiotic-Induced Motor Dysfunction in Mice by Regulating the Brain-Gut Functions.

When consumed in appropriate quantities, probiotics, which are live microorganisms, are good for health. In this study, a mouse model of antibiotic-induced dyskinesia was established using a sterile mixed antibiotic solution to investigate the preventive impact of Limosilactobacillus fermentum ZS09 (LFZS09) on this condition in mice. Following modeling, alterations in the serum and brain tissue of mice were assessed for motor measures such as running and swimming, malondialdehyde (MDA), superoxide dismutase, reduced glutathione, interleukin (IL-6, IL-10), and tumor necrosis factor (TNF)-α. The mouse cecum was used to evaluate the relative mRNA expression levels of the intestinal barrier genes, namely occludin-1, zona occludens-1 (ZO-1), and claudin-1. The relative mRNA expression levels of cAMP-response element binding protein (CREB), extracellular signal-regulated kinase (ERK), and brain-derived neurotrophic factor (BDNF) genes in the mouse brain tissue were also evaluated. Compared with the model group, LFZS09 considerably increased the swimming and running duration of mice, significantly decreased the levels of the inflammatory factors TNF-α and IL-6 and increased SOD expression in the mouse brain, and decreased MDA accumulation in the mouse brain and serum. Furthermore, LFZS09 upregulated occludin-1 gene expression in the cecal tissue to maintain the intestinal barrier, which in turn maintained the normal physiological function of the body. LFZS09 also enhanced the effect of BDNF and increased the expression of BDNF metabolic pathway-related genes, namely CREB, ERK1/2, and BDNF, in the mouse brain tissue. LFZS09 increased the number of Lactobacillus and Bifidobacterium in the gut of mice with motor dysregulation, and decreased the number of Enterococcus and Clostridium perfringens. The findings indicate that LFZS09 regulates antibiotic-induced motor impairment in mice, thereby offering a theoretical foundation for future studies and probiotic or parabiotics production aimed at augmenting motor function.

Systematic Approach in the Development of Chitosan Functionalized Iloperidone Nanoemulsions for Transnasal Delivery, In Vitro and In Vivo Studies.

Iloperidone, a second-generation USFDA approved antipsychotic and BCS class II drug shows poor oral bioavailability of 28%. The present research deals with optimization of transnasal nanoemulsions of Iloperidone using Design Expert (Version 11) and further surface functionalization with chitosan for potentiating nose to brain delivery. Chitosan functionalized transnasal Iloperidone nanoemulsions were developed using oleic acid, charge inducer, Tween 80, TranscutolHP and chitosan using ultrasonication technique and evaluated. Droplet size, polydispersity index and zeta potential of Iloperidone nanoemulsions was found to be 173 ± 0.5nm, 0.413 ± 0.2 and - 22.5 ± 0.1mV while that of chitosan functionalized Iloperidone nanoemulsions was 146.4 ± 0.5nm, 0.291 ± 0.02 and + 23.6 ± 0.3mV respectively. Ninhydrin assay, TEM and FTIR studies confirmed surface functionalization of Iloperidone nanoemulsion droplets with chitosan. In vitro release of Iloperidone from nanoemulsions and chitosan functionalized nanoemulsions was 90.41 ± 2.1% and 72.02 ± 0.21% while ex vivo permeation of Iloperidone across goat nasal mucosa was 1270.58 ± 0.023μg/cm2 and 1096.13 ± 0.043μg/cm2 respectively at the end of 8h. Studies in RPMI 2650 nasal and Neuro2A brain cell line lines indicated safety of chitosan functionalized transnasal Iloperidone nanoemulsions. Studies in Wistar rats showed increased cataleptic effects, reduced cognitive impairment and anxiety-related behaviour with greater brain accumulation indicating promising potential of this approach in nose to brain drug delivery.

Manifestation of polystyrene microplastic accumulation in brain with emphasis on morphometric and histopathological changes in limbic areas of Swiss albino mice

The widespread problem of microplastic (MP) contamination is becoming a major threat to the globe. Although most of the research to date has concentrated on the physiological impacts of MPs exposure, a relatively new field of study is beginning to examine its effects on the behaviour and limbic regions of the brain. In this study, exposure to polystyrene MPs (PS-MPs) for acute and sub-chronic durations negatively affected cognition and induced anxiety-like behaviour in mice. PS-MPs were detected in vital organs of mice, including the brain, which induced neurobehavioural and pathological changes in the limbic system. Furthermore, morphometric analysis revealed a significant decrease in the total cell count in the Dentate Gyrus (DG) and Cornu Ammonis (CA) regions of the hippocampus. Signs of neuronal injury and dystrophic changes were observed in the cortex, amygdala, and hypothalamus, potentially affecting anxiety and fear responses. Our study thus provides insight into the effect of PS-MPs on the neurobiology of the brain’s limbic system and related behavioural alterations.

Intranasal Carrier-Free Nanomodulator Addresses Both Symptomatology and Etiology of Alzheimer's Disease by Restoring Neuron Plasticity and Reprogramming Lesion Microenvironment.

The unsatisfactory treatment outcome of Alzheimer's disease (AD) can be attributed to two primary factors, the intricate pathogenic mechanisms leading to restricted treatment effectiveness against single targets and the hindered drug accumulation in brain due to blood-brain barrier obstruction. Therefore, we developed a carrier-free nanomodulator (NanoDS) through the self-assembly of donepezil and simvastatin for direct nose-to-brain delivery. This approach facilitated a rapid and efficient traversal through the nasal epithelial barrier, enabling subsequent drug release and achieving multiple therapeutic effects. Among them, donepezil effectively ameliorated the symptoms of AD and restored synaptic plasticity. Simvastatin exerted a neurotrophic effect and facilitated the clearance of amyloid-β aggregation. At the same time, NanoDS demonstrated effective anti-inflammatory and antioxidative stress effects. This therapy for AD is approached from both symptomatic and etiological perspectives. In the treatment of FAD4T transgenic mice, it highly improved spatial memory impairment and cognitive deficits while restoring the homeostasis of brain microenvironment. Collectively, our study presented a paradigm for both achieving efficient brain delivery and offering pleiotropic therapies for AD.

Preparation, physicochemical characterization, ex vivo, and in vivo evaluations of asiatic acid-loaded solid lipid nanoparticles formulated with natural waxes for nose-to-brain delivery

Asiatic acid (AA) has neuroprotective potential for prevention and treatment of Alzheimer's disease. Natural waxes with various ratios of Tween 80 and Span 80 or soybean lecithin were formulated to obtain AA-loaded solid lipid nanoparticles (AA-SLN) to improve direct nose to brain transport. Optimal AA-SLN had particle size below 200 nm with uniform size distribution and zeta potential of nearly -30 mV indicating a low risk of particle aggregation. Formulation with rice bran wax, Tween 80, and soybean lecithin (AA-RwS100) showed the highest entrapment efficiency and yield of >98 % while in vitro AA release of AA-SLN was linearly up to 48 h For ex vivo permeation, confocal laser scanning microscopy (CLSM) and histopathological studies on porcine olfactory mucosa (OM) and respiratory mucosa (RM), AA-SLN showed significantly higher permeation across OM than RM (p < 0.05) up to 6 h and AA-RwS100 also showed the highest amount of drug permeated as confirmed by CLSM results. Although AA-SLN showed non-significantly lower permeation than AA solution (AA-SOL) (p > 0.05), no epithelial and mucosal structure damages were observed in OM treated with AA-RwS100 and RM treated with all AA-SLNs indicating safety for nasal administration while AA-SOL showed significant damage to both OM and RM. In addition, in vivo brain distribution study by fluorescence imaging using Rhodamine (R6g) showed higher brain distribution after intranasal administration of R6g-loaded solid lipid nanoparticles (R6g-SLN) than R6g solution (R6g-SOL) and intravenous administration of R6g-SLN, and R6g-RwS100 also showed the highest brain accumulation at 8 h post administration.

AIMP2 accumulation in brain leads to cognitive deficits and blood secretion in Parkinson’s disease

BackgroundPropagation of neuronal α-synuclein aggregate pathology to the cortex and hippocampus correlates with cognitive impairment in Parkinson’s disease (PD) dementia and dementia with Lewy body disease. Previously, we showed accumulation of the parkin substrate aminoacyl-tRNA synthetase interacting multifunctional protein-2 (AIMP2) in the temporal lobe of postmortem brains of patients with advanced PD. However, the potential pathological role of AIMP2 accumulation in the cognitive dysfunction of patients with PD remains unknown.MethodsWe performed immunofluorescence imaging to examine cellular distribution and accumulation of AIMP2 in brains of conditional AIMP2 transgenic mice and postmortem PD patients. The pathological role of AIMP2 was investigated in the AIMP2 transgenic mice by assessing Nissl-stained neuron counting in the hippocampal area and Barnes maze to determine cognitive functions. Potential secretion and cellular uptake of AIMP2 was monitored by dot blot analysis and immunofluorescence. The utility of AIMP2 as a new PD biomarker was evaluated by dot blot and ELISA measurement of plasma AIMP2 collected from PD patients and healthy control followed by ROC curve analysis.ResultsWe demonstrated that AIMP2 is toxic to the dentate gyrus neurons of the hippocampus and that conditional AIMP2 transgenic mice develop progressive cognitive impairment. Moreover, we found that neuronal AIMP2 expression levels correlated with the brain endothelial expression of AIMP2 in both AIMP2 transgenic mice and in the postmortem brains of patients with PD. AIMP2, when accumulated, was released from the neuronal cell line SH-SY5Y cells. Secreted AIMP2 was taken up by human umbilical vein endothelial cells. Consistent with the fact that AIMP2 can be released into the extracellular space, we showed that AIMP2 transgenic mice have higher levels of plasma AIMP2. Finally, ELISA-based assessment of AIMP2 in plasma samples from patients with PD and controls, and subsequent ROC curve analysis proved that high plasma AIMP2 expression could serve as a reliable molecular biomarker for PD diagnosis.ConclusionsThe pathological role in the hippocampus and the cell-to-cell transmissibility of AIMP2 provide new therapeutic avenues for PD treatment, and plasma AIMP2 combined with α-synuclein may improve the accuracy of PD diagnosis in the early stages.

Distinct regional vulnerability to Aβ and iron accumulation in post mortem AD brains.

The paramagnetic iron, diamagnetic amyloid beta (Aβ) plaques and their interaction are crucial in Alzheimer's disease (AD) pathogenesis, complicating non-invasive magnetic resonance imaging for prodromal AD detection. We used a state-of-the-art sub-voxel quantitative susceptibility mapping method to simultaneously measure Aβ and iron levels in post mortem human brains, validated by histology. Further transcriptomic analysis using Allen Human Brain Atlas elucidated the underlying biological processes. Regional increased paramagnetic and diamagnetic susceptibility were observed in medial prefrontal, medial parietal, and para-hippocampal cortices associated with iron deposition (R=0.836, p=0.003) and Aβ accumulation (R=0.853, p=0.002) in AD brains. Higher levels of gene expression relating to cell cycle, post-translational protein modifications, and cellular response to stress were observed. These findings provide quantitative insights into the variable vulnerability of cortical regions to higher levels of Aβ aggregation, iron overload, and subsequent neurodegeneration, indicating changes preceding clinical symptoms. The vulnerability of distinct brain regions to amyloid beta (Aβ) and iron accumulation varies. Histological validation was performed on stained sections of ex-vivo human brains. Regional variations in susceptibility were linked to gene expression profiles. Iron and Aβ levels in ex-vivo brains were simultaneously quantified.

Brain Exposure to the Macrocyclic ALK Inhibitor Zotizalkib is Restricted by ABCB1, and Its Plasma Disposition is Affected by Mouse Carboxylesterase 1c.

Zotizalkib (TPX-0131), a fourth-generation macrocyclic anaplastic lymphoma kinase (ALK) inhibitor, is designed to overcome resistance due to secondary ALK mutations in non-small cell lung cancer (NSCLC). We here evaluated the pharmacokinetic roles of the ABCB1 (P-gp/MDR1) and ABCG2 (BCRP) efflux transporters, OATP1 influx transporters and the metabolizing enzymes CES1 and CYP3A in plasma and tissue disposition of zotizalkib after oral administration in relevant mouse models. Zotizalkib was efficiently transported by hABCB1 in vitro. In vivo, a significant ∼9-fold higher brain-to-plasma ratio was observed in Abcb1a/b-/- and Abcb1a/b;Abcg2-/- compared to wild-type mice. No change in brain disposition was observed in Abcg2-/- mice, suggesting that mAbcb1a/b markedly restricts the brain accumulation of zotizalkib. ABCB1-mediated efflux of zotizalkib was completely inhibited by elacridar, a dual ABCB1/ABCG2 inhibitor, increasing brain exposure without any signs of acute CNS-related toxicities. In Oatp1a/b-/- mice, no marked changes in plasma exposure or tissue-to-plasma ratios were observed, indicating that zotizalkib is not a substantial in vivo substrate for mOatp1a/b. Zotizalkib may further be metabolized by CYP3A4 but only noticeably at low plasma concentrations. In Ces1-/- mice, a 2.5-fold lower plasma exposure was seen compared to wild-type, without alterations in tissue distribution. This suggests increased plasma retention of zotizalkib by binding to the abundant mouse plasma Ces1c. Notably, the hepatic expression of human CES1 did not affect zotizalkib plasma exposure or tissue distribution. The obtained pharmacokinetic insights may be useful for the further development and optimization of therapeutic efficacy and safety of zotizalkib and related compact macrocyclic ALK inhibitors.

Altered copper transport in oxidative stress-dependent brain endothelial barrier dysfunction associated with Alzheimer's disease

Oxidative stress and blood-brain barrier (BBB) disruption due to brain endothelial barrier dysfunction contribute to Alzheimer's Disease (AD), which is characterized by beta-amyloid (Aβ) accumulation in senile plaques. Copper (Cu) is implicated in AD pathology and its levels are tightly controlled by several Cu transport proteins. However, their expression and role in AD, particularly in relation to brain endothelial barrier function remains unclear. In this study, we examined the expression of Cu transport proteins in the brains of AD mouse models as well as their involvement in Aβ42-induced brain endothelial barrier dysfunction. We found that the Cu uptake transporter CTR1 was upregulated, while the Cu exporter ATP7A was downregulated in the hippocampus of AD mouse models and in Aβ42-treated human brain microvascular endothelial cells (hBMECs). In the 5xFAD AD mouse model, Cu levels (assessed by ICP-MS) were elevated in the hippocampus. Moreover, in cultured hBMECs, Aβ42-induced reactive oxygen species (ROS) production, ROS-dependent loss in barrier function (measured by transendothelial electrical resistance), and tyrosine phosphorylation of CDH5 were all inhibited by either a membrane permeable Cu chelator or by knocking down CTR1 expression. These findings suggest that dysregulated expression of Cu transport proteins may lead to intracellular Cu accumulation in the AD brain, and that Aβ42 promotes ROS-dependent brain endothelial barrier dysfunction and CDH5 phosphorylation in a CTR1-Cu-dependent manner. Our study uncovers the critical role of Cu transport proteins in oxidative stress-related loss of BBB integrity in AD.

Heteroaryl derivatives of suvorexant as OX1R selective PET ligand candidates: Cu-mediated 18F-fluorination of boroxines, in vitro and initial in vivo evaluation

BackgroundThe orexin receptor (OXR) plays a role in drug addiction and is aberrantly expressed in colorectal tumors. Subtype-selective OXR PET ligands suitable for in vivo use have not yet been reported. This work reports the development of 18F-labeled OXR PET ligand candidates derived from the OXR antagonist suvorexant and the OX1R-selective antagonist JH112.ResultsComputational analysis predicted that fluorine substitution (1e) and introduction of the fluorobenzothiazole scaffold (1f) would be suitable for maintaining high OX1R affinity. After multi-step synthesis of 1a–1f, in vitro OXR binding studies confirmed the molecular dynamics calculations and revealed single-digit nanomolar OX1R affinities for 1a–f, ranging from 0.69 to 2.5 nM. The benzothiazole 1f showed high OX1R affinity (Ki = 0.69 nM), along with 77-fold subtype selectivity over OX2R. Cu-mediated 18F-fluorination of boroxine precursors allowed for a shortened reaction time of 5 min to provide the non-selective OXR ligand [18F]1c and its selective OX1R congener [18F]1f in activity yields of 14% and 22%, respectively, within a total synthesis time of 52–76 min. [18F]1c and [18F]1f were stable in plasma and serum in vitro, with logD7.4 of 2.28 ([18F]1c) and 2.37 ([18F]1f), and high plasma protein binding of 66% and 77%, respectively. Dynamic PET imaging in rats showed similar brain uptake of [18F]1c (0.17%ID/g) and [18F]1f (0.15%ID/g). However, preinjection of suvorexant did not significantly block [18F]1c or [18F]1f uptake in the rat brain. Pretreatment with cyclosporine A to study the role of P-glycoprotein (P-gp) in limiting brain accumulation moderately increased brain uptake of [18F]1c and [18F]1f. Accordingly, in vitro experiments demonstrated that the P-gp inhibitor zosuquidar only moderately inhibited polarized, basal to apical transport of 1c (p < 0.05) and had no effect on the transport of 1f, indicating that P-gp does not play a relevant role in brain accumulation of [18F]1c and [18F]1f in vivo.ConclusionsThe in vitro and in vivo results of [18F]1c and [18F]1f provide a solid basis for further development of suitable OXR PET ligands for brain imaging.

Cell-penetrating peptides TAT and 8R functionalize P22 virus-like particles to enhance tissue distribution and retention in vivo.

Virus-like particles (VLPs) are used as nanocontainers for targeted drug, protein, and vaccine delivery. The phage P22 VLP is an ideal macromolecule delivery vehicle, as it has a large exterior surface area, which facilitates multivalent genetic and chemical modifications for cell recognition and penetration. Arginine-rich cell-penetrating peptides (CPPs) can increase cargo transport efficiency in vivo. However, studies on the tissue distribution and retention of P22 VLPs mediated by TAT and 8R are lacking. This study aimed to analyze the TAT and 8R effects on the P22 VLPs transport efficiency and tissue distribution both in vitro and in vivo. We used a prokaryotic system to prepare P22 VLP self-assembled particles and expressed TAT-or 8R-conjugated mCherry on the VLP capsid protein as model cargoes and revealed that the level of P22 VLP-mCherry penetrating the cell membrane was low. However, both TAT and 8R significantly promoted the cellular uptake efficiency of P22 VLPs in vitro, as well as enhanced the tissue accumulation and retention of P22 VLPs in vivo. At 24 h postinjection, TAT enhanced the tissue distribution and retention in the lung, whereas 8R could be better accumulation in brain. Thus, TAT was superior in terms of cellular uptake and tissue accumulation in the P22 VLPs delivery system. Understanding CPP biocompatibility and tissue retention will expand their potential applications in macromolecular cargo delivery.

Active Immunotherapy for the Prevention of Alzheimer's and Parkinson's Disease.

Neurodegenerative diseases (ND) give rise to significant declines in motor, autonomic, behavioral, and cognitive functions. Of these conditions, Alzheimer's disease (AD) and Parkinson's disease (PD) are the most prevalent, impacting over 55 million people worldwide. Given the staggering financial toll on the global economy and their widespread manifestation, NDs represent a critical issue for healthcare systems worldwide. Current treatment options merely seek to provide symptomatic relief or slow the rate of functional decline and remain financially inaccessible to many patients. Indeed, no therapy has yet demonstrated the potential to halt the trajectory of NDs, let alone reverse them. It is now recognized that brain accumulation of pathological variants of AD- or PD-associated proteins (i.e., amyloid-β, Tau, α-synuclein) begins years to decades before the onset of clinical symptoms. Accordingly, there is an urgent need to pursue therapies that prevent the neurodegenerative processes associated with pathological protein aggregation long before a clinical diagnosis can be made. These therapies must be safe, convenient, and affordable to ensure broad coverage in at-risk populations. Based on the need to intervene long before clinical symptoms appear, in this review, we present a rationale for greater investment to support the development of active immunotherapy for the prevention of the two most common NDs based on their safety profile, ability to specifically target pathological proteins, as well as the significantly lower costs associated with manufacturing and distribution, which stands to expand accessibility to millions of people globally.

The effect of iron status on gadolinium deposition in the rat brain: mechanistic implications.

Introduction: Sites associated with gadolinium (Gd) deposition in the brain (e.g., the globus pallidus) are known to contain high concentrations of ferric iron. There is considerable debate over the mechanism of Gd deposition in the brain. The role of iron transport mechanisms in Gd deposition has not been determined. Thus, we seek to identify if Gd deposition can be controlled by modifying iron exposure. Methods: Female Sprague-Dawley rats were given diets with controlled iron levels at 2-6ppm, 6ppt (20g/kg Fe carbonyl) or 48ppm for 3weeks to induce iron deficiency, overload or normalcy. They were kept on those diets while receiving a cumulative 10mmol/kg dose of gadodiamide intravenously over 2weeks, then left to washout gadodiamide for 3days or 3weeks before tissues were harvested. Gd concentrations in tissues were analyzed by ICP-MS. Results: There were no significant effect of dietary iron and total Gd concentrations in the organs, but there was a significant effect of iron status on Gd distribution in the brain. For the 3-week washout cohort, there was a non-significant trend of increasing total brain deposition and decreasing dietary iron, and about 4-fold more Gd in the olfactory bulbs of the low iron group compared to the other groups. Significant brain accumulation was observed in the low iron group total brain Gd in the 3-week washout group relative to the 3-day washout group and no accumulation was observed in other tissues. There was a strong negative correlation between femur Gd concentrations and concentrations in other organs when stratifying by dietary iron. Discussion: Gd brain deposition from linear Gd-based contrast agents (GBCAs) are dependent upon iron status, likely through variable transferrin saturation. This iron dependence appears to be associated with redistribution of peripheral deposited Gd (e.g., in the bone) into the brain.

Associations between Brain Alpha-Tocopherol Stereoisomer Profile and Hallmarks of Brain Aging in Centenarians.

Brain alpha-tocopherol (αT) concentration was previously reported to be inversely associated with neurofibrillary tangle (NFT) counts in specific brain structures from centenarians. However, the contribution of natural or synthetic αT stereoisomers to this relationship is unknown. In this study, αT stereoisomers were quantified in the temporal cortex (TC) of 47 centenarians in the Georgia Centenarian Study (age: 102.2 ± 2.5 years, BMI: 22.1 ± 3.9 kg/m2) and then correlated with amyloid plaques (diffuse and neuritic plaques; DPs, NPs) and NFTs in seven brain regions. The natural stereoisomer, RRR-αT, was the primary stereoisomer in all subjects, accounting for >50% of total αT in all but five subjects. %RRR was inversely correlated with DPs in the frontal cortex (FC) (ρ = -0.35, p = 0.032) and TC (ρ = -0.34, p = 0.038). %RSS (a synthetic αT stereoisomer) was positively correlated with DPs in the TC (ρ = 0.39, p = 0.017) and with NFTs in the FC (ρ = 0.37, p = 0.024), TC (ρ = 0.42, p = 0.009), and amygdala (ρ = 0.43, p = 0.008) after controlling for covariates. Neither RRR- nor RSS-αT were associated with premortem global cognition. Even with the narrow and normal range of BMIs, BMI was correlated with %RRR-αT (ρ = 0.34, p = 0.021) and %RSS-αT (ρ = -0.45, p = 0.002). These results providing the first characterization of TC αT stereoisomer profiles in centenarians suggest that DP and NFT counts, but not premortem global cognition, are influenced by the brain accumulation of specific αT stereoisomers. Further study is needed to confirm these findings and to determine the potential role of BMI in mediating this relationship.

Polystyrene nanoplastics induced learning and memory impairments in mice by damaging the glymphatic system

The excessive usage of nanoplastics (NPs) has posed a serious threat to the ecological environment and human health, which can enter the brain and then result in neurotoxicity. However, research on the neurotoxic effects of NPs based on different exposure routes and modifications of functional groups is lacking. In this study, the neurotoxicity induced by NPs was studied using polystyrene nanoplastics (PS-NPs) of different modifications (PS, PS-COOH, and PS-NH2). It was found that PS-NH2 through intranasal administration (INA) exposure route exhibited the greatest accumulation in the mice brain after exposure for 7 days. After the mice were exposed to PS-NH2 by INA means for 28 days, the exploratory ability and spatial learning ability were obviously damaged in a dose-dependent manner. Further analysis indicated that these damages induced by PS-NH2 were closely related to the decreased ability of glymphatic system to clear β-amyloid (Aβ) and phosphorylated Tau (P-Tau) proteins, which was ascribed to the loss of aquaporin-4 (AQP4) polarization in the astrocytic endfeet. Moreover, the loss of AQP4 polarization might be regulated by the NF-κB pathway. Our current study establishes the connection between the neurotoxicity induced by PS-NPs and the glymphatic system dysfunction for the first time, which will contribute to future research on the neurotoxicity of NPs.