Dual-targeted magnetic mesoporous silica nanoparticles reduce brain amyloid-ß burden via depolymerization and intestinal metabolism.

Rationale: Active removal of excess peripheral amyloid-ß (Aß) can potentially treat Alzheimer's disease (AD). However, the peripheral clearance of Aß using an anti-Aß monoclonal antibody (mAb) cannot remove PET-detectable Aß within the brain. This may be due to the inability of mAb to cross the blood-brain barrier (BBB) to degrade insoluble brain Aß plaques and block liver dysfunction. Methods: We developed a dual-targeted magnetic mesoporous silica nanoparticle (HA-MMSN-1F12) through surface-coupled Aß42-targeting antibody 1F12 and CD44-targeting ligand hyaluronic acid (HA). Results: HA-MMSN-1F12 had a high binding affinity toward Aß42 oligomers (Kd = 1.27 ± 0.34 nM) and revealed robust degradation of Aß42 aggregates. After intravenous administration of HA-MMSN-1F12 into ten-month-old APP/PS1 mice for three weeks (4 mg/kg/week), HA-MMSN-1F12 could cross the BBB and depolymerize brain Aß plaques into soluble Aß species. In addition, it also avoided hepatic uptake and excreted captured Aß species through intestinal metabolism, thereby reducing brain Aß load and neuroinflammation and improving memory deficits of APP/PS1 mice. Furthermore, the biochemical analysis showed that HA-MMSN-1F12 did not detect any toxic side effects on the liver and kidney. Thus, the efficacy of HA-MMSN-1F12 is associated with the targeted degradation of insoluble brain Aß plaques, avoidance of non-specific hepatic uptake, and excretion of peripheral Aß through intestinal metabolism. Conclusions: The study provides a new avenue for treating brain diseases by excreting disease-causing biohazards using intestinal metabolism.

Mesoporous silica nanoparticle-encapsulated Bifidobacterium attenuates brain Aß burden and improves olfactory dysfunction of APP/PS1 mice by nasal delivery.

BACKGROUND: Dysbiosis or imbalance of gut microbiota in Alzheimer's disease (AD) affects the production of short-chain fatty acids (SCFAs), whereas exogenous SCFAs supplementation exacerbates brain Aß burden in APP/PS1 mice. Bifidobacterium is the main producer of SCFAs in the gut flora, but oral administration of Bifidobacterium is ineffective due to strong acids and bile salts in the gastrointestinal tract. Therefore, regulating the levels of SCFAs in the gut is of great significance for AD treatment. METHODS: We investigated the feasibility of intranasal delivery of MSNs-Bifidobacterium (MSNs-Bi) to the gut and their effect on behavior and brain pathology in APP/PS1 mice. RESULTS: Mesoporous silica nanospheres (MSNs) were efficiently immobilized on the surface of Bifidobacterium. After intranasal administration, fluorescence imaging of MSNs-Bi in the abdominal cavity and gastrointestinal tract revealed that intranasally delivered MSNs-Bi could be transported through the brain to the peripheral intestine. Intranasal administration of MSNs-Bi not only inhibited intestinal inflammation and reduced brain Aß burden but also improved olfactory sensitivity in APP/PS1 mice. CONCLUSIONS: These findings suggested that restoring the balance of the gut microbiome contributes to ameliorating cognitive impairment in AD, and that intranasal administration of MSNs-Bi may be an effective therapeutic strategy for the prevention of AD and intestinal disease.

Current trends in blood biomarker detection and imaging for Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease that causes cognitive impairments in areas such as memory, language, and reasoning. Currently, a definitive diagnosis of AD is based on histological examination of brain specimens. Hence, it is imperative to develop practical AD detection and diagnostic tools. Blood tests are less invasive, more accessible than lumbar puncture for cerebrospinal fluid collection, and are an ideal source of biomarkers. Various detection techniques related to AD biomarkers have emerged, and have been used in the detection of AD blood samples. However, to improve the diagnostic accuracy of AD blood testing in clinical practice, basic research needs more detailed guidelines to determine how to implement the use of biomarkers in diagnostic procedures. Therefore, combining blood biomarker detection with imaging markers may help improve the accuracy of AD diagnosis. In this review, we discuss the development trend of AD-related blood biomarker detection technologies including optoelectrical analysis platforms, and look forward to the development prospects of joint detection with optoelectronic and imaging technologies in clinical diagnosis.

Visualizing dynamic changes in PD-L1 expression in non-small cell lung carcinoma with radiolabeled recombinant human PD-1.

PURPOSE: Tumor heterogeneity limits the predictive value of PD-L1 expression and influences the outcomes of the immunohistochemical assay for therapy-induced changes in PD-L1 levels. This study aimed to determine the predictive value of PD-L1 for non-small cell lung carcinoma (NSCLC), thereby developing imaging agents to non-invasively image and examine the effect of the therapeutic response to PD-L1 blockade therapy. METHODS: A cohort of 102 patients with lung cancer was analyzed, and the prognostic significance of PD-L1 expression level was investigated. Recombinant human PD-1 ECD protein (rhPD1) was expressed, purified, and labeled with 64Cu for the evaluation of PD-L1 status in tumors. Mice subcutaneously bearing PD-L1 high-expressing tumor HCC827 and PD-L1 low-expressing tumor A549 were used to determine tracer-target specificity and examine the effect of therapeutic response to PD-L1 blockade therapy. RESULTS: PD-L1 was proved to be a good prognosis marker for NSCLC, and its expression was correlated with the histology of NSCLC. PET imaging revealed high tumor accumulation of 64Cu-NOTA-rhPD1 in HCC827 tumors (9.0 ± 0.5%ID/g), whereas it was 3.2 ± 0.4%ID/g in A549 tumors at 3 h post-injection. The lower tumor uptake (3.1 ± 0.3%ID/g) of 64Cu-labeled denatured rhPD1 in HCC827 tumors at 3 h post-injection (p < 0.001) demonstrated the target specificity of 64Cu-NOTA-rhPD1. Furthermore, PET showed that 64Cu-NOTA-rhPD1 sensitively monitored treatment-related changes in PD-L1 expression, and seemed to be superior to [18F]FDG. CONCLUSION: We identified PD-L1 as a good prognosis marker for surgically resected NSCLC and developed the PET tracer 64Cu-NOTA-rhPD1 with high target specificity for PD-L1.

Nanozyme sensor array based on manganese dioxide for the distinction between multiple amyloid ß peptides and their dynamic aggregation process.

The determination of the amyloid ß (Aß) peptide and its aggregation intermediates helps to understand the pathological mechanism of Alzheimer's disease (AD) caused by toxic amyloid fragments. Because of the transient and heterogeneous properties of Aß aggregates, it is very difficult to dynamically detect Aß and its aggregation intermediates. Herein, we successfully constructed a two-dimensional manganese dioxide (MnO2) nanozyme sensor array by modulating the peroxidase-mimicking activity using various Aß species and accurately distinguished among six types of Aß within 1 h through linear discriminant analysis (LDA), with a dynamic detection range of 0.01-500 nmol/L and a detection limit of 0.44 pmol/L. Subsequently, 30 unknown blind samples were used to verify the practicability of the sensor array, and all unknown samples were identified with 100% accuracy. It is worth noting that the sensor array successfully distinguished healthy individuals from AD patients using clinical blood samples. This study provides a convenient and reliable nanozyme biosensing system for detecting Aß species and their related aggregation processes.

Dynamic Changes in the Levels of Amyloid-ß42 Species in the Brain and Periphery of APP/PS1 Mice and Their Significance for Alzheimer's Disease.

Although amyloid-ß42 (Aß42) has been used as one of the core biomarkers for Alzheimer's disease (AD) diagnosis, the dynamic changes of its different forms in the brain, blood, and even intestines and its correlation with the progression of AD disease remain obscure. Herein, we screened Aß42-specific preferred antibody pairs 1F12/1F12 and 1F12/2C6 to accurately detect Aß42 types using sandwich ELISA, including total Aß42, Aß42 oligomers (Aß42Os), and Aß42 monomers (Aß42Ms). The levels of Aß42 species in the brain, blood, and intestines of different aged APP/PS1 mice were quantified to study their correlation with AD progression. Total Aß42 levels in the blood were not correlated with AD progression, but Aß42Ms level in the blood of 9-month-old APP/PS1 mice was significantly reduced, and Aß42Os level in the brain was significantly elevated compared to 3-month-old APP/PS1, demonstrating that the levels of Aß42Ms and Aß42Os in the blood and brain were correlated with AD progression. Interestingly, in 9-month-old APP/PS1 mice, the level of Aß42 in the intestine was higher than that in 3-month-old APP/PS1 mice, indicating that the increased level of Aß42 in the gastrointestinal organs may also be related to the progression of AD. Meanwhile, changes in the gut microbiota composition of APP/PS1 mice with age were also observed. Therefore, the increase in Aß derived from intestinal tissues and changes in microbiome composition can be used as a potential early diagnosis tool for AD, and further used as an indicator of drug intervention to reduce brain amyloid.