5-FAM-Amyloid β-Protein (1-42)

Background: Increases in blood of amyloid beta-protein (Aβ) have been noted in patients with Alzheimer's dementia (AD). Recent studies have shown that blood amyloid beta-protein 1-42 (Aβ1-42) level is closely related to poststroke cognitive impairment (PSCI), which may be the influencing factor and even a predictor of PSCI. The aim of this systematic review was to synthesize the evidence for the association of cognitive impairment among PSCI. Methods: PubMed (MEDLINE), EMBASE, Cochrane Library, the Cochrane Central Register of Controlled Trial (CENTRAL), CNKI, and WanFang data were searched. Case-control, cohort, and cross-sectional studies that evaluated the association between blood Aβ1-42 and PSCI were included irrespective of language and date of publication. The outcomes of this review consisted of (1) any dementia, (2) any cognitive impairment, and (3) any cognitive impairment no dementia, which were assessed at least 3 months (90 days) after stroke. Exposure of interest was blood Aβ1-42 level (including serum and plasma). Results: Of 617 records retrieved, 8 studies (6 case-control and 2 cohort studies) involving 931 stroke patients were included for further analysis. 8 studies with 931 subjects explored the correlation between Aβ1-42 and PSCI. PSCI was reported in 457 patients, and the pooled SMD of amyloid beta-protein 1-42 was -0.96 (95% CI -1.10~-0.82, I 2 = 15%, P < 0.01). The results remained robust in sensitivity analysis adjusting for study quality, sample source, and cognitive scale score in analysis of studies, as well as in analysis adjusted for publication bias. Conclusions: Blood Aβ1-42 level was significantly negatively related to the risk for PSCI, and more prospective studies with large sample size are needed to define a precise threshold value of blood Aβ1-42 level to predict PSCI in the future. This study is registered with PROSPERO, registration number: CRD42021246165.

To facilitate clinical trials of disease-modifying therapies for Alzheimer's disease, which are expected to be most efficacious at the earliest and mildest stages of the disease, supportive biomarker information is necessary. The only validated methods for identifying amyloid-β deposition in the brain-the earliest pathological signature of Alzheimer's disease-are amyloid-β positron-emission tomography (PET) imaging or measurement of amyloid-β in cerebrospinal fluid. Therefore, a minimally invasive, cost-effective blood-based biomarker is desirable. Despite much effort, to our knowledge, no study has validated the clinical utility of blood-based amyloid-β markers. Here we demonstrate the measurement of high-performance plasma amyloid-β biomarkers by immunoprecipitation coupled with mass spectrometry. The ability of amyloid-β precursor protein (APP)669-711/amyloid-β (Aβ)1-42 and Aβ1-40/Aβ1-42 ratios, and their composites, to predict individual brain amyloid-β-positive or -negative status was determined by amyloid-β-PET imaging and tested using two independent data sets: a discovery data set (Japan, n = 121) and a validation data set (Australia, n = 252 including 111 individuals diagnosed using 11C-labelled Pittsburgh compound-B (PIB)-PET and 141 using other ligands). Both data sets included cognitively normal individuals, individuals with mild cognitive impairment and individuals with Alzheimer's disease. All test biomarkers showed high performance when predicting brain amyloid-β burden. In particular, the composite biomarker showed very high areas under the receiver operating characteristic curves (AUCs) in both data sets (discovery, 96.7%, n = 121 and validation, 94.1%, n = 111) with an accuracy approximately equal to 90% when using PIB-PET as a standard of truth. Furthermore, test biomarkers were correlated with amyloid-β-PET burden and levels of Aβ1-42 in cerebrospinal fluid. These results demonstrate the potential clinical utility of plasma biomarkers in predicting brain amyloid-β burden at an individual level. These plasma biomarkers also have cost-benefit and scalability advantages over current techniques, potentially enabling broader clinical access and efficient population screening.

The present study was designed to investigate the role of β-amyloid (Aβ1-42 ) in inducing neuronal pyroptosis and its mechanism. Mice cortical neurons (MCNs) were used in this study, LPS + Nigericin was used to induce pyroptosis in MCNs (positive control group), and Aβ1-42 was used to interfere with MCNs. In addition, propidium iodide (PI) staining was used to examine cell permeability, lactate dehydrogenase (LDH) release assay was employed to detect cytotoxicity, immunofluorescence (IF) staining was used to investigate the expression level of the key protein GSDMD, Western blot was performed to detect the expression levels of key proteins, and enzyme-linked immunosorbent assay (ELISA) was utilized to determine the expression levels of inflammatory factors in culture medium, including IL-1β, IL-18 and TNF-α. Small interfering RNA (siRNA) was used to silence the mRNA expression of caspase-1 and GSDMD, and Aβ1-42 was used to induce pyroptosis, followed by investigation of the role of caspase-1-mediated GSDMD cleavage in pyroptosis. In addition, necrosulfonamide (NSA), an inhibitor of GSDMD oligomerization, was used for pre-treatment, and Aβ1-42 was subsequently used to observe the pyroptosis in MCNs. Finally, AAV9-siRNA-caspase-1 was injected into the tail vein of APP/PS1 double transgenic mice (Alzheimer's disease mice) for caspase-1 mRNA inhibition, followed by observation of behavioural changes in mice and measurement of the expression of inflammatory factors and pyroptosis-related protein. As results, Aβ1-42 could induce pyroptosis in MCNs, increase cell permeability and enhance LDH release, which were similar to the LPS + Nigericin-induced pyroptosis. Meanwhile, the expression levels of cellular GSDMD and p30-GSDMD were up-regulated, the levels of NLRP3 inflammasome and GSDMD-cleaved protein caspase-1 were up-regulated, and the levels of inflammatory factors in the medium were also up-regulated. siRNA intervention in caspase-1 or GSDMD inhibited Aβ1-42 -induced pyroptosis, and NSA pre-treatment also caused the similar inhibitory effects. The behavioural ability of Alzheimer's disease (AD) mice was relieved after the injection of AAV9-siRNA-caspase-1, and the expression of pyroptosis-related protein in the cortex and hippocampus was down-regulated. In conclusion, Aβ1-42 could induce pyroptosis by GSDMD protein, and NLRP3-caspase-1 signalling was an important signal to mediate GSDMD cleavage, which plays an important role in Aβ1-42 -induced pyroptosis in neurons. Therefore, GSDMD is expected to be a novel therapeutic target for AD.