ABSTRACT
Amyloid-ß, tau pathology, and biomarkers of neurodegeneration make up the core diagnostic biomarkers of Alzheimer disease (AD). However, these proteins represent only a fraction of the complex biological processes underlying AD, and individuals with other brain diseases in which AD pathology is a comorbidity also test positive for these diagnostic biomarkers. More AD-specific early diagnostic and disease staging biomarkers are needed. In this study, we performed tandem mass tag proteomic analysis of paired cerebrospinal fluid (CSF) and serum samples in a discovery cohort comprising 98 participants. Candidate biomarkers were validated by parallel reaction monitoring-based targeted proteomic assays in an independent multicenter cohort comprising 288 participants. We quantified 3,238 CSF and 1,702 serum proteins in the discovery cohort, identifying 171 and 860 CSF proteins and 37 and 323 serum proteins as potential early diagnostic and staging biomarkers, respectively. In the validation cohort, 58 and 21 CSF proteins, as well as 12 and 18 serum proteins, were verified as early diagnostic and staging biomarkers, respectively. Separate 19-protein CSF and an 8-protein serum biomarker panels were built by machine learning to accurately classify mild cognitive impairment (MCI) due to AD from normal cognition with areas under the curve of 0.984 and 0.881, respectively. The 19-protein CSF biomarker panel also effectively discriminated patients with MCI due to AD from patients with other neurodegenerative diseases. Moreover, we identified 21 CSF and 18 serum stage-associated proteins reflecting AD stages. Our findings provide a foundation for developing blood-based tests for AD screening and staging in clinical practice.
ABSTRACT
Genetic factors play an important role in early-onset Parkinson's disease (EOPD). The genetic spectrum of patients with EOPD varies widely among different ethnicities, with extensive investigations having been performed in Caucasian populations; however, research in Chinese populations remains limited. In this study, we performed multiplex ligation-dependent probe amplification assay and whole-exome sequencing in 15 unrelated Chinese EOPD patients with age of onset before 40 years. Among them, a patient carried compound heterozygous exon duplications in Parkin (exon 3 duplication and exon 4 duplication) (6.67 %) and two patients carried the homozygous pathogenic variant (p.D331Y) in PLA2G6 (13.33 %). Three novel variants in EIF4G1 (p.P1043S, p.R1505Q, and p.P266A) were identified and classified as uncertain significance. Additionally, a risk variant in GBA (p.L483P) was detected in one patient (6.67 %). PLA2G6 (13.33 %) was the most common causative gene among our EOPD patients. Furthermore, detailed clinical features were presented. Our results broaden the genetic spectrum and clinical phenotypic spectrum of EOPD patients.
Subject(s)
Parkinson Disease , Humans , Adult , Parkinson Disease/genetics , Age of Onset , Mutation , Ubiquitin-Protein Ligases/genetics , ChinaABSTRACT
Familial Alzheimer's disease (FAD) present as a positive family history of cognitive decline, with early onset and an autosomal dominant inheritance pattern. FAD is mainly caused by the mutations in the genes encoding for amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2). In the present study, we identified a variant (c.529T > G, p.Phe177Val) in PSEN1 across three generations in a Chinese family with FAD using whole-exome sequencing. The mean age of onset was 39 years (range: 37 to 40 years) in this family. In cell transfection studies, the mutant PSEN1 protein carrying p.Phe177Val increased both the production of Aß42 and the ratio of Aß42 over Aß40, as compared to wild-type PSEN1. Our results confirm the pathogenicity of PSEN1 p.Phe177Val variant in FAD and broaden the clinical phenotype spectrum of FAD patients with PSEN1 p.Phe177Val variant.
ABSTRACT
AIM: Appoptosin (SLC25A38) is a pro-apoptotic protein, which is upregulated in Alzheimer's disease (AD) brains and plays an important role in promoting the pathological progress of AD. The aim of this study was to investigate the effects of curcumin from the rhizome of Curcuma longa on appoptosin-induced apoptosis in SH-SY5Y cells. METHODS: SH-SY5Y cells were pretreated with curcumin, then transfected with appoptosin or vector. The apoptotic cells were detected with Annexin V staining analysis by flow cytometry. The expression of cleaved caspase-3, appoptosin, heme oxygenase-1 (HO-1) was examined using Western blotting. Intracellular level of ROS was measured with DCFH-DA staining by flow cytometry analysis. Mitochondrial membrane potential (ΔΨm) was detected with JC-1 staining under a fluorescence microscope and quantified by fluorescence ratio detection.Overexpression of appoptosin in SH-SY5Y cells markedly increased cell apoptosis accompanied by reduced HO-1 expression, increased intracellular heme level, ROS overproduction and ΔΨm impairment. Treatment of SH-SY5Y cells with curcumin (2.5-20 µmol/L) for 24 h did not significantly affect their viability. However, pretreatment with curcumin (2.5-20 µmol/L) dose-dependently attenuated all above-mentioned pathological changes in appoptosin-transfected SH-SY5Y cells. RESULTS: Overexpression of appoptosin in SH-SY5Y cells markedly increased cell apoptosis accompanied by reduced HO-1 expression, increased intracellular heme level, ROS overproduction and ΔΨm impairment. Treatment of SH-SY5Y cells with curcumin (2.5-20 µmol/L) for 24 h did not significantly affect their viability. However, pretreatment with curcumin (2.5-20 µmol/L) dose-dependently attenuated all above-mentioned pathological changes in appoptosin-transfected SH-SY5Y cells. CONCLUSION: Curcumin inhibits appoptosin-induced apoptosis in SH-SY5Y cells by upregulating the expression of HO-1, reducing the production of intracellular heme and ROS, and preventing the ΔΨm loss.
