Multi-tissue proteomics identifies molecular signatures for sporadic and genetically defined Alzheimer disease cases

Alzheimer disease (AD) is a heterogeneous disease with many genes are associated with AD risk. Most proteomic studies, while instrumental in identifying AD pathways and genes, focus on single tissues and sporadic AD cases. Multi-tissue proteomic signatures for sporadic and genetically defined AD (e.g., pathogenic variant carriers in APP and PSEN1/2 and risk variant carriers in TREM2) will illuminate the biology of this heterogeneous disease.1,2 Here, we present one of the largest multi-tissue proteomic profiles, accessible through our web portal, based on 1,305 proteins in brain (n=360), cerebrospinal fluid (CSF; n=717), and plasma (n=490) from the Knight Alzheimer Disease Research Center (Knight ADRC) and Dominantly Inherited Alzheimer Network (DIAN) cohorts.3-5 We identified proteomic signatures in brain, CSF, and plasma for sporadic AD status and replicated these findings in multiple, independent datasets. The area under the curve (AUC) for CSF proteins was 0.89 in discovery and 0.90 in the replication dataset, which was significantly higher than the AUC for CSF p-tau181/Aβ42 (AUC = 0.81; P = 2.4×10-6). We also identified a specific proteomic signature for TREM2 variant carriers that differentiated TREM2 variant carriers from sporadic AD cases and controls with high sensitivity and specificity (AUC = 0.81 - 1). In addition, the proteins that showed differential levels in sporadic AD were also altered in autosomal dominant AD, but with greater effect size (1.4 times, P = 3.8×10-5), and proteins associated with autosomal dominant AD, in brain tissue also replicated on CSF (p=1.36×10-9). Enrichment analyses highlighted several pathways including AD (calcineurin, APOE, GRN), Parkinson disease (α-synuclein, LRRK2), and innate immune response (SHC1, MAPK3, SPP1) for the sporadic AD or TREM2 variant carriers. Our findings show the power of multi-tissue proteomics’ contribution to the understanding of AD biology and to the creation of tissue-specific prediction models for individuals with specific genetic profiles, ultimately supporting its utility in creating individualized disease risk evaluation and treatment.

A Proteomics Study on the Mechanism of Nutmeg-Induced Hepatotoxicity

Nutmeg is a traditional spice and medicinal plant with a variety of pharmacological activities. However, nutmeg abuse due to its hallucinogenic characteristics and poisoning cases are frequently reported. Our previous metabolomics study proved the hepatotoxicity of nutmeg and demonstrated that high-dose nutmeg can affect the synthesis and secretion of bile acids and cause oxidative stress. In order to further investigate the hepatotoxicity of nutmeg, normal saline, 1 g/kg, 4 g/kg nutmeg were administrated to male Kunming mice by intragastrical gavage for 7 days. Histopathological investigation of liver tissue, proteomics and biochemical analysis were employed to explore the mechanism of liver damage caused by nutmeg. The results showed that a high-dose (4 g/kg) of nutmeg can cause significant increased level of CYP450s and depletion of antioxidants, resulting in obvious oxidative stress damage and lipid metabolism disorders; but this change was not observed in low-dose group (1 g/kg). In addition, the increased level of malondialdehyde and decreased level of glutathione peroxidase were found after nutmeg exposure. Therefore, the present study reasonably speculates that nutmeg exposure may lead to liver injury through oxidative stress and the degree of this damage is related to the exposure dose.

Tissue Proteomic Approaches to Understand the Pathogenesis of Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) has become a global disease encompassing a group of progressive disorders characterized by recurrent chronic inflammation of the gut with variable disease courses and complications. Despite recent advances in the knowledge of IBD pathophysiology, the elucidation of its etiopathology and progression is far from fully understood, requiring complex and multiple approaches. Therefore, limited clinical progress in diagnosis, assessment of disease activity, and optimal therapeutic regimens have been made over the past few decades. This review explores recent advances and challenges in tissue proteomics with an emphasis on biomarker discovery and better understanding of the molecular mechanisms underlying IBD pathogenesis. Future multi-omic studies are required for the comprehensive molecular characterization of disease biology in real time with a future impact on early detection, disease monitoring, and prediction of the clinical outcome.

MALDI-IMS combined with shotgun proteomics identify and localize new factors in male infertility

Spermatogenesis is a complex multi-step process involving intricate interactions between different cell types in the male testis. Disruption of these interactions results in infertility. Combination of shotgun tissue proteomics with MALDI imaging mass spectrometry is markedly potent in revealing topological maps of molecular processes within tissues. Here, we use a combinatorial approach on a characterized mouse model of hormone induced male infertility to uncover misregulated pathways. Comparative testicular proteome of wild-type and mice overexpressing human P450 aromatase (AROM+) with pathologically increased estrogen levels unravels gross dysregulation of spermatogenesis and emergence of pro-inflammatory pathways in AROM+ testis. In situ MS allowed us to localize misregulated proteins/peptides to defined regions within the testis. Results suggest that infertility is associated with substantial loss of proteomic heterogeneity, which define distinct stages of seminiferous tubuli in healthy animals. Importantly, considerable loss of mitochondrial factors, proteins associated with late stages of spermatogenesis and steroidogenic factors characterize AROM+ mice. Thus, the novel proteomic approach pinpoints in unprecedented ways the disruption of normal processes in testis and provides a signature for male infertility.

Postmortem Tissue Proteomics Reveals the Pathogenesis of Multiorgan Injuries of COVID-19

Multiorgan injuries are a major complication of severe COVID-19; however, its pathogenesis is barely understood. Herein, we profiled the host responses to SARS-CoV-2 infection by performing quantitative proteomics of COVID-19 postmortem samples, and provided a comprehensive proteome map covering the protein alterations in eight different organs/tissues. Our results revealed that lung underwent the most abundant protein alterations mainly enriched in immune-/inflammation-related or morphology-related processes, while surprisingly, other organs/tissues exhibited significant protein alterations mainly enriched in processes related with organ movement, respiration, and metabolism. These results indicate that the major cause of lung injury was excessive inflammatory response, and subsequent intravascular thrombosis and pulmonary architecture/function destruction, while other organs/tissues were mainly injured by hypoxia and functional impairment. Therefore, our findings demonstrate the significant pathophysiological alternations of host proteins/pathways associated with multiorgan injuries of COVID-19, which provides invaluable knowledge about COVID-19-associated host responses and sheds light on the pathogenesis of COVID-19.

Imaging mass spectrometry and shotgun proteomics reveal dysregulated pathways in hormone induced male infertility

Spermatogenesis is a complex multi-step process involving intricate interactions between different cell types in the male testis. Disruption of these interactions results in infertility. Combination of shotgun tissue proteomics with MALDI imaging mass spectrometry is markedly potent in revealing topological maps of molecular processes within tissues. Here, we use a combinatorial approach on a characterized mouse model of hormone induced male infertility to uncover misregulated pathways. Comparative testicular proteome of wildtype and mice overexpressing human P450 aromatase (AROM+) with pathologically increased estrogen levels unravels gross dysregulation of spermatogenesis and emergence of proinflammatory pathways in AROM+ testis. In situ MS allowed us to localize misregulated proteins/peptides to defined regions within the testis. Results suggest that infertility is associated with substantial loss of proteomic heterogeneity, which define distinct stages of seminiferous tubuli in healthy animals. Importantly, considerable loss of mitochondrial factors, proteins associated with late stages of spermatogenesis and steroidogenic factors characterise AROM+ mice. Thus, the novel proteomic approach pinpoints in unprecedented ways the disruption of normal processes in testis and provides a signature for male infertility.