👤 Edison Osorio

Protein biomarkers in biofluids are highly sensitive indicators of prodromal cognitive impairment yet remain limited for primary prevention. Lipids, essential to brain structure and function, offer untapped prognostic value. Here, we identify a lipidomic signature in serum from asymptomatic PSEN1-E280A mutation carriers aged 6-40 years, that differentiate carriers from non-carriers with an AUC 80-90%. Similarly, to symptomatic carriers (≥41 years; 93%) and sporadic AD cases (85%), using high-resolution mass spectrometry. Latent profile analysis revealed lipid-based signatures of dementia risk and resilience, shaped by genotype, sex, and APOE isoform, and supported by SIMOA protein biomarkers. Age-dependent dysregulation in sphingolipid and glycolipid metabolism was validated by enzymatic activity (TLC), glial phenotyping (flow cytometry), and gene expression (snRNAseq) in postmortem brain. Ganglioside clearance deficits emerged by age 6-12, followed by proinflammatory shifts from age 13 and p-tau217 elevation by age 20, with greater burden in females and APOE4 carriers. APOE3Ch individuals showed differential salvage pathways of ceramides and gangliosides. These findings position early lipid pathway dysregulation as a biological contributor to Alzheimer's pathogenesis and a potential therapeutic target for primary prevention. Show less

Adipocytes transfer mitochondria to macrophages in white and brown adipose tissues to maintain metabolic homeostasis. In obesity, adipocyte-to-macrophage mitochondria transfer is impaired, and instead, adipocytes release mitochondria into the blood to induce a protective antioxidant response in the heart. We found that adipocyte-to-macrophage mitochondria transfer in white adipose tissue is inhibited in murine obesity elicited by a lard-based high-fat diet, but not a hydrogenated-coconut-oil-based high-fat diet, aging, or a corn-starch diet. The long-chain fatty acids enriched in lard suppress mitochondria capture by macrophages, diverting adipocyte-derived mitochondria into the blood for delivery to other organs, such as the heart. The depletion of macrophages rapidly increased the number of adipocyte-derived mitochondria in the blood. These findings suggest that dietary lipids regulate mitochondria uptake by macrophages locally in white adipose tissue to determine whether adipocyte-derived mitochondria are released into systemic circulation to support the metabolic adaptation of distant organs in response to nutrient stress. Show less

Long-term feeding of high-grain diets to dairy cows often results in systemic inflammation characterized by alterations in acute-phase proteins and other biomarkers, both in plasma and immune-responsive tissues like the liver. The molecular and systemic changes that characterize an acute grain feeding challenge remain unclear. The current study involved 6 Holstein and 6 Jersey cows in a replicated 2 × 2 Latin square. Periods (10 d) were divided into 4 stages (S): S1, d 1 to 3, served as baseline with total mixed ration (TMR) ad libitum; S2, d 4, served as restricted feeding, with cows offered 50% of the average daily intake observed in S1; S3, d 5, a grain challenge was performed, in which cows were fed a TMR ad libitum without (CON) or with an additional pellet wheat-barley (1:1; HIG) at 20% of dry matter intake top-dressed onto the TMR; S4, d 6 to 10, served as recovery during which cows were allowed ad libitum access to the TMR. Among the 28 biomarkers analyzed in blood 12 h after grain challenge on d 5, the concentrations of fatty acids and bilirubin increased in HIG Holstein but not Jersey cows. In Holsteins, feeding HIG also increased total protein and albumin while decreasing ceruloplasmin, myeloperoxidase, and alkaline phosphatase concentrations. At the molecular level, hepatic genes associated with inflammation (IL1B, IL6, TNF, TLR4, MYD88, and NFKB1) were upregulated in Holstein cows fed HIG versus CON. Despite such response, expression of the acute-phase proteins SAA and HP in Holsteins fed HIG compared with CON was markedly downregulated. In Holsteins fed HIG versus CON, the marked downregulation of SCD, ELOVL6, and MTTP along with upregulated CPT1A, ACOX1, and APOA5 indicated alterations in fatty acid and lipoprotein metabolism during grain challenge. Genes related to ketogenesis (HMGCS2 and ACAT1) were upregulated in Jerseys, and gluconeogenic genes (PDK4 and PCK1) were upregulated in Holstein cows fed HIG, suggesting alterations in ketone body and glucose production. Expression of phosphorylated p70S6K1, RPS6, and 4EBP1 proteins, as well as total mechanistic target of rapamycin (mTOR) protein, decreased in Holsteins fed HIG, whereas phosphorylated mTOR and 4EBP1 proteins increased in Jerseys fed HIG. From a metabolic and inflammatory biomarker standpoint, data indicate that Jersey cows better tolerated the acute grain challenge. Alterations in mTOR signaling proteins in both Jerseys and Holsteins fed HIG suggest a potential role for exogenous AA in the hepatic adaptations to grain challenge. It remains to be determined if these acute responses to a grain challenge can elicit long-term liver dysfunction, which could negatively affect welfare of the cow. Show less

High frequencies of loss of heterozygosity (LOH) in chromosome 11q22-qter have been observed in various malignancies, including breast cancer. Previous studies on breast carcinomas by Winqvist et al (Cancer Res 55: 2660-2664) have indicated that a survival factor gene is located in band 11q23, and that the highly informative microsatellite polymorphism at the APOC3 locus would be a suitable tool to perform more extensive LOH studies. In this European multicentre study, we have examined the occurrence of APOC3 LOH and evaluated the effect of LOH of this chromosomal subregion on the clinical behaviour of the disease in a cohort of 766 breast cancer patients in more detail. LOH for APOC3 was found in 42% of the studied tumours, but it was not found to be significantly associated with any of the studied clinical variables, including cancer-specific survival time or survival time after recurrent/metastatic disease. According to the present findings, the putative survival factor gene on 11q23 is not located close enough to the APOC3 gene, but apparently at a more proximal location. Show less