This research evaluated the potential of activation and attachment, as sequential companion biomarkers of phagocytosis by earthworm, Lumbricus terrestris, immunoactive coelomocytes for use in immunotoxicology. The potential was assessed by exposing earthworms to sublethal concentrations of CuSO4 and Arochlor 1254®, chemicals used as reference or standard immunotoxicants.

Coelomocyte migration responses, both random and chemotatic, were examined in the earthworm Lumbricus terrestris. Coelomocyte random migration patterns towards non-stimulatory, non-chemotatic solutions were described. Migration responses to immunostimulatory agents lipopolysaccharides (LPS), N-formly-methionyl-leucyl-phenylalanine (FMLP), sheep erythrocytes, Saccharomyces cerevisiae, Aeromonas hydrophila, Eisenia fetida and Rhabditis pellio were characterized. Chemotaxis was reported to LPS, FMLP, sheep erythrocytes, S. cerivesae and E. fetida. Bio-indicator potential of chemotaxis is discussed relative to variability in migration responses.

M.Sc. / Heat shock proteins (HSP) are a group of highly conserved proteins induced in pro- and eukaryotes by a wide variety of environmental stresses such as heat shock (HS) and oxidative injury. HSP are classified into families according to their apparent molecular mass and respective inducers. Induction of HSP is primarily regulated on transcriptional level through multiple copies of a conserved cis-acting heat shock element (HSE) in the promoter region of all hsp genes to which the heat shock transcription factor (HSF) binds. Members of the HSP family function collectively as molecular chaperone systems, and fulfil essential roles under normal conditions and provide protection and adaptation during and following stress. The induction of HSP following stress and the subsequent protection confer HSP the potential application in stress therapy and in biomarking of stress. During a previous study in which the effect of Mycobacterium tuberculosis (M.tb) on the stress response of peripheral blood moncytes (PBM) from different donors was investigated, it was observed that different individuals from different South African populations showed differential a HSP synthesis in response to M.tb. This compelled us to investigate the following: Variation in HSP synthesis in peripheral blood monocytes (PBM) from different individuals in response to the classical HSP inducer, HS. The most appropriate technique to study HSP expression on protein level. HSP synthesis was studied in PBM from 36 individuals (European (E): n=22; non-Europeans (nE): n=14) using biometabolic labelling. Three techniques were compared in the determination of HSP expression in six donors in terms of HSP synthesis, which is measured by biometabolic labelling, and accumulation of hsp70 that were measured by Western blot analysis and flow cytometry. Results obtained are : European (E) and non-European (nE) populations differed significantly (p < 0.05) from each other in spite of a prominent variation in HSP synthesis within donors ; Flow cytometry is the technique of choice for the analysis of HSP levels, since it allows fast and safe measurement of HSP levels in single cel populations within a mixed population. Data from flow cytometry correlate with Western blot analysis, but not with biometabolic labelling. The means and ranges for different HSP synthesis in different populations reported in this study, set a standard for the use of HSP as biomarker of pa environmental stress for populations inhabiting southern Africa. Efficient measurement of HSP expression as biomarker of stress can therefore be implemented in routine analysis of environmental stress, as well as investigations concerning the implications of HSP in pathology.

Orientador: Joaquim Gonçalves Machado Neto / Banca: Luciana Maria Saran / Banca: Cynthia Venâncio Ikefuti / Banca: Marcello Pardi de Castro / Banca: Silvia Patrícia Carraschi de Oliveira / Resumo: Objetivou-se avaliar a capacidade de recuperação de alevinos de peixes das espécies de cativeiro pacu (Piaractus mesopotamicus) e tilápia (Oreochromis niloticus) após a intoxicação aguda com fipronil. A capacidade de recuperação foi avaliada nos peixes sobreviventes as concentrações de fipronil (Regent® 800WG) (0,56; 0,59; 0,61 e 0,64 mg.L-1 para o pacu; e 0,9; 0,11; 0,15 e 0,20 mg.L-1 para a tilápia) que causaram aproximadamente 10, 30, 50 e 70% de mortalidade após 24 horas de exposição aguda. Os peixes sobreviventes foram transferidos para água limpa. As avaliações foram realizadas no dia da transferência para a água limpa, e aos 15 e 30 dias de recuperação. Foram avaliadas as lesões em tecidos de brânquias, fígado e rins, e a atividade da enzima acetilcolinesterase (AChE) no cérebro e no músculo. Os sinais observados foram natação errática, espasmos musculares e mudança de coloração. Após 24 horas de exposição aguda, o fipronil, nas concentrações avaliadas, causou lesões estruturais nas brânquias, fígado e rins dos peixes, entre 70 e 73% de inibição da atividade da AChE no cérebro e entre 20 e 35% da AChE no músculo. Os peixes se recuperaram completamente dos sinais de intoxicação no terceiro dia. Aos 30 dias de recuperação, os peixes das duas espécies se recuperaram das lesões nos tecidos das brânquias, fígado e rins causadas pelo fipronil em concentração nas águas de até 0,61 mg.L-1 para o pacu, que causa até 54,2 % mortalidades; e de até 0,15 mg.L-1 para a tilápia, que ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The aim of this study was to evaluate the recovery capacity of juvenile fishes of the species pacu (Piaractus mesopotamicus) and tilapia (Oreochromis niloticus) after acute intoxication with fipronil. Recovery capacity was evaluated in fishes survivors from fipronil concentrations (Regent® 800WG) (0,56; 0,59; 0,61 e 0,64 mg.L-1 para for pacu; e 0,9; 0,11; 0,15 e 0,20 mg.L-1 for tilápia) in water that caused about 10, 30, 50 and 70% of mortality after 24 hours of acute exposure. The survivors were transferred to clean water. The evaluations were done on the day of transfer to clean water, and at 15 and 30 days of recovering. Damages were evaluated in gills, liver and kidneys tissues and the enzyme acetylcholinesterase (AChE) activity in the brain and muscle. The signs observed were erratic swimming, muscle spasms and color change. After 24 hours of acute exposure, fipronil at the tested concentrations causes histological damages in the gills, liver and kidneys of the fishes, 70 to 73% inhibition of AChE activity in the brain and between 20 and 35% in AChE in the muscle. The fishes recover completely from the intoxication signs on the third day. At 30 days of recovering, fishes from both species recovered from the damage in gills, liver and kidneys caused by fipronil at concentrations up to 0.61 mg.L-1 for pacu, which cause up to 54.2% of mortality; and up to 0.15 mg.L-1 for tilapia, which cause up to 46.7% of mortality. In higher concentrations than these, fipronil causes high... (Complete abstract click electronic access below) / Doutor

Thesis (MSc (Biomedical Sciences))--Cape Peninsula University of Technology, 2018. / Background: Early detection of individuals who are at risk of developing Glucose Intolerance would decrease the morbidity and mortality associated with this disease. MicroRNA is one of the most widely studied biomolecules involved in epigenetic mechanisms, hence it offers unique opportunities in this regard. Circulating microRNAs are associated with disease pathogenesis during the asymptomatic stage of disease. This has therefore attracted a lot of attention as a potential biomarker for identifying individuals who have an increased risk of developing Glucose Intolerance. The identification of high risk biomarkers for Glucose Intolerance will go a long way to eliminate the possible complications that arise due to late diagnosis and treatment of Glucose Intolerance. This could ultimately lead to better ways to prevent, manage and control the Glucose Intolerance epidemic that is rampant worldwide. The aim of the study is to investigate expression of circulating microRNA’s in blood of mixed ancestry subjects with glucose intolerance. Methods: A quantitative cross-sectional study design involving 36 individuals [who were age, gender and BMI (Body Mass Index) matched] from a total population of 1989 participants of mixed ancestry descent, residing in Bellville South, South Africa was used. Participants were classified as controls (normoglycemic), pre-diabetic (preDM) and diabetic (DM) (screen detected diabetic) according to WHO criteria of 1998. MicroRNAs were extracted from serum using the Qiagen miRNeasy Serum/Plasma Kit (ThermoFisher). The purified micro RNAs were reverse-transcribed to cDNA (complementary deoxyribonucleic acid) using the Qiagen RT2 First Strand Kit. Then, using Qiagen miScript SYBR Green PCR kit and miScript miRNA PCR arrays (ThermoFisher), the real time polymerase chain reaction was done to determine the expression profile the circulating micro RNAs present in the serum of the participants. Results: The 36 participants were evenly divided into 3 groups of 12 participants each as mentioned earlier. There were significant differences between groups in the waist (cm) (p=0.0415) and waist/hip ratio (p=0.0011) with highest values in the DM group and lowest in the normal group. Clinical parameters varied significantly according to glycemic status. As expected, the FBG (mmol/L) (p<0.0001), 2 HRs Post Glucose (mmol/L) (p<0.0001), HbA1c (%) (p=0.0009), Fasting Insulin (mIU/L) (p=0.0039), were all highest in the DM and lowest in the control group. In contrast, the 2 HRs Post Insulin (mIU/L) (p = 0.0027) was highest in the preDM group and lowest in the normal group, while the Glucose/Insulin ratio (p=0.0477) was highest in the normal group and lowest in the preDM group. Triglycerides (mmol/L) (p=0.0043) and Total Chol (mmol/L) (p=0.0429) were significantly increased through the three groups, with highest values in the DM group and lowest in the normal group. Furthermore, 12 of the 84 miRNAs studied were expressed through all the 3 groups and they exhibited both inverse and positive correlations between the clinical parameters, especially the glucose parameters (Fasting blood glucose, 2 hours post glucose, Fasting blood insulin, 2 hours post insulin and Glycated Hemoglobin).

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by Chen Ming-jie. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1994. / Includes bibliographical references (leaves 81-95). / List of Abbreviations --- p.I / List of Tables --- p.II / List of Figures --- p.III / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Background of Volvariella volvacea and the purposes of this study --- p.1 / Chapter 1.1.1 --- Background of Volvariella volvacea --- p.1 / Chapter 1.1.2 --- Purposes of this molecular study on Volvariella volvacea --- p.5 / Chapter 1.2 --- Molecular studies in edible mushrooms --- p.5 / Chapter 1.2.1 --- Recombinant DNA technology --- p.5 / Chapter 1.2.2 --- Restriction fragment length polymorphisms (RFLPs) --- p.6 / Chapter 1.2.3 --- Polymerase chain reaction (PCR) --- p.7 / Chapter 1.2.3.1 --- Ribosomal RNA gene-PCR (rDNA-PCR) --- p.8 / Chapter 1.2.3.2 --- Random amplified DNAs by polymerase chain reaction --- p.10 / Chapter 1.2.3 --- Pulsed field gel electrophoresis --- p.12 / Chapter Chapter 2 --- Materials and Methods --- p.17 / Chapter 2.1 --- Organisms --- p.17 / Chapter 2.2 --- Cell cultivation and maintenance --- p.17 / Chapter 2.3 --- Solutions and chemicals --- p.17 / Chapter 2.3.1 --- Solutions for DNA extraction --- p.17 / Chapter 2.3.2 --- Solutions for agarose gel electrophoresis --- p.18 / Chapter 2.3.3 --- Solutions for DNA labeling and detection --- p.18 / Chapter 2.3.3.1 --- Colorimetry --- p.18 / Chapter 2.3.3.2 --- Chemiluminescence --- p.19 / Chapter 2.3.4 --- Hybridization solution --- p.19 / Chapter 2.3.5 --- PCR primers --- p.19 / Chapter 2.3.6 --- SOC medium --- p.20 / Chapter 2.4 --- Agarose gel electrophoresis --- p.20 / Chapter 2.5 --- DNA extraction and purification --- p.20 / Chapter 2.5.1 --- Genomic DNAs --- p.20 / Chapter 2.5.2 --- Plasmid DNA --- p.21 / Chapter 2.6 --- Formation of complementary ends --- p.23 / Chapter 2.6.1 --- Partial digestion of genomic DNA with the restriction enzyme Sau3A I --- p.23 / Chapter 2.6.2 --- Production of vector arms --- p.23 / Chapter 2.7 --- Ligation --- p.24 / Chapter 2.8 --- Transformation --- p.24 / Chapter 2.8.1 --- Chemical transformation method --- p.24 / Chapter 2.8.1.1 --- Preparation of competent E. coli cells --- p.24 / Chapter 2.8.1.2 --- Transformation --- p.25 / Chapter 2.8.2 --- Electroporation --- p.25 / Chapter 2.8.2.1 --- Preparation of electro-competent cells --- p.25 / Chapter 2.8.2.2 --- Electroporation --- p.26 / Chapter 2.9 --- Southern transfer and hybridization using non- radioactive method --- p.27 / Chapter 2.9.1 --- Random labeling the V.volvacea genomic DNA by digoxigenin-11-dUTP --- p.28 / Chapter 2.9.2 --- Conventional PCR to amplify and label cloned DNA inserts --- p.28 / Chapter 2.9.3 --- Southern blotting --- p.29 / Chapter 2.9.4 --- Prehybridization --- p.29 / Chapter 2.9.5 --- Hybridization --- p.30 / Chapter 2.9.6 --- High stringency washing --- p.30 / Chapter 2.9.7 --- Detection --- p.30 / Chapter 2.9.7.1 --- Color detection --- p.30 / Chapter 2.9.7.2 --- Chemiluminescent detection --- p.31 / Chapter 2.9.8 --- Reprobing --- p.31 / Chapter 2.9.9 --- Colony hybridization --- p.31 / Chapter 2.10 --- Polymerase chain reaction (PCR) --- p.32 / Chapter 2.10.1 --- Arbitrarily primed polymerase chain reaction (AP- PCR) --- p.32 / Chapter 2.10.2 --- Random amplification of polymorphic DNA (RAPD) --- p.32 / Chapter 2.10.3 --- Amplification of ribosomal RNA gene (rDNA- PCR) --- p.33 / Chapter 2.11 --- Pulsed field gel electrophoresis --- p.33 / Chapter 2.11.1 --- Preparation of protoplasts --- p.33 / Chapter 2.11.2 --- Embedding of chromosomal DNAs --- p.34 / Chapter 2.11.3 --- Electrophoresis --- p.34 / Chapter 2.11.4 --- Southern blotting and hybridization --- p.35 / Chapter Chapter 3 --- Results --- p.36 / Chapter 3.1 --- Construction of a partial genomic library for Volvariella volvacea --- p.36 / Chapter 3.1.1 --- Genomic DNA purification and restriction enzyme digestion --- p.36 / Chapter 3.1.2 --- Preparation of vector arms --- p.36 / Chapter 3.1.3 --- Ligation and transformation --- p.36 / Chapter 3.2 --- Characterization of clones in the genomic library --- p.42 / Chapter 3.3 --- Fishing out ribosomal RNA gene from the genomic library by homologous rDNA probe --- p.45 / Chapter 3.4 --- Strain typing --- p.50 / Chapter 3.4.1 --- Strain typing by RFLPs using moderately repetitive probes --- p.50 / Chapter 3.4.2 --- Strain typing by PCR-based protocols: AP-PCR and RAPD --- p.50 / Chapter 3.4.3 --- Strain typing by PCR- RFLPs --- p.56 / Chapter 3.5 --- Electrophoretic karyotype analysis by pulsed field gel electrophoresis --- p.56 / Chapter 3.5.1 --- Protoplast preparation --- p.56 / Chapter 3.5.2 --- The electrophoresis condition --- p.56 / Chapter 3.5.3 --- Southern hybridization --- p.65 / Chapter Chapter 4 --- Discussion --- p.68 / Chapter 4.1 --- Genomic library --- p.68 / Chapter 4.2 --- Generation of molecular markers --- p.70 / Chapter 4.2.1 --- RFLPs --- p.70 / Chapter 4.4.2 --- AP-PCR and RAPD methods --- p.71 / Chapter 4.2.3 --- PCR- RFLP of rRNA gene --- p.72 / Chapter 4.2.4 --- Comparison of the four types of molecular markers --- p.72 / Chapter 4.3 --- Electrophoretic karyotype by PFGE --- p.74 / Conclusion --- p.80 / References --- p.81

by Lai, Shiu Hong. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1993. / Includes bibliographical references (leaves 129-147). / TITLE PAGE --- p.I / THESIS COMMITTEE --- p.II / ABSTRACT --- p.III / ACKNOWLEDGMENTS --- p.V / ABBREVIATIONS --- p.VI / TABLE OF CONTENTS --- p.VII / LIST OF TABLES --- p.XI / LIST OF FIGURES --- p.XII / Chapter Chapter 1. --- Arbitrarily Primed Polymerase Chain Reaction (AP-PCR) Analysis of Lent inula edodes / Chapter 1. --- Introduction / Chapter 1.1 --- General Introduction --- p.1 / Chapter 1.2 --- Purpose of Study --- p.4 / Chapter 2. --- Literature Review / Chapter 2.1 --- Biology of Lentinula edodes / Chapter 2.1.1 --- "Overview," --- p.6 / Chapter 2.1.2 --- Life Cycle of Lentinula edodes --- p.6 / Chapter 2.1.3 --- Dedikaryotization (Monokaryotization) --- p.12 / Chapter 2.2 --- Genome Analysis of the Mushroom --- p.13 / Chapter 2.3 --- Genetic Markers of Lentinula edodes / Chapter 2.3.1 --- Overview --- p.15 / Chapter 2.3.2 --- Auxotrophic Markers --- p.16 / Chapter 2.3.3 --- Biochemical Markers --- p.17 / Chapter 2.3.4 --- Molecular Markers / Chapter 2.3.4.1 --- RFLPs --- p.19 / Chapter 2.3.4.2 --- PCR-Based Markers --- p.20 / Chapter 2.4 --- Polymerase Chain Reaction (PCR) / Chapter 2.4.1 --- The principle of PCR --- p.22 / Chapter 2.4.2 --- Applications of PCR on Mushroom Studies --- p.26 / Chapter 2.5 --- Arbitrarily Primed Polymerase Chain Reaction / Chapter 2.5.1 --- Principle of AP-PCR --- p.27 / Chapter 2.5.2 --- Applications of AP-PCR on Mushroom Studies --- p.29 / Chapter 2.6 --- Genetic Linkage Analysis / Chapter 2.6.1 --- Overview --- p.31 / Chapter 2.6.2 --- The LOD Score Method --- p.34 / Chapter 3. --- Materials and Methods / Chapter 3.1 --- Mushroom Strains and Culture Media --- p.36 / Chapter 3.2 --- Culture Method --- p.36 / Chapter 3.3 --- Solutions --- p.36 / Chapter 3.4 --- Primers --- p.38 / Chapter 3.5 --- Isolation of DNA from Lentinula edodes / Chapter 3.5.1 --- Mini-Preparation of Fungal DNA from L. edodes for PCR amplification --- p.42 / Chapter 3.5.2 --- Cesium Chloride Method: Mini-Preparation of Fungal DNA for PCR amplification --- p.43 / Chapter 3.6 --- Quantitative Measurements of DNA --- p.44 / Chapter 3.7 --- Arbitrarily Primed Polymerase Chain Reaction (AP-PCR) for the Amplification of Genomic DNA of L. edodes --- p.45 / Chapter 3.8 --- Analysis of DNA Samples with Agarose Gel Electrophoresis --- p.46 / Chapter 3.9 --- Analysis of DNA Samples with Polyacrylamide Gel Electrophoresis (PAGE) --- p.47 / Chapter 3.10 --- Silver Staining --- p.48 / Chapter 3.11 --- Single Stranded Conformation Polymorphism (SSCP) Analysis of Polymorphic DNA Fragments / Chapter 3.11.1 --- Elution and Amplification of DNA --- p.49 / Chapter 3.11.2 --- PCR-SSCP --- p.50 / Chapter 3.12 --- Segregation and Linkage Analysis / Chapter 3.12.1 --- Chi-Square Test --- p.51 / Chapter 3.12.2 --- The LOD Score Method --- p.52 / Chapter 4. --- Results / Chapter 4.1 --- DNA Extraction --- p.54 / Chapter 4.2 --- AP-PCR Amplified Fragments and Fragment Number --- p.58 / Chapter 4.3 --- Dedikaryotization Demonstration --- p.60 / Chapter 4.4 --- Identification of Polymorphic Genetic Markers --- p.64 / Chapter 4.4.1 --- AP-PCR Fingerprints from Single Primer --- p.66 / Chapter 4.4.2 --- AP-PCR Fingerprints Using Two Primers --- p.76 / Chapter 4.5 --- Segregation of Polymorphic Markers in Single Spore Isolates (SSIs) --- p.81 / Chapter 4.6 --- Single Stranded Conformation Polymorphism (SSCP) of Identified Polymorphic DNA Fragments --- p.86 / Chapter 4.7 --- Linkage Analysis of the Identified AP-PCR Markers --- p.89 / Chapter 5. --- Discussions / Chapter 5.1 --- DNA Extraction --- p.92 / Chapter 5.2 --- Arbitrary Primers --- p.93 / Chapter 5.3 --- Dedikaryotization Demonstration --- p.95 / Chapter 5.4 --- Identification of Polymorphic Genetic Markers --- p.96 / Chapter 5.5 --- AP-PCR Analysis of a Mushroom --- p.97 / Chapter 5.6 --- Mendelian Segregation Pattern of the Polymorphic Markers --- p.99 / Chapter 6. --- Conclusion and Further Studies --- p.101 / Chapter 2. Electrophoretic Karyotype Analysis of Lentinula edodes / Chapter 7. --- Introduction --- p.106 / Chapter 8. --- Literature Review / Chapter 8.1 --- Overview --- p.108 / Chapter 8.2 --- Protoplasts --- p.109 / Chapter 8.3 --- Pulsed Field Gel Electrophoresis (PFGE) / Chapter 8.3.1 --- Principle --- p.110 / Chapter 8.3.2 --- Applications of PFGE in Studies of Fungi --- p.112 / Chapter 9. --- Materials and Methods / Chapter 9.1 --- Strains and Culture Media --- p.114 / Chapter 9.2 --- Solutions --- p.114 / Chapter 9.3 --- Production of Lentinula edodes Protoplast --- p.115 / Chapter 9.4 --- Electrophoretic Conditions --- p.116 / Chapter 9.4.1 --- Condition for Saccharomyces cerevisiae chromosomes --- p.117 / Chapter 9.4.2 --- Condition for Candida albicans chromosomes --- p.117 / Chapter 9.4.3 --- Condition for Schizosaccharomyces pombe chromosomes --- p.118 / Chapter 10. --- Results / Chapter 10.1 --- Protoplast Production of Lentinula edodes / Chapter 10.1.1 --- Effects of Age of Mycelium on Protoplast Yield --- p.119 / Chapter 10.1.2 --- Effects of Various Osmotic Stabilizers on Protoplast Yield --- p.121 / Chapter 10.1.3 --- Effects of Two Lytic Enzymes on Protoplast Yield --- p.123 / Chapter 10.1.4 --- The Optimal Condition --- p.123 / Chapter 10.2 --- Electrophoretic Karyotype of L. edodes --- p.124 / Chapter 11. --- Discussions / Chapter 11.1 --- Protoplast Production of Lentinula edodes --- p.126 / Chapter 11.2 --- Electrophoretic Karyotype --- p.127 / REFERENCES

This dissertation proposes a family of algorithms for deriving signatures of mutually associated features, to which we refer as attractor metafeatures, or simply attractors. Specifically, we present multi-cancer attractor derivation algorithms, identifying correlated features in signatures from multiple biological data sets in one analysis, as well as the groups of samples or cells that exclusively express these signatures. Our results demonstrate that these signatures can be used, in proper combinations, as biomarkers that predict a patient’s survival rate, based on the transcriptome of the tumor sample. They can also be used as features to analyze the composition of the tumor. Through analyzing large data sets of 18 cancer types and three high-throughput platforms from The Cancer Genome Atlas (TCGA) PanCanAtlas Project and multiple single-cell RNA-seq data sets, we identified novel cancer attractor signatures and elucidated the identity of the cells that express these signatures. Using these signatures, we developed a prognostic biomarker for breast cancer called the Breast Cancer Attractor Metagenes (BCAM) biomarker as well as a software platform to analyze the tumor sample, called Analysis of the Single-Cell Omics for Tumor (ASCOT).

Endosomal dysfunction has been mechanistically linked to Alzheimer’s Disease (AD). To date, no in vivo biomarkers for this cellular deficit exist. Yet such biomarkers are required for determining its prevalence in AD and tracking its time course—both in disease progression and potential clinical trials. With this goal in mind, we made use of an assortment of mouse models bearing AD-related endosomal trafficking defects through selective deletion of retomer core proteins. We collected CSF and brain exosomes from these retromer-deficient models and performed a battery of molecular inquiries which included lipidomic and proteomic screens, as well as hypothesis-driven biochemistry. The results of this comprehensive investigation include the first characterization of the murine CSF lipidome and the deepest characterization to date of the murine CSF proteome. Herein, we report that VPS26a haploinsufficiency in the brain imparts no detectable protein changes in the CSF as measured by labeled LC-MS/MS at three months of age. This deficit does, however, cause a reliable reduction of CSF sphingomyelin d18:1/18:1, which is exacerbated by age, extending to other sphingomyelins and other lipid classes including dihydrosphingomyelins and monohexosylceramides. Complete knockout of its paralog VPS26b promotes an enrichment of BACE1-cleaved APP CTFs (Beta-CTFs) in brain-derived exosomes and may alter exosomal biogenic pathways. Similar trends were seen in a neuronal-specific knockout (via Camk2-Cre recombinase) of retromer’s linchpin, VPS35. Most importantly, an unbiased proteomic screen of CSF collected from mice with a selective knock out of VPS35 in forebrain neurons (engineered using the Camk2 system) uncovered a total of 71 hits (52 parametric and 19 nonparametric) from the 1505 proteins detected. Pathway analysis and follow-up studies identified two distinct molecular categories with previously established relevance to AD: BACE1 substrates and MAPT (more commonly referred to as tau). We report that, both in vivo and in vitro, neuronal-selective knockout of VPS35 causes increased secretion of the N-terminal fragments (NTFs) of BACE1 substrates APLP1 and CHL1 as well as total tau, and importantly, that these events occur independent of cell death. Further, we find evidence of convergence of these pathways in both mouse and human CSF. However, as these BACE1 substrates likely accumulate in plaques, we propose CSF total tau as a biomarker of endosomal dysfunction with utility over the entire course of AD progression. We have identified and validated a series of in vivo biomarkers that are reflective of AD-associated endosomal dysfunction. While clearly sensitive to this cellular pathology, future work is required to determine their specificity. Additionally, follow-up studies are required to show that interventions which rescue endosomal dysfunction affect this molecular profile. The identified biomarkers hold great promise for early detection of endosomal dysfunction in AD and for tracking its course, during the disease progression and for clinical trials. Furthermore, the unexpected but validated finding, showing that increased CSF tau is reflective of AD-associated endosomal dysfunction, suggests that endosomal dysfunction is a universal deficit shared among AD patients in its earliest stages of disease.