Introduction Extracellular vesicles (EVs) from human Alzheimer's disease (AD) biospecimens contain amyloid beta (Aβ) peptide and tau. While AD EVs are known to affect brain disease pathobiology, their biochemical and molecular characterizations remain ill defined. Methods EVs were isolated from the cortical gray matter of 20 AD and 18 control brains. Tau and Aβ levels were measured by immunoassay. Differentially expressed EV proteins were assessed by quantitative proteomics and machine learning. Results Levels of pS396 tau and Aβ1–42 were significantly elevated in AD EVs. High levels of neuron‐ and glia‐specific factors are detected in control and AD EVs, respectively. Machine learning identified ANXA5, VGF, GPM6A, and ACTZ in AD EV compared to controls. They distinguished AD EVs from controls in the test sets with 88% accuracy. Discussion In addition to Aβ and tau, ANXA5, VGF, GPM6A, and ACTZ are new signature proteins in AD EVs.
The sea urchin larval skeleton offers a simple model for formation of developmental patterns. The calcium carbonate skeleton is secreted by primary mesenchyme cells (PMCs) in response to largely unknown patterning cues expressed by the ectoderm. To discover novel ectodermal cues, we performed an unbiased RNA-Seq-based screen and functionally tested candidates; we thereby identified several novel skeletal patterning cues. Among these, we show that SLC26a2/7 is a ventrally expressed sulfate transporter that promotes a ventral accumulation of sulfated proteoglycans, which is required for ventral PMC positioning and skeletal patterning. We show that the effects of SLC perturbation are mimicked by manipulation of either external sulfate levels or proteoglycan sulfation. These results identify novel skeletal patterning genes and demonstrate that ventral proteoglycan sulfation serves as a positional cue for sea urchin skeletal patterning.
previous studies on parkinson's disease mechanisms have shown dysregulated extracellular transport of α-synuclein and growth factors in the extracellular space. In the human brain these consist of perineuronal nets, interstitial matrices, and basement membranes, each composed of a set of collagens, non-collagenous glycoproteins, proteoglycans, and hyaluronan. The manner by which amyloidogenic proteins spread extracellularly, become seeded, oligomerize, and are taken up by cells, depends on intricate interactions with extracellular matrix molecules. We sought to assess the alterations to structure of glycosaminoglycans and proteins that occur in pD brain relative to controls of similar age. We found that PD differs markedly from normal brain in upregulation of extracellular matrix structural components including collagens, proteoglycans and glycosaminoglycan binding molecules. We also observed that levels of hemoglobin chains, possibly related to defects in iron metabolism, were enriched in PD brains. These findings shed important new light on disease processes that occur in association with pD. The volume of the extracellular space (~ 20%) that separates brain cell surfaces and through which molecules diffuse displays regional patterns that change during development, aging and neurodegeneration 1,2. The passage of protein molecules through the extracellular space depends on the geometries and chemical compositions of extracellular and cell surface molecular complexes, the specific binding domains thereof, and the fixed negative charges of glycosaminoglycan chains 3,4. Brain extracellular matrix (ECM) is composed of perineuronal nets (PNNs), interstitial matrices, and basement membranes (blood brain barrier), each consisting of a network of glycoproteins, proteoglycans, hyaluronan and collagens 5. Despite the obvious importance of the extracellular space to neural plasticity and neurodegeneration 6,7 , there is little information available on the alterations that occur to these molecules during Parkinson's disease (PD). Inflammation and disruption of the blood brain barrier can lead to infiltration of fibroblasts and trigger a fibrotic response in an attempt to restore normal function 8. Such fibrosis demolishes the structure of the ECM, and impedes healing by secreting inhibitory molecules and serves as a barrier to axons. Infiltration of fibroblasts leads to deposition of thrombin and fibrinogen and destruction of the integrity of the ECM. These inflammatory reactions lead to local neural degeneration and activation of glial cells. In PD, the activation of glial cells and recruitment of T-cells leads to increased pro-inflammatory cytokine release and increased levels of reactive oxygen and nitrogen species. While disruption is not believed to occur, activated microglia appear to induce blood brain barrier dysfunction in PD 9. Despite this, limited information is available concerning the changes in the distribution of ECM molecules in PD, with the exception of glycosaminoglycans (GAGs) found in senile plaques and...
Abbreviations: (A1C) hemoglobin A1c, (BG) blood glucose, (BGM) blood glucose monitoring, (T1DM) type 1 diabetes mellitus Keywords: adherence, bolus calculator software, children and adolescents, insulin pumps, type 1 diabetes mellitus
Parkinson's disease (PD) is a neurological disorder characterized by the progressive loss of functional dopaminergic neurons in the nigrostriatal pathway in the brain. Although current treatments provide only symptomatic relief, gene therapy has the potential to slow or halt the degeneration of nigrostriatal dopamine neurons in PD patients. Adeno-associated viruses (AAV) are vectors of choice in gene therapy because of their well-characterized safety and efficacy profiles; however, although gene therapy has been successful in preclinical models of the disease, clinical trials in humans have failed to demonstrate efficacy. Significantly, all primary AAV receptors of the virus are glycans. We thus hypothesize that age related changes in glycan receptors of heparan sulfate (HS) proteoglycans (receptor for rAAV2), and/or -glycans with terminal galactose (receptor for rAAV9) results in poor adeno-associated virus binding in either the striatum or substantia nigra, or both, affecting transduction and gene delivery. To test our hypothesis we analyzed the striatum and substantia nigra for changes in HS,-glycans and proteomic signatures in young aged rat brain striatum and substantia nigra. We observed different brain region-specific HS disaccharide profiles in aged compared with young adult rats for brain region-specific profiles in striatum substantia nigra. We observed brain region- and age-specific -glycan compositional profiles with respect to the terminal galactose units that serve as receptors for AAV9. We also observed brain region-specific changes in protein expression in the aging nigrostriatal pathway. These studies provide insight into age- and brain region-specific changes in glycan receptors and proteome that will inform design of improved viral vectors for Parkinson Disease (PD) gene therapy.
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