Changes in Activity and Kinetic Properties of the Proteasome in Different Rat Organs during Development and Maturation

The proteasome is considered the most important proteolytic system for removal of damaged proteins with aging. Using fluorogenic peptide substrates, the chymotrypsin-like, the trypsin-like, and the peptidylglutamyl peptidase activities of the proteasome were measured in the soluble fractions of liver, brain, and lens rat homogenates. Specific activity was significantly decreased in liver and brain homogenates with maturation of the animal, that is, from newborn (7 days old) to fertile rats (2–4 months old). Rat lens homogenate exhibited an increase in activity with maturation and also with aging. Chymotrypsin-like activity was stimulated by calcium and this proteolytic activity was significantly decreased with maturation of the rat brain. The Michaelis-Menten constant (Km) increased with age in rat liver and lens, indicating a loss of affinity for its substrates by the proteasome in the animal with maturation and aging. The present data suggest that the loss of function of the proteasome with maturation may be due to structural changes of the proteasome or a decreased content of regulatory components

Incentivizing BECCS - A Swedish Case Study

Negative carbon dioxide (CO2)-emissions are prevalent in most global emissions pathways that meet the Paris temperature targets and are a critical component for reaching net-zero emissions in Year 2050. However, economic incentives supporting commercialization and deployment of BioEnergy Carbon Capture and Storage (BECCS) are missing. This Policy and Practice Review discusses five different models for creating incentives and financing for BECCS, using Sweden as an example: (1) governmental guarantees for purchasing BECCS outcomes; (2) quota obligation on selected sectors to acquire BECCS outcomes; (3) allowing BECCS credits to compensate for hard-to-abate emissions within the EU ETS; (4) private entities for voluntary compensation; and (5) other states acting as buyers of BECCS outcomes to meet their mitigation targets under the Paris Agreement. We conclude that successful implementation of BECCS is likely to require a combination of several of the Policy Models, implemented in a sequential manner. The governmental guarantee model (Model 1) is likely to be required in the shorter term, so as to establish BECCS. Policy Models 2 and 3 may become more influential over time once BECCS has been established and accepted. Model 3 links BECCS to a large carbon-pricing regime with opportunities for cost-effectiveness and expanded financing. We conclude that Policy Models 4 and 5 are associated with high levels of uncertainty regarding the timing and volume of negative emissions that can be expected—Thus, they are unlikely to trigger BECCS implementation in the short term, although may have roles in the longer term. Based on this study, we recommend that policymakers carefully consider a policy sequencing approach that is predictable and sustainable over time, for which further analyses are required. It is not obvious how such sequencing can be arranged, as the capacities to implement the different Policy Models are vested in different organizations (national governments, EU, private firms). Furthermore, it is important that a BECCS policy is part of an integrated climate policy framework, in particular one that is in line with policies aimed at the mitigation of greenhouse gas (GHG) emissions and the creation of a circular economy. It will be important to ensure that BECCS and the associated biomass resource are not overexploited. A well-designed policy package should guarantee that BECCS is neither used to postpone the reduction of fossil fuel-based emissions nor overused in the short term as a niche business for “greenwashing” while not addressing fossil fuel emissions

CSF protein biomarkers predicting longitudinal reduction of CSF β-amyloid42 in cognitively healthy elders.

β-amyloid (Aβ) plaque accumulation is a hallmark of Alzheimer's disease (AD). It is believed to start many years prior to symptoms and is reflected by reduced cerebrospinal fluid (CSF) levels of the peptide Aβ1-42 (Aβ42). Here we tested the hypothesis that baseline levels of CSF proteins involved in microglia activity, synaptic function and Aβ metabolism predict the development of Aβ plaques, assessed by longitudinal CSF Aβ42 decrease in cognitively healthy people. Forty-six healthy people with three to four serial CSF samples were included (mean follow-up 3 years, range 2-4 years). There was an overall reduction in Aβ42 from a mean concentration of 211-195 pg ml(-1) after 4 years. Linear mixed-effects models using longitudinal Aβ42 as the response variable, and baseline proteins as explanatory variables (n=69 proteins potentially relevant for Aβ metabolism, microglia or synaptic/neuronal function), identified 10 proteins with significant effects on longitudinal Aβ42. The most significant proteins were angiotensin-converting enzyme (ACE, P=0.009), Chromogranin A (CgA, P=0.009) and Axl receptor tyrosine kinase (AXL, P=0.009). Receiver-operating characteristic analysis identified 11 proteins with significant effects on longitudinal Aβ42 (largely overlapping with the proteins identified by linear mixed-effects models). Several proteins (including ACE, CgA and AXL) were associated with Aβ42 reduction only in subjects with normal baseline Aβ42, and not in subjects with reduced baseline Aβ42. We conclude that baseline CSF proteins related to Aβ metabolism, microglia activity or synapses predict longitudinal Aβ42 reduction in cognitively healthy elders. The finding that some proteins only predict Aβ42 reduction in subjects with normal baseline Aβ42 suggest that they predict future development of the brain Aβ pathology at the earliest stages of AD, prior to widespread development of Aβ plaques

Salivary Biomarkers for Alzheimer's Disease and Related Disorders

The search for accessible and cost-effective biomarkers to complement current cerebrospinal fluid (CSF) and imaging biomarkers in the accurate detection of Alzheimer disease (AD) and other common neurodegenerative disorders remains a challenging task. The advances in ultra-sensitive detection methods has highlighted blood biomarkers (e.g. amyloid-β and neurofilament light) as a valuable and realistic tool in a diagnostic or screening process. Saliva, however, is also a rich source of potential biomarkers for disease detection and offers several practical advantages over biofluids that are currently examined for neurodegenerative disorders. However, while this may be true for the general population, challenges in collecting saliva from an elderly population should be seriously considered. In this review, we begin by discussing how saliva is produced and how age-related conditions can modify saliva production and composition. We then focus on the data available which support the concept of salivary amyloid-β, tau species and novel biomarkers in detecting AD and alpha-synuclein (α-syn) in Parkinson’s disease (PD)

Fluid biomarkers and risk of neurodegenerative disease in retired athletes with multiple concussions: Results from the International Concussion and Head Injury Research Foundation Brain health in Retired athletes Study of Ageing and Impact-Related Neurodegenerative Disease (ICHIRF-BRAIN study)

Objectives To investigate the association and utility of blood plasma markers of neurodegeneration in a population of retired athletes self-reporting multiple concussions throughout a sporting career. It is hypothesised that this type of athletic history would cause an increased prevalence of neurodegenerative disease, as detected by biomarkers for neurodegenerative disease processes. Methods One hundred and fifty-nine participants were recruited (90 males, 69 females, mean age 61.3±9.13 years), including 121 participants who had retired from playing professional or semiprofessional sports and self-reported ≥1 concussion during their careers (range 1-74; mean concussions=10.7). The control group included 38 age-matched and sex-matched controls, with no history of concussion. We measured neurofilament light (NfL) and tau (neurodegeneration markers), glial fibrillar acidic protein (GFAP) (astrocytic activation marker) and 40 and 42 amino acid-long amyloid beta (Aβ40 and Aβ42) (Alzheimer-associated amyloid pathology markers) concentrations using ultrasensitive single molecule array technology. Results We found retired athletes reporting one or more concussions throughout an athletic career showed no significant changes in NfL, tau, GFAP and Aβ40 and Aβ42 concentrations in comparison to a control group. No correlations were found between biomarkers and number of concussions (mean=10.7). A moderate correlation was found between NfL concentration and age. Conclusion No difference in blood concentrations of neurodegeneration markers NfL, tau, GFAP and Aβ40 and Aβ42 was found in retired athletes with a history of concussion compared with controls. An increased prevalence of neurodegenerative diseases is not detected by biomarkers in a population self-reporting multiple concussions. Trial registration number ISRCTN 1131209

Sulfatide in health and disease. The evaluation of sulfatide in cerebrospinal fluid as a possible biomarker for neurodegeneration

Sulfatide (3-O-sulfogalactosylceramide, SM4) is a glycosphingolipid, highly multifunctional and particularly enriched in the myelin sheath of neurons. The role of sulfatide has been implicated in various biological fields such as the nervous system, immune system, host-pathogen recognition and infection, beta cell function and haemostasis/thrombosis. Thus, alterations in sulfatide metabolism and production are associated with several human diseases such as neurological and immunological disorders and cancers. The unique lipid-rich composition of myelin reflects the importance of lipids in this specific membrane structure. Sulfatide has been shown to be involved in the regulation of oligodendrocyte differentiation and in the maintenance of the myelin sheath by influencing membrane dynamics involving sorting and lateral assembly of myelin proteins as well as ion channels. Sulfatide is furthermore essential for proper formation of the axo-glial junctions at the paranode together with axonal glycosphingolipids. Alterations in sulfatide metabolism are suggested to contribute to myelin deterioration as well as synaptic dysfunction, neurological decline and inflammation observed in different conditions associated with myelin pathology (mouse models and human disorders). Body fluid biomarkers are of importance for clinical diagnostics as well as for patient stratification in clinical trials and treatment monitoring. Cerebrospinal fluid (CSF) is commonly used as an indirect measure of brain metabolism and analysis of CSF sulfatide might provide information regarding whether the lipid disruption observed in neurodegenerative disorders is reflected in this body fluid. In this review, we evaluate the diagnostic utility of CSF sulfatide as a biomarker for neurodegenerative disorders associated with dysmyelination/demyelination by summarising the current literature on this topic. We can conclude that neither CSF sulfatide levels nor individual sulfatide species consistently reflect the lipid disruption observed in many of the demyelinating disorders. One exception is the lysosomal storage disorder metachromatic leukodystrophy, possibly due to the genetically determined accumulation of non-metabolised sulfatide. We also discuss possible explanations as to why myelin pathology in brain tissue is poorly reflected by the CSF sulfatide concentration. The previous suggestion that CSF sulfatide is a marker of myelin damage has thereby been challenged by more recent studies using more sophisticated laboratory techniques for sulfatide analysis as well as improved sample selection criteria due to increased knowledge on disease pathology

Cooperative action in eukaryotic gene regulation: physical properties of a viral example

The Epstein-Barr virus (EBV) infects more than 90% of the human population, and is the cause of several both serious and mild diseases. It is a tumorivirus, and has been widely studied as a model system for gene (de)regulation in human. A central feature of the EBV life cycle is its ability to persist in human B cells in states denoted latency I, II and III. In latency III the host cell is driven to cell proliferation and hence expansion of the viral population, but does not enter the lytic pathway, and no new virions are produced, while the latency I state is almost completely dormant. In this paper we study a physico-chemical model of the switch between latency I and latency III in EBV. We show that the unusually large number of binding sites of two competing transcription factors, one viral and one from the host, serves to make the switch sharper (higher Hill coefficient), either by cooperative binding between molecules of the same species when they bind, or by competition between the two species if there is sufficient steric hindrance.Comment: 7 pages, 6 figures, 1 tabl

Serum Neurofilament Light Protein as a Marker for Diffuse Axonal Injury: Results from a Case Series Study

Diffuse axonal injury (DAI) is an important cause of morbidity in patients with traumatic brain injury (TBI). There is currently no simple and reliable technique for early identification of patients with DAI, or to prognosticate long-term outcome in this patient group. In the present study, we examined acute serum concentrations of neurofilament light (NFL) in nine patients with severe TBI and DAI using a novel ultrasensitive single molecule array (Simoa) assay. The relationships between the NFL concentrations and MRI in the acute stage as well as clinical outcome and magnetic resonance diffusion tensor imaging (MR-DTI) parameters at 12 months were analyzed. We found that the mean NFL concentrations among the patients displayed a 30-fold increase compared with controls, and that NFL completely discriminated between the patients and controls. We also found a relationship between serum NFL and MR-DTI parameters, with higher NFL concentrations in patients with higher trace (R2 = 0.79) and lower fractional anisotropy (FA) (R 2 = 0.83). These results suggest that serum NFL may be a valuable blood biomarker for TBI, reflecting the severity of DAI

Amyloid mis-metabolism in idiopathic normal pressure hydrocephalus

BACKGROUND: Patients with idiopathic normal pressure hydrocephalus (iNPH) have reduced cerebrospinal fluid (CSF) concentrations of amyloid-β (Aβ) and α- and β-cleaved soluble forms of amyloid precursor protein (sAPPα and sAPPβ). The aims of this study were to examine if changes could also be seen in the CSF for secreted metabolites of APP-like protein 1 (APLP1) and to explore the prognostic value of amyloid-related CSF biomarkers, as well as markers of neuronal injury and astroglial activation, as regards to clinical outcome after shunt surgery. METHODS: Twenty patients diagnosed with iNPH, 10 improved and 10 unchanged by shunt surgery, and 20 neurologically healthy controls were included. All patients were examined clinically prior to surgery and at 6-month follow-up after surgery using the iNPH scale. Lumbar puncture was performed pre-operatively. CSF samples were analyzed for neurofilament light (NFL), Aβ isoforms Aβ38, Aβ40 and Aβ42, sAPPα, sAPPβ, APLP1 β-derived peptides APL1β25, APL1β 27 and APL1β 28 and YKL40 by immunochemical methods. RESULTS: The concentrations of all soluble forms of APP, all Aβ isoforms and APL1β28 were lower, whilst APL1β25 and APL1β27 were higher in the CSF of iNPH patients compared to controls. There was no difference in biomarker concentrations between patients who improved after surgery and those who remained unchanged. CONCLUSIONS: The reduced CSF concentrations of Aβ38, Aβ40, Aβ42, sAPPα and sAPPβ suggest that APP expression could be downregulated in iNPH. In contrast, APLP1 concentration in the CSF seems relatively unchanged. The increase of APL1β25 and APL1β27 in combination with a slight decreased APL1β28 could be caused by more available γ-secretase due to reduced availability of its primary substrate, APP. The data did not support the use of these markers as indicators of shunt responsiveness

Repeated lumbar punctures within 3 days may affect CSF biomarker levels

Lumbar puncture (LP) is a common way of collecting cerebrospinal fluid (CSF) both in the clinic and in research. In this extension of a study on the relationship between sleep deprivation and CSF biomarkers for Alzheimer’s disease, we investigated CSF biomarker dynamics in relation to rebound sleep after sleep deprivation. Two LPs were performed within 3 days in 13 healthy volunteers. We noticed an unexpected sharp rise in biomarker concentrations in the second sample and therefore repeated the experiment, but without sleep intervention, in four additional individuals. The findings were similar in these subjects, suggesting an inherent methodological problem with repeated LPs. The result corroborates findings in studies with repeated CSF collection via indwelling lumbar catheters, and needs to be addressed in, for instance, pharmacodynamic studies employing these techniques