Decreased Clearance of CNS -Amyloid in Alzheimer's Disease

Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Science (Impact Factor: 33.61). 12/2010; 330(6012):1774. DOI: 10.1126/science.1197623
Source: PubMed

ABSTRACT Alzheimer’s disease is hypothesized to be caused by an imbalance between β-amyloid (Aβ) production and clearance that leads
to Aβ accumulation in the central nervous system (CNS). Aβ production and clearance are key targets in the development of
disease-modifying therapeutic agents for Alzheimer’s disease. However, there has not been direct evidence of altered Aβ production
or clearance in Alzheimer’s disease. By using metabolic labeling, we measured Aβ42 and Aβ40 production and clearance rates
in the CNS of participants with Alzheimer’s disease and cognitively normal controls. Clearance rates for both Aβ42 and Aβ40
were impaired in Alzheimer’s disease compared with controls. On average, there were no differences in Aβ40 or Aβ42 production
rates. Thus, the common late-onset form of Alzheimer’s disease is characterized by an overall impairment in Aβ clearance.

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Available from: Vitaliy Ovod, Sep 26, 2015
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    • "For example, the lack of the innate immunity receptor CD36 or RAGE protects endothelium-dependent responses and neurovascular coupling by attenuating vascular oxidative stress in WT mice treated with Ab and amyloid precursor protein (APP) transgenic mice (Park et al. 2011, 2013). Furthermore, impairments in Ab clearance through the BBB may also have an impact on the brain amyloid accumulation in AD (Taheri et al. 2011; Zlokovic 2008; Mawuenyega et al. 2010; Roberts et al. 2014). Thus, the reduced expression of the BBB transporters LRP-1, P-glycoprotein, and PICALM or the increased expression of Mfsda2 in the brain endothelium promotes vascular Ab accumulation and may worsen the vascular dysfunction (Bell et al. 2009; Deane et al. 2003; Zhao et al. 2015; Ben- Zvi et al. 2014). "
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    ABSTRACT: Alzheimer's disease (AD) and cerebrovascular diseases share common vascular risk factors that have disastrous effects on cerebrovascular regulation. Endothelial cells, lining inner walls of cerebral blood vessels, form a dynamic interface between the blood and the brain and are critical for the maintenance of neurovascular homeostasis. Accordingly, injury in endothelial cells is regarded as one of the earliest symptoms of impaired vasoregulatory mechanisms. Extracellular buildup of amyloid-β (Aβ) is a central pathogenic factor in AD. Aβ exerts potent detrimental effects on cerebral blood vessels and impairs endothelial structure and function. Recent evidence implicates vascular oxidative stress and activation of the non-selective cationic channel transient receptor potential melastatin (TRPM)-2 on endothelial cells in the mechanisms of Aβ-induced neurovascular dysfunction. Thus, Aβ triggers opening of TRPM2 channels in endothelial cells leading to intracellular Ca(2+) overload and vasomotor dysfunction. The cerebrovascular dysfunction may contribute to AD pathogenesis by reducing the cerebral blood supply, leading to increased susceptibility to vascular insufficiency, and by promoting Aβ accumulation. The recent realization that vascular factors contribute to AD pathobiology suggests new targets for the prevention and treatment of this devastating disease.
    Cellular and Molecular Neurobiology 09/2015; DOI:10.1007/s10571-015-0256-9 · 2.51 Impact Factor
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    • " Floden and Combs , 2011 ; Zhao et al . , 2014 ) , as well as its capacity to migrate ( Sheng et al . , 1998 ; Damani et al . , 2011 ) and shift among inflammatory activation patterns towards a more phagocytic stage ( Sierra et al . , 2007 ; Streit et al . , 2009 ; Schuitemaker et al . , 2012 ) . Similar results have been reported on AD patients ( Mawuenyega et al . , 2010 ) . There is an age - related impairment of phagocytosis ( Harry et al . , 2000 ; Zhao et al . , 2014 ) and clearance . Clearance by both microglia and astrocytes appears to depend on peroxisome proliferator - activated receptor - γ ( PPARγ ) and apolipoprotein E ( apoE ) levels , which promote the proteolytic clearance of soluble forms"
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    ABSTRACT: Aging is the main risk factor for neurodegenerative diseases. In aging, microglia undergo phenotypic changes compatible with their activation. Glial activation can lead to neuroinflammation, which is increasingly accepted as part of the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD). We hypothesize that in aging, aberrant microglia activation leads to a deleterious environment and neurodegeneration. In aged mice, microglia exhibit an increased expression of cytokines and an exacerbated inflammatory response to pathological changes. Whereas LPS increases nitric oxide secretion in microglia from young mice, induction of reactive oxygen species (ROS) predominates in older mice. Furthermore, there is accumulation of DNA oxidative damage in mitochondria of microglia during aging, and also an increased intracellular ROS production. Increased ROS activates the redox-sensitive nuclear factor kappa B, which promotes more neuroinflammation, and can be translated in functional deficits, such as cognitive impairment. Mitochondria-derived ROS and cathepsin B, are also necessary for the microglial cell production of interleukin-1β, a key inflammatory cytokine. Interestingly, whereas the regulatory cytokine TGFβ1 is also increased in the aged brain, neuroinflammation persists. Assessing this apparent contradiction, we have reported that TGFβ1 induction and activation of Smad3 signaling after inflammatory stimulation are reduced in adult mice. Other protective functions, such as phagocytosis, although observed in aged animals, become not inducible by inflammatory stimuli and TGFβ1. Here, we discuss data suggesting that mitochondrial and endolysosomal dysfunction could at least partially mediate age-associated microglial cell changes, and, together with the impairment of the TGFβ1-Smad3 pathway, could result in a reduction of protective activation and a facilitation of cytotoxic activation of microglia, resulting in the promotion of neurodegeneration.
    Frontiers in Aging Neuroscience 08/2015; 7:124. DOI:10.3389/fnagi.2015.00124 · 4.00 Impact Factor
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    • "In the latter study, lumbar cerebrospinal fluid (CSF) was collected serially and the rates of synthesis and clearance of Alzheimer's disease (AD) biomarkers such as amyloid β peptides and apolipoprotein E were determined, yielding some hitherto unprecedented pathophysiological information. [16] [17] [18] [19] [20] In the present study, in which we extended Bateman's procedure , we detected hundreds of peptides in their unlabeled and 13 C 6 -leucine forms by performing bottom-up proteomics. This novel MS approach, which we have called "Stable Isotope Labeling by Amino acid in Vivo" (SILAV), yields invaluable, hitherto inaccessible, information about protein metabolism in humans, and therefore promises to have many interesting applications in the future. "
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    ABSTRACT: RationaleIntravenous administration of stable isotope labeled amino acid (13C6-leucine) to humans recently made it possible to study the metabolism of specific biomarkers in cerebrospinal fluid (CSF) using targeted mass spectrometry (MS). This labeling approach could be of great interest for monitoring many leucine-containing peptides in parallel, using high-resolution MS. This will make it possible to quantify the rates of synthesis and clearance of a large range of proteins in humans with a view to obtaining new insights into protein metabolism processes and the pathophysiology of diseases such as Alzheimer's disease.Methods Proteins from human lumbar and ventricular CSF samples collected at different times after intravenous 13C6-leucine infusion were digested enzymatically with LysC/trypsin after being denatured, reduced and alkylated. Desalted tryptic peptides were fractionated using Strong Cation eXchange chromatography (SCX) and analyzed using nanoflow liquid chromatography (nano-LC) coupled to a QTOF Impact II (Bruker Daltonics) mass spectrometer. Data-dependent acquisition (DDA) mode was used to identify and quantify light and heavy 13C6-leucine peptides. The ratios of 13C6-leucine incorporation were calculated using the Skyline software program in order to determine the rates of appearance and clearance of proteins in the CSF.ResultsAfter SCX fractionation and quadrupole time-of-flight (QTOF) analysis, 4528 peptides containing leucine were identified in five fractions prepared from 40 μL of CSF. Upon analyzing one of these fractions, 66 peptides (2.7%) corresponding to 61 individual proteins had significant and reproducible rate of 13C6-leucine incorporation at various time points. The plots of the light-to-heavy peptide ratios showed the existence of proteins with different patterns of appearance and clearance in the CSF.Conclusions The Stable Isotope Labeling Amino acid in Vivo (SILAV) method presented here, which yields unprecedented information about protein metabolism in humans, constitutes a promising new approach which certainly holds great potential in the field of clinical proteomics. Copyright © 2015 John Wiley & Sons, Ltd.
    Rapid Communications in Mass Spectrometry 07/2015; 29(20):1-9. DOI:10.1002/rcm.7289 · 2.25 Impact Factor
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