The cellular prion protein (PrPC) consists of a flexible N-terminal tail (FT, aa 23-128) hinged to a membrane-anchored globular domain (GD, aa 129-231). Ligation of the GD with antibodies induces ...rapid neurodegeneration, which is prevented by deletion or functional inactivation of the FT. Therefore, the FT is an allosteric effector of neurotoxicity. To explore its mechanism of action, we generated transgenic mice expressing the FT fused to a GPI anchor, but lacking the GD (PrPΔ141-225, or "FTgpi"). Here we report that FTgpi mice develop a progressive, inexorably lethal neurodegeneration morphologically and biochemically similar to that triggered by anti-GD antibodies. FTgpi was mostly retained in the endoplasmic reticulum, where it triggered a conspicuous unfolded protein response specifically activating the PERK pathway leading to phosphorylation of eIF2α and upregulation of CHOP ultimately leading to neurodegeration similar to what was observed in prion infection.
Pyroglutamylation of truncated Aβ peptides, which is catalysed by enzyme glutaminyl cyclase (QC), generates pE-Aβ species with enhanced aggregation propensities and resistance to most ...amino-peptidases and endo-peptidases. pE-Aβ species have been identified as major constituents of Aβ plaques and reduction of pE-Aβ species is associated with improvement of cognitive tasks in animal models of Alzheimer's disease (AD). Pharmacological inhibition of QC has thus emerged as a promising therapeutic approach for AD. Here, we question whether cerebrospinal fluid (CSF) QC enzymatic activity differs between AD patients and controls and whether inflammatory or angiogenesis mediators, some of which are potential QC substrates, and/or Aβ peptides may serve as pharmacodynamic read-outs for QC inhibition.
QC activity, Aβ peptides and inflammatory or angiogenesis mediators were measured in CSF of a clinically well-characterized cohort of 20 mild AD patients, 20 moderate AD patients and 20 subjective memory complaints (SMC) controls. Correlation of these parameters with core diagnostic CSF AD biomarkers (Aβ42, tau and p-tau) and clinical features was evaluated.
QC activity shows a tendency to decrease with AD progression (p = 0.129). The addition of QC activity to biomarkers tau and p-tau significantly increases diagnostic power (ROC-AUC
= 0.878, ROC-AUC
&
= 0.939 and ROC-AUC
= 0.820, ROC-AUC
&
= 0.948). In AD and controls, QC activity correlates with Aβ38 (r = 0.83, p < 0.0001) and Aβ40 (r = 0.84, p < 0.0001), angiogenesis mediators (Flt1, Tie2, VEGFD, VCAM-1 and ICAM-1, r > 0.5, p < 0.0001) and core diagnostic biomarkers (r > 0.35, p = <0.0057). QC activity does not correlate with MMSE or ApoE genotype.
Aβ38, Aβ40 and angiogenesis mediators (Flt1, Tie2, VEGFD, VCAM-1 and ICAM-1) are potential pharmacodynamic markers of QC inhibition, because their levels closely correlate with QC activity in AD patients. The addition of QC activity to core diagnostic CSF biomarkers may be of specific interest in clinical cases with discordant imaging and biochemical biomarker results.
The cellular form of the prion protein, PrP(C), undergoes extensive proteolysis at the alpha site (109K see textH110). Expression of non-cleavable PrP(C) mutants in transgenic mice correlates with ...neurotoxicity, suggesting that alpha-cleavage is important for PrP(C) physiology. To gain insights into the mechanisms of alpha-cleavage, we generated a library of PrP(C) mutants with mutations in the region neighbouring the alpha-cleavage site. The prevalence of C1, the carboxy adduct of alpha-cleavage, was determined for each mutant. In cell lines of disparate origin, C1 prevalence was unaffected by variations in charge and hydrophobicity of the region neighbouring the alpha-cleavage site, and by substitutions of the residues in the palindrome that flanks this site. Instead, alpha-cleavage was size-dependently impaired by deletions within the domain 106-119. Almost no cleavage was observed upon full deletion of this domain. These results suggest that alpha-cleavage is executed by an alpha-PrPase whose activity, despite surprisingly limited sequence specificity, is dependent on the size of the central region of PrP(C).
The clinical course of relapsing-remitting multiple sclerosis (RRMS) is highly heterogeneous and prognostic biomarkers at time of diagnosis are lacking.
We investigated the predictive value of the ...plasma proteome at time of diagnosis in RRMS patients.
The plasma proteome was interrogated using a novel aptamer-based proteomics platform, which allows to measure the levels of a predefined set of 1310 proteins.
In 67 clinically and radiologically well characterized RRMS patients, we found no association between the plasma proteome at diagnosis and clinical, cognitive or MRI outcomes after 11 years.
Proteomics studies on cerebrospinal fluid may be better suited to identify prognostic biomarkers in early RRMS.
There is a strong unmet clinical need for objective body fluid biomarkers to assist early diagnosis and estimate long-term prognosis, monitor treatment response and predict potential adverse effects ...in multiple sclerosis (MS). Here, we review recent studies (focusing on 2012 to early 2015) on body fluid markers in MS from the perspective of their clinical utility. Because the first step towards clinical implementation of a newly discovered biomarker is independent replication, we focus on biomarkers that have been validated in at least two independent cohorts. We also discuss recent data challenging earlier findings, and biomarkers for which new clinical uses are suggested. For early MS diagnosis and prediction of conversion from clinically isolated syndrome to MS, several new B-cell-associated candidate blood biomarkers have emerged. For prognosis, several novel axonal damage markers should be adopted to biomarker panels. The number of disease-modifying treatments for MS has increased sharply, but biomarkers for treatment response monitoring and adverse effect prediction are scarce, and markers for subtyping and staging of MS are still lacking. In view of the availability and implementation of several standardized protocols to optimize biomarker studies, we expect biomarker development for MS to be improved and accelerated, with clinical implementation in the near future.
Autoimmune encephalitis (AE) are a group of rare inflammatory diseases of the central nervous system that can manifest as subacute cognitive impairment. Despite the presence of diagnostic criteria, ...it can be challenging to identify this disease in certain age groups. In this article, we present the two main clinical phenotypes of AE associated with cognitive impairment, the factors contributing to the long-term cognitive outcome and its management after the acute phase.
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