BackgroundYKL-40 (also known as Chitinase 3-like 1) is a glycoprotein produced by inflammatory, cancer and stem cells. Its physiological role is not completely understood but YKL-40 is elevated in the brain and cerebrospinal fluid (CSF) in several neurological and neurodegenerative diseases associated with inflammatory processes. Yet the precise characterization of YKL-40 in dementia cases is missing.MethodsIn the present study, we comparatively analysed YKL-40 levels in the brain and CSF samples from neurodegenerative dementias of different aetiologies characterized by the presence of cortical pathology and disease-specific neuroinflammatory signatures.ResultsYKL-40 was normally expressed in fibrillar astrocytes in the white matter. Additionally YKL-40 was highly and widely expressed in reactive protoplasmic cortical and perivascular astrocytes, and fibrillar astrocytes in sporadic Creutzfeldt-Jakob disease (sCJD). Elevated YKL-40 levels were also detected in Alzheimer’s disease (AD) but not in dementia with Lewy bodies (DLB). In AD, YKL-40-positive astrocytes were commonly found in clusters, often around β-amyloid plaques, and surrounding vessels with β-amyloid angiopathy; they were also distributed randomly in the cerebral cortex and white matter. YKL-40 overexpression appeared as a pre-clinical event as demonstrated in experimental models of prion diseases and AD pathology.CSF YKL-40 levels were measured in a cohort of 288 individuals, including neurological controls (NC) and patients diagnosed with different types of dementia. Compared to NC, increased YKL-40 levels were detected in sCJD (p < 0.001, AUC = 0.92) and AD (p < 0.001, AUC = 0.77) but not in vascular dementia (VaD) (p > 0.05, AUC = 0.71) or in DLB/Parkinson’s disease dementia (PDD) (p > 0.05, AUC = 0.70). Further, two independent patient cohorts were used to validate the increased CSF YKL-40 levels in sCJD. Additionally, increased YKL-40 levels were found in genetic prion diseases associated with the PRNP-D178N (Fatal Familial Insomnia) and PRNP-E200K mutations.ConclusionsOur results unequivocally demonstrate that in neurodegenerative dementias, YKL-40 is a disease-specific marker of neuroinflammation showing its highest levels in prion diseases. Therefore, YKL-40 quantification might have a potential for application in the evaluation of therapeutic intervention in dementias with a neuroinflammatory component.Electronic supplementary materialThe online version of this article (10.1186/s13024-017-0226-4) contains supplementary material, which is available to authorized users.

Ligand-stimulated enzymatic release or cellular degradation of PrP may interfere with neurodegeneration-associated toxicity.

A BS TRACT: Background: The cellular prion protein (PrP C ) is a membrane-bound, multifunctional protein mainly expressed in neuronal tissues. Recent studies indicate that the native trafficking of PrP C can be misused to internalize misfolded amyloid beta and α-synuclein (aSyn) oligomers. Objectives: We define PrP C 's role in internalizing misfolded aSyn in α-synucleinopathies and identify further involved proteins. Methods: We performed comprehensive behavioral studies on four transgenic mouse models (ThySyn and ThySynPrP00, TgM83 and TgMPrP00) at different ages. We developed PrP C -(over)-expressing cell models (cell line and primary cortical neurons), used confocal laser microscopy to perform colocalization studies, applied mass spectrometry to identify interactomes, and determined disassociation constants using surface plasmon resonance (SPR) spectroscopy. Results: Behavioral deficits (memory, anxiety, locomotion, etc.), reduced lifespans, and higher oligomeric aSyn levels were observed in PrP C -expressing mice (ThySyn and TgM83), but not in homologous Prnp ablated mice (ThySynPrP00 and TgMPrP00). PrP C colocalized with and facilitated aSyn (oligomeric and monomeric) internalization in our cell-based models. Glimepiride treatment of PrP Coverexpressing cells reduced aSyn internalization in a dosedependent manner. SPR analysis showed that the binding affinity of PrP C to monomeric aSyn was lower than to oligomeric aSyn. Mass spectrometry-based proteomic studies identified clathrin in the immunoprecipitates of PrP C and aSyn. SPR was used to show that clathrin binds to recombinant PrP, but not aSyn. Experimental disruption of clathrincoated vesicles significantly decreased aSyn internalization. Conclusion: PrP C 's native trafficking can be misused to internalize misfolded aSyn through a clathrin-based mechanism, which may facilitate the spreading of pathological aSyn. Disruption of aSyn-PrP C binding is, therefore, an appealing therapeutic target in α-synucleinopathies.

The analysis of the cerebrospinal fluid (CSF) biomarkers in patients with suspected prion diseases became a useful tool in diagnostic routine. Prion diseases can only be identified at clinical stages when the disease already spread throughout the brain and massive neuronal damage occurs. Consequently, the accuracy of CSF tests detecting non-symptomatic patients is unknown. Here, we aimed to investigate the usefulness of CSF-based diagnostic tests in pre-clinical and clinical naturally occurring scrapie. While decreased total prion protein (PrP) levels and positive PrP seeding activity were already detectable at pre-symptomatic stages, the surrogate markers of neuronal damage total tau (tau) and 14-3-3 proteins were exclusively increased at clinical stages. The present findings confirm that alterations in PrP levels and conformation are primary events in the pathology of prion diseases preceding neuronal damage. Our work also supports the potential use of these tests in the screening of pre-symptomatic scrapie and human prion disease cases.