Dataset Information

Remarkably Efficient Blood-Brain Barrier Crossing Polyfluorene-Chitosan Nanoparticle Selectively Tweaks Amyloid Oligomer in Cerebrospinal Fluid and A?1-40.

ABSTRACT: Amyloid oligomers have emerged as a key neurotoxin in Alzheimer's dementia. Amyloid aggregation inhibitors and modulators have therefore offered potential applications in therapeutics and diagnosis. However, crossing the blood-brain barrier (BBB) and finding the toxic aggregates among aggregates of different sizes and shapes remain a challenge. The ability of identifying early aggregates can provide a new approach to find inhibitors of the initial nucleation events correlating presenile dementia. In this study, we have prepared polyfluorene nanoparticles using chitosan as an additive, which enables it to cross BBB efficiently and employed as a highly efficient amyloid oligomer modulator. The polymer conjugate, polyfluorene-chitosan (PC), shows no toxicity in MTT assay and precludes self-aggregation of A?1-40 and human cerebrospinal fluid oligomers to final fibril formation. This modulation strategy is supported by thioflavin T assay, circular dichroism studies, atomic force microscope images, and Fourier transform infrared analysis. The polymer-protein interface exhibits the presence of co-aggregates and responded with a stable optical response. The simple synthesis to get desired sizes and shapes with necessary photophysical behavior, biocompatibility, and most prominently BBB permeability makes this polymer conjugate very unique and highly attractive for modulation of amyloid oligomers selectively as well as for developing next generation nanotheranostic materials toward presenile dementia.

SUBMITTER: Roy Chowdhury S

PROVIDER: S-EPMC6072248 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Remarkably Efficient Blood-Brain Barrier Crossing Polyfluorene-Chitosan Nanoparticle Selectively Tweaks Amyloid Oligomer in Cerebrospinal Fluid and Aβ1-40.

Roy Chowdhury Sayan S Mondal Subrata S Muthuraj Balakrishnan B Balaji S N SN Trivedi Vishal V Krishnan Iyer Parameswar P

ACS omega 20180719 7

Amyloid oligomers have emerged as a key neurotoxin in Alzheimer's dementia. Amyloid aggregation inhibitors and modulators have therefore offered potential applications in therapeutics and diagnosis. However, crossing the blood-brain barrier (BBB) and finding the toxic aggregates among aggregates of different sizes and shapes remain a challenge. The ability of identifying early aggregates can provide a new approach to find inhibitors of the initial nucleation events correlating presenile dementia ...[more]

PMID: 30087934

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Project description:Proteolytic fragments of amyloid and post-translational modification of tau species in Cerebrospinal fluid (CSF) as well as cerebral amyloid deposition are important biomarkers for Alzheimer's Disease. We conducted genome-wide association study to identify genetic factors influencing CSF biomarker level, cerebral amyloid deposition, and disease progression. The genome-wide association study was performed via a meta-analysis of two non-overlapping discovery sample sets to identify genetic variants other than APOE ε4 predictive of the CSF biomarker level (Aβ1-42, t-Tau, p-Tau181P, t-Tau:Aβ1-42 ratio, and p-Tau181P:Aβ1-42 ratio) in patients enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. Loci passing a genome-wide significance threshold of P < 5 x 10-8 were followed-up for replication in an independent sample set. We also performed joint meta-analysis of both discovery sample sets together with the replication sample set. In the discovery phase, we identified variants in FRA10AC1 associated with CSF Aβ1-42 level passing the genome-wide significance threshold (directly genotyped SNV rs10509663 PFE = 1.1 x 10-9, imputed SNV rs116953792 PFE = 3.5 x 10-10), rs116953792 (Pone-sided = 0.04) achieved replication. This association became stronger in the joint meta-analysis (directly genotyped SNV rs10509663 PFE = 1.7 x 10-9, imputed SNV rs116953792 PFE = 7.6 x 10-11). Additionally, we identified locus 15q21 (imputed SNV rs1503351 PFE = 4.0 x 10-8) associated with CSF Aβ1-42 level. No other variants passed the genome-wide significance threshold for other CSF biomarkers in either the discovery sample sets or joint analysis. Gene set enrichment analyses suggested that targeted genes mediated by miR-33, miR-146, and miR-193 were enriched in various GWAS analyses. This finding is particularly important because CSF biomarkers confer disease susceptibility and may be predictive of the likelihood of disease progression in Alzheimer's Disease.

Project description: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 ?-amyloid plaques, and surrounding vessels with ?-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.

Dataset Information

Remarkably Efficient Blood-Brain Barrier Crossing Polyfluorene-Chitosan Nanoparticle Selectively Tweaks Amyloid Oligomer in Cerebrospinal Fluid and A?1-40.

Publications

Remarkably Efficient Blood-Brain Barrier Crossing Polyfluorene-Chitosan Nanoparticle Selectively Tweaks Amyloid Oligomer in Cerebrospinal Fluid and Aβ1-40.

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