Aggregation states of Aβ[subscript 1-40], Aβ[subscript 1-42] and Aβp[subscript 3-42] amyloid beta peptides: a SANS study

Aggregation states of amyloid beta peptides for amyloid beta A β[subscript 1-40] to A β[subscript 1-42] and A βp[subscript 3-42] are investigated through small angle neutron scattering (SANS). The knowledge of these small peptides and their aggregation state are of key importance for the comprehension of neurodegenerative diseases (e.g., Alzheimer’s disease). The SANS technique allows to study the size and fractal nature of the monomers, oligomers and fibrils of the three different peptides. Results show that all the investigated peptides have monomers with a radius of gyration of the order of 10 Å, while the oligomers and fibrils display differences in size and aggregation ability, with A βp[subscript 3-42] showing larger oligomers. These properties are strictly related to the toxicity of the corresponding amyloid peptide and indeed to the development of the associated disease. Keywords: beta amyloid; aggregation state; small angle neutron scattering; Alzheimer’s diseaseCNR-STFC (grant no. 2014-2020 (N. 3420)

Amyloid-Mediated Cholinergic Dysfunction in Motor Impairment Related to Alzheimer's Disease

Although motor disturbances parallel the course of dementia, worsening both quality of life and social costs, the pathogenesis remains still unclear

Amyloid-Mediated Cholinergic Dysfunction in Motor Impairment Related to Alzheimer's Disease

reserved9noAlthough motor disturbances parallel the course of dementia, worsening both quality of life and social costs, the pathogenesis remains still unclear.mixedSchirinzi, Tommaso; Di Lorenzo, Francesco; Sancesario, Giulia Maria; Di Lazzaro, Giulia; Ponzo, Viviana; Pisani, Antonio; Mercuri, Nicola Biagio; Koch, Giacomo; Martorana, AlessandroSchirinzi, Tommaso; Di Lorenzo, Francesco; Sancesario, Giulia Maria; Di Lazzaro, Giulia; Ponzo, Viviana; Pisani, Antonio; Mercuri, Nicola Biagio; Koch, Giacomo; Martorana, Alessandr

Constipation distinguishes different clinical-biochemical patterns in de novo Parkinson's disease

Introduction: Prodromal constipation (PC) at Parkinson's disease (PD) onset may mark a distinct neurodegen-erative trajectory; accordingly, presenting phenotype, biochemical signature, and progression of PD patients with PC (PD + PC) might differ from those without (PDwoPC). We compared the clinical-biochemical profile of de novo PD patients with and without PC, and the respective mid-term progression, to establish the grouping effect of PC. Methods: Motor and non-motor scores were collected at diagnosis in n = 57 PD + PC patients and n = 73 PDwoPC. Paired CSF biomarkers (alpha-synuclein, amyloid and tau peptides, lactate, CSF/serum albumin ratio or AR) were assessed into a smaller sample and n = 46 controls. Clinical progression was estimated as Hoehn and Yahr stage (HY) and levodopa equivalent daily dose (LEDD) change 2.06 +/- 1.35 years after diagnosis. Results: At onset, PD + PC patients had higher HY and MDS-UPDRS-part III scores, and higher CSF AR. PDwoPC had higher Non-Motor Symptoms Scale domain-2 score, and lower CSF alpha-synuclein level. At follow-up, PD + PC had greater LEDD. Conclusions: PC identifies a group of de novo patients with more severe motor impairment, possible blood brain barrier disruption, and greater dopaminergic requirement at mid-term; conversely, de novo PDwoPC patients had prominent fatigue, and pronounced central synucleinopathy

Phospho-S129 Alpha-Synuclein Is Present in Human Plasma but Not in Cerebrospinal Fluid as Determined by an Ultrasensitive Immunoassay

Accumulation and aggregation of misfolded alpha-synuclein is believed to be a cause of Parkinson's disease (PD). Phosphorylation of alpha-synuclein at S129 is known to be associated with the pathological misfolding process, but efforts to investigate the relevance of this post-translational modification for pathology have been frustrated by difficulties in detecting and quantifying it in relevant samples. We report novel, ultrasensitive immunoassays based on single-molecule counting technology, useful for detecting alpha-synuclein and its S129 phosphorylated form in clinical samples in the low pg/ml range. Using human CSF and plasma samples, we find levels of alpha-synuclein comparable to those previously reported. However, while alpha-synuclein phosphorylated on S129 could easily be detected in human plasma, where its detection is extremely sensitive to protein phosphatases, its levels in CSF were undetectable, with a possible influence of a matrix effect. In plasma samples from a small test cohort comprising 5 PD individuals and five age-matched control individuals we find that pS129 alpha-synuclein levels are increased in PD plasma samples, in line with previous reports. We conclude that pS129 alpha-synuclein is not detectable in CSF and recommend the addition of phosphatase inhibitors to plasma samples at the time of collection. Moreover, the findings obtained on the small cohort of clinical plasma samples point to plasma pS129 alpha-synuclein levels as a candidate diagnostic biomarker in PD

Tau and Amyloid-beta Peptides in Serum of Patients With Parkinson's Disease: Correlations With CSF Levels and Clinical Parameters

Relevance of blood-based biomarkers is increasing into the neurodegenerative diseases field, but data on Parkinson's disease (PD) remain still scarce. In this study, we used the SiMoA technique to measure serum content of total tau protein and amyloid-beta peptides (A beta-42, A beta-40) in 22 PD patients and ten control subjects. Serum levels of each biomarker were correlated with the respective CSF levels in both the groups; in PD patients, also the correlations between serum biomarkers and main clinical parameters were tested (motor, non-motor, cognitive scores and levodopa equivalent daily dose). Serum biomarkers did not exhibit quantitative differences between patients and controls; however, only PD patients had inter-fluids (serum-CSF) associations in tau and amyloid-beta-42 levels. Moreover, serum content of tau protein was inversely correlated with cognitive performances (MoCA score). These findings, albeit preliminary, indicate that brain-derived peptides may change in parallel in both peripheral blood and CSF of PD patients, eventually even in association with some clinical features. Further studies are now needed to validate the use of blood-based biomarkers in PD