Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer's disease

The molecular architecture of amyloids formed in vivo can be interrogated using luminescent conjugated oligothiophenes (LCOs), a unique class of amyloid dyes. When bound to amyloid, LCOs yield fluorescence emission spectra that reflect the 3D structure of the protein aggregates. Given that synthetic amyloid-β peptide (Aβ) has been shown to adopt distinct structural conformations with different biological activities, we asked whether Aβ can assume structurally and functionally distinct conformations within the brain. To this end, we analyzed the LCO-stained cores of β-amyloid plaques in postmortem tissue sections from frontal, temporal, and occipital neocortices in 40 cases of familial Alzheimer's disease (AD) or sporadic (idiopathic) AD (sAD). The spectral attributes of LCO-bound plaques varied markedly in the brain, but the mean spectral properties of the amyloid cores were generally similar in all three cortical regions of individual patients. Remarkably, the LCO amyloid spectra differed significantly among some of the familial and sAD subtypes, and between typical patients with sAD and those with posterior cortical atrophy AD. Neither the amount of Aβ nor its protease resistance correlated with LCO spectral properties. LCO spectral amyloid phenotypes could be partially conveyed to Aβ plaques induced by experimental transmission in a mouse model. These findings indicate that polymorphic Aβ-amyloid deposits within the brain cluster as clouds of conformational variants in different AD cases. Heterogeneity in the molecular architecture of pathogenic Aβ among individuals and in etiologically distinct subtypes of AD justifies further studies to assess putative links between Aβ conformation and clinical phenotype

Neurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage in humans and mice

With molecular treatments coming into reach for spinocerebellar ataxia type 3 (SCA3), easily accessible, cross-species validated biomarkers for human and preclinical trials are warranted, particularly for the preataxic disease stage. We assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in ataxic and preataxic subjects of two independent multicentric SCA3 cohorts and in a SCA3 knock-in mouse model. Ataxic SCA3 subjects showed increased levels of both NfL and pNfH. In preataxic subjects, NfL levels increased with proximity to the individual expected onset of ataxia, with significant NfL elevations already 7.5 years before onset. Cross-sectional NfL levels correlated with both disease severity and longitudinal disease progression. Blood NfL and pNfH increases in human SCA3 were each paralleled by similar changes in SCA3 knock-in mice, here also starting already at the presymptomatic stage, closely following ataxin-3 aggregation and preceding Purkinje cell loss in the brain. Blood neurofilaments, particularly NfL, might thus provide easily accessible, cross-species validated biomarkers in both ataxic and preataxic SCA3, associated with earliest neuropathological changes, and serve as progression, proximity-to-onset and, potentially, treatment-response markers in both human and preclinical SCA3 trials.Acknowledgements: This work was supported by the Horizon 2020 research and innovation programme (grant 779257 Solve-RD to MS and RS), the National Ataxia Foundation (grant to CW and MS), the Wilhelm Vaillant Stiftung (grant to CW), the EU Joint Programme—Neurodegenerative Disease Research (JPND) through participating national funding agencies, and the European Union’s Horizon 2020 research and innovation programme under grant agreement No 643417. BM was supported in part from the grant NKFIH 119540. HJ was funded by the Medical Faculty of the University of Heidelberg. CB was funded by the University of Basel (PhD Program in Health Sciences). The funding sources had no role in the study design, data collection, data analysis, data interpretation or writing of the manuscript

Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease

Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer's disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini-Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer's disease, which supports its potential utility as a clinically useful biomarker

Deposition of collagen IV and aggrecan in leptomeningeal arteries of hereditary brain haemorrhage with amyloidosis.

To access publisher's full text version of this article click on the hyperlink at the bottom of the pageHereditary Cystatin C Amyloid Angiopathy (HCCAA) is a rare genetic disease in Icelandic families caused by a mutation in the cystatin C gene, CST3. HCCAA is classified as a cerebral amyloid angiopathy and mutant cystatin C forms amyloid deposits in cerebral arteries resulting in fatal haemorrhagic strokes in young adults. The aetiology of HCCAA pathology is not clear and there is, at present, no animal model of the disease. The aim of this study was to increase understanding of the cerebral vascular pathology of HCCAA patients with an emphasis on structural changes within the arterial wall of affected leptomeningeal arteries. Examination of post-mortem samples revealed extensive changes in the walls of affected arteries characterised by deposition of extracellular matrix constituents, notably collagen IV and the proteoglycan aggrecan. Other structural abnormalities were thickening of the laminin distribution, intimal thickening concomitant with a frayed elastic layer, and variable reduction in the integrity of endothelia. Our results show that excess deposition of extracellular matrix proteins in cerebral arteries of HCCAA is a prominent feature of the disease and may play an important role in its pathogenesis.Icelandic Centre for Research (RANNIS) University of Iceland Research Fund Icelandic Centre for Research - Student's Innovation Fund Heilavernd fund Memorial fund of Hafdis Kjartansdottir Memorial fund of Helga Jonsdottir and Sigurlidi Kristjansso

Synthesis and preliminary characterisation of new silicate, phosphate and titanite reference glasses

Eleven synthetic silicate and phosphate glasses were prepared to serve as reference materials for in situ microanalysis of clinopyroxenes, apatite and titanite, and other phosphate and titanite phases. Analytical results using different micro-analytical techniques showed that the glass fragments were homogeneous in major and trace elements down to the micrometre scale. Trace element determinations using inductively coupled plasma-mass spectrometry (ICP-MS), multi-collector inductively coupled plasma-mass spectrometry (MC-ICP-MS), laser-ablation inductively coupled plasma-mass spectrometry (LA-ICP-MS) and secondary ionisation mass spectrometry (SIMS) showed good agreement for most elements (Li, Be, B, Cs, Rb, Ba, Sr, Ga, Pb, U, Th, Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Er, Tm, Yb, Lu, Zr, Hf, Ta, Nb) studied and provide provisional recommended values

Increase in CSF Abeta during the very early phase of cerebral Abeta deposition in mouse models

Abnormalities in the brain of Alzheimer’s Disease (AD) patients are thought to start long before the first clinical symptoms emerge. The identification of affected individuals at this “preclinical AD” stage relies on biomarkers such as decreased levels of the β-amyloid peptide (Aβ) in the cerebrospinal fluid (CSF) and brain retention of amyloid-binding agents using positron emission tomography. However, these biomarkers are limited by the lack of longitudinal profiles and lack pathological conformation in brain. To this end we have studied CSF Aβ changes in three genetically-defined amyloid precursor protein (APP) transgenic mouse models focusing our analysis on the time of the initial Aβ deposition in brain, which differs significantly between the models studied. Remarkably, while we confirmed the CSF Aβ decrease during the course of brain amyloid deposition, a temporary 20-30% increase in CSF Aβ40 and 42 was found at the time of the appearance of the first individual Aβ plaques in all the three models. These results together with emerging indications of similar CSF Aβ increases at very early stages in familial and sporadic AD suggest that increased CSF Aβ levels may constitute the first detectable biomarker change in the AD pathological process. This important observation opens new perspectives in patient selection and stratification for preventive treatment strategies and is an incentive to the discovery of additional “preclinical AD” biomarkers

Prevention of tau increase in cerebrospinal fluid of APP transgenic mice suggests downstream effect of BACE1 inhibition

The inhibition of the beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is a main therapeutic approach for the treatment of Alzheimer's disease (AD). The characterization of BACE1 inhibitors has largely focused on direct effects, i.e. the reduction of β-amyloid (Aβ) generation and deposition in the brain. We reported previously the age-related increase of tau protein in the cerebrospinal fluid (CSF) of Aβ precursor protein (APP) transgenic mice reminiscent of similar changes in AD CSF. Using a novel high-sensitivity tau sandwich immunoassay we now demonstrate that BACE1 inhibition prevents CSF tau increase in both, early-depositing APP tg mice and mice with moderate Aβ pathology. Our results demonstrate that BACE1 inhibition not only reduces Aβ generation but also downstream AD pathologies. The tight correlation between Aβ aggregation in brain and tau levels in CSF renders CSF tau a valuable marker to predict the effectiveness of BACE inhibitors in current clinical trials