Giil L.M.,Haraldsplass Deaconess Hospital |
Kristoffersen E.K.,University of Bergen |
Vedeler C.A.,University of Bergen |
Aarsland D.,Center for Alzheimer Research |
And 8 more authors.
Journal of Alzheimer's Disease | Year: 2015
Autoantibodies with agonist function are described in cardiovascular disorders. Since vascular risk factors are associated with an increased risk for Alzheimer's disease (AD), we investigated a potential association between antibodies to the angiotensin 2 type 1 receptor (anti-AT1R) and AD. Objective: The primary objective of this study was to investigate the association between anti-AT1R and AD. The secondary objective was to investigate the association between clinical or biomarker features of AD and anti-AT1R. Methods: Samples from patients with mild AD participating in a longitudinal study in Western Norway (n = 92, 65 [71%] females, mean age 74.8 [range 50-89]) and age- and gender-matched healthy controls (n = 102) were included. Cerebrospinal fluid (CSF) AD biomarkers were assessed in a subgroup of patients. Patients were examined annually, including Mini-Mental State Examination. ELISA was used to measure anti-AT1R in serum. Non-parametric tests were used for statistical calculations and a p < 0.05 was considered significant. Results: AD patients had significantly higher levels of anti-AT1R compared with healthy controls (10.2 U/mL versus 8.1 U/mL, p = 0.04). This difference was found only in patients without hypertension and diabetes. Anti-AT1R levels correlated with CSF total tau (p = 0.03) and phosphorylated tau (p = 0.03) levels, and inversely with blood pressure in AD (Spearman R ?0.277, p = 0.008). Discussion:ADis associated with increased levels of anti-AT1R, and the antibodies correlated withCSFtotal, and phosphorylated tau levels. Further research is needed to understand the blood pressure response in AD without hypertension and a potential link between tau and anti-AT1R in AD. © 2015 - IOS Press and the authors. All rights reserved.
Orellana C.,Center for Alzheimer Research |
Ferreira D.,Center for Alzheimer Research |
Muehlboeck J.-S.,Center for Alzheimer Research |
Mecocci P.,University of Perugia |
And 10 more authors.
Neurodegenerative Diseases | Year: 2016
Background: Global brain atrophy is present in normal aging and different neurodegenerative disorders such as Alzheimer's disease (AD) and is becoming widely used to monitor disease progression. Summary: The brain volume/cerebrospinal fluid index (BV/CSF index) is validated in this study as a measurement of global brain atrophy. We tested the ability of the BV/CSF index to detect global brain atrophy, investigated the influence of confounders, provided normative values and cut-offs for mild, moderate and severe brain atrophy, and studied associations with different outcome variables. A total of 1,009 individuals were included [324 healthy controls, 408 patients with mild cognitive impairment (MCI) and 277 patients with AD]. Magnetic resonance images were segmented using FreeSurfer, and the BV/CSF index was calculated and studied both cross-sectionally and longitudinally (1-year follow-up). Both AD patients and MCI patients who progressed to AD showed greater global brain atrophy compared to stable MCI patients and controls. Atrophy was associated with older age, larger intracranial volume, less education and presence of the ApoE ε4 allele. Significant correlations were found with clinical variables, CSF biomarkers and several cognitive tests. Key Messages: The BV/CSF index may be useful for staging individuals according to the degree of global brain atrophy, and for monitoring disease progression. It also shows potential for predicting clinical changes and for being used in the clinical routine.Background: Effective therap. © 2015 S. Karger AG, Basel.
Ferreira D.,Center for Alzheimer Research |
Cavallin L.,Karolinska Institutet |
Cavallin L.,Karolinska University Hospital |
Larsson E.-M.,Uppsala University |
And 12 more authors.
Journal of Internal Medicine | Year: 2015
Background: Atrophy in the medial temporal lobe, frontal lobe and posterior cortex can be measured with visual rating scales such as the medial temporal atrophy (MTA), global cortical atrophy - frontal subscale (GCA-F) and posterior atrophy (PA) scales, respectively. However, practical cut-offs are urgently needed, especially now that different presentations of Alzheimer's disease (AD) are included in the revised diagnostic criteria. Aims: The aim of this study was to generate a list of practical cut-offs for the MTA, GCA-F and PA scales, for both diagnosis of AD and determining prognosis in mild cognitive impairment (MCI), and to evaluate the influence of key demographic and clinical factors on these cut-offs. Methods: AddNeuroMed and ADNI cohorts were combined giving a total of 1147 participants (322 patients with AD, 480 patients with MCI and 345 control subjects). The MTA, GCA-F and PA scales were applied and a broad range of cut-offs was evaluated. Results: The MTA scale showed better diagnostic and predictive performances than the GCA-F and PA scales. Age, apolipoprotein E (ApoE) ε4 status and age at disease onset influenced all three scales. For the age ranges 45-64, 65-74, 75-84 and 85-94 years, the following cut-offs should be used. MTA: ≥1.5, ≥1.5, ≥2 and ≥2.5; GCA-F, ≥1, ≥1, ≥1 and ≥1; and PA, ≥1, ≥1, ≥1 and ≥1, respectively, with an adjustment for early-onset ApoE ε4 noncarrier AD patients (MTA: ≥2, ≥2, ≥3 and ≥3; and GCA-F: ≥1, ≥1, ≥2 and ≥2, respectively). Conclusions: If successfully validated in clinical settings, the list of practical cut-offs proposed here might be useful in clinical practice. Their use might also (i) promote research on atrophy subtypes, (ii) increase the understanding of different presentations of AD, (iii) improve diagnosis and prognosis and (iv) aid population selection and enrichment for clinical trials. © 2015 The Association for the Publication of the Journal of Internal Medicine.
PubMed | Karolinska Institutet, Aristoteleion Panepistimeion Thessalonikis, Medical University of Lódz, University of Perugia and 6 more.
Type: Journal Article | Journal: Journal of internal medicine | Year: 2015
Atrophy in the medial temporal lobe, frontal lobe and posterior cortex can be measured with visual rating scales such as the medial temporal atrophy (MTA), global cortical atrophy - frontal subscale (GCA-F) and posterior atrophy (PA) scales, respectively. However, practical cut-offs are urgently needed, especially now that different presentations of Alzheimers disease (AD) are included in the revised diagnostic criteria.The aim of this study was to generate a list of practical cut-offs for the MTA, GCA-F and PA scales, for both diagnosis of AD and determining prognosis in mild cognitive impairment (MCI), and to evaluate the influence of key demographic and clinical factors on these cut-offs.AddNeuroMed and ADNI cohorts were combined giving a total of 1147 participants (322 patients with AD, 480 patients with MCI and 345 control subjects). The MTA, GCA-F and PA scales were applied and a broad range of cut-offs was evaluated.The MTA scale showed better diagnostic and predictive performances than the GCA-F and PA scales. Age, apolipoprotein E (ApoE) 4 status and age at disease onset influenced all three scales. For the age ranges 45-64, 65-74, 75-84 and 85-94years, the following cut-offs should be used. MTA: 1.5, 1.5, 2 and 2.5; GCA-F, 1, 1, 1 and 1; and PA, 1, 1, 1 and 1, respectively, with an adjustment for early-onset ApoE 4 noncarrier AD patients (MTA: 2, 2, 3 and 3; and GCA-F: 1, 1, 2 and 2, respectively).If successfully validated in clinical settings, the list of practical cut-offs proposed here might be useful in clinical practice. Their use might also (i) promote research on atrophy subtypes, (ii) increase the understanding of different presentations of AD, (iii) improve diagnosis and prognosis and (iv) aid population selection and enrichment for clinical trials.
Rising A.,Swedish University of Agricultural Sciences |
Johansson J.,Center for Alzheimer Research
Nature Chemical Biology | Year: 2015
Spider silk is strong and extensible but still biodegradable and well tolerated when implanted, making it the ultimate biomaterial. Shortcomings that arise in replicating spider silk are due to the use of recombinant spider silk proteins (spidroins) that lack native domains, the use of denaturing conditions under purification and spinning and the fact that the understanding of how spiders control silk formation is incomplete. Recent progress has unraveled the molecular mechanisms of the spidroin N- and C-terminal nonrepetitive domains (NTs and CTs) and revealed the pH and ion gradients in spiders' silk glands, clarifying how spidroin solubility is maintained and how silk is formed in a fraction of a second. Protons and CO2, generated by carbonic anhydrase, affect the stability and structures of the NT and CT in different ways. These insights should allow the design of conditions and devices for the spinning of recombinant spidroins into native-like silk. © 2015 Nature America, Inc. All rights reserved.
Huber T.,Rockefeller University |
Sakmar T.P.,Rockefeller University |
Sakmar T.P.,Center for Alzheimer Research
Chemistry and Biology | Year: 2014
G protein-coupled receptors (GPCRs) are targets for a quarter of prescription drugs. Despite recent progress in structural biology of GPCRs, only few key conformational states in the signal transduction process have been elucidated. Agonist ligands frequently display functional selectivity where activated receptors are biased to either G protein- or arrestin-mediated downstream signaling pathways. Selective manipulation of individual steps in the GPCR activation scheme requires precise information about the kinetics of ligand binding and the dynamics of downstream signaling. One approach is to obtain time-resolved information using receptors tagged with fluorescent or structural probes. Recent advances allow for site-specific introduction of genetically encoded unnatural amino acids into expressed GPCRs. We describe how bioorthogonal functional groups on GPCRs enable the mapping of receptor-ligand interactions and how bioorthogonal chemical reactions can be used to introduce fluorescent labels for single-molecule fluorescence applications to study the kinetics and conformational dynamics of GPCR signaling complexes ("signalosomes"). © 2014 Elsevier Ltd.
Cohen S.I.A.,University of Cambridge |
Arosio P.,University of Cambridge |
Presto J.,Center for Alzheimer Research |
Kurudenkandy F.R.,Center for Alzheimer Research |
And 13 more authors.
Nature Structural and Molecular Biology | Year: 2015
Alzheimer's disease is an increasingly prevalent neurodegenerative disorder whose pathogenesis has been associated with aggregation of the amyloid-β peptide (Aβ42). Recent studies have revealed that once Aβ42 fibrils are generated, their surfaces effectively catalyze the formation of neurotoxic oligomers. Here we show that a molecular chaperone, a human Brichos domain, can specifically inhibit this catalytic cycle and limit human Aβ42 toxicity. We demonstrate in vitro that Brichos achieves this inhibition by binding to the surfaces of fibrils, thereby redirecting the aggregation reaction to a pathway that involves minimal formation of toxic oligomeric intermediates. We verify that this mechanism occurs in living mouse brain tissue by cytotoxicity and electrophysiology experiments. These results reveal that molecular chaperones can help maintain protein homeostasis by selectively suppressing critical microscopic steps within the complex reaction pathways responsible for the toxic effects of protein misfolding and aggregation. © 2015 Nature America, Inc.
PubMed | Karolinska Institutet, Tallinn University and Center for Alzheimer Research
Type: Journal Article | Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience | Year: 2014
The amyloid- hypothesis of Alzheimers Disease (AD) focuses on accumulation of amyloid- peptide (A) as the main culprit for the myriad physiological changes seen during development and progression of AD including desynchronization of neuronal action potentials, consequent development of aberrant brain rhythms relevant for cognition, and final emergence of cognitive deficits. The aim of this study was to elucidate the cellular and synaptic mechanisms underlying the A-induced degradation of gamma oscillations in AD, to identify aggregation state(s) of A that mediate the peptides neurotoxicity, and to test ways to prevent the neurotoxic A effect. We show that A(1-42) in physiological concentrations acutely degrades mouse hippocampal gamma oscillations in a concentration- and time-dependent manner. The underlying cause is an A-induced desynchronization of action potential generation in pyramidal cells and a shift of the excitatory/inhibitory equilibrium in the hippocampal network. Using purified preparations containing different aggregation states of A, as well as a designed ligand and a BRICHOS chaperone domain, we provide evidence that the severity of A neurotoxicity increases with increasing concentration of fibrillar over monomeric A forms, and that A-induced degradation of gamma oscillations and excitatory/inhibitory equilibrium is prevented by compounds that interfere with A aggregation. Our study provides correlative evidence for a link between A-induced effects on synaptic currents and AD-relevant neuronal network oscillations, identifies the responsible aggregation state of A and proofs that strategies preventing peptide aggregation are able to prevent the deleterious action of A on the excitatory/inhibitory equilibrium and on the gamma rhythm.