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Bit-Ivan E.N.,Northwestern University | Suh E.,University of Pennsylvania | Shim H.-S.,University of Iowa | Weintraub S.,Northwestern University | And 12 more authors.
Journal of Neuropathology and Experimental Neurology | Year: 2014

Understanding of frontotemporal lobar degeneration, the underlying pathology most often linked to the clinical diagnosis of frontotemporal dementia, is rapidly increasing. Mutations in 7 known genes (MAPT, GRN, C9orf72, VCP, CHMP2B, and, rarely, TARDBP and FUS) are associated with frontotemporal dementia, and the pathologic classification of frontotemporal lobar degeneration has recently been modified to reflect these discoveries. Mutations in one of these genes (GRN), which encodes progranulin, have been implicated in up to a quarter of cases of frontotemporal lobar degeneration with TDP-43 (TAR DNA-binding protein 43)-positive inclusions; currently, there are more than 60 known pathogenic mutations of the gene. We present the clinical, pathologic, and genetic findings on 6 cases from 4 families, 5 of which were shown to have a novel GRN c.708+6-+9delTGAG mutation. Copyright © 2014 by the American Association of Neuropathologists, Inc.


Hort J.,Charles University | Bartos A.,Alzheimer Disease Center | Bartos A.,Charles University | Pirttila T.,Kuopio University Hospital | Scheltens P.,VU University Amsterdam
European Journal of Neurology | Year: 2010

Background and purpose: Cerebrospinal fluid (CSF) biomarkers have been reported to be useful in dementia diagnosis. Not much is known about their use in clinical practice in Europe. Methods: We analyzed data from a survey on the use of CSF biomarkers in the diagnosis of dementia across Europe using a questionnaire which was filled out by representatives of the 25 member countries of the European Federation of Neurological Societies (EFNS). Results: Cerebrospinal fluid beta-amyloid, total tau, and phosphorylated tau proteins are frequently evaluated in the majority of the countries (in 18 out of 23 countries). No major technical or ethical issues were found that would hamper the procedure's ability to become routine in early and differential diagnostics of Alzheimer's disease. Cut-off values for beta-amyloid (median 500, range 300-849 pg/ml), total tau (367; 195-450 pg/ml) and phosphorylated tau (60; 40-85 pg/ml) varied considerably amongst countries and even within every country. Conclusions: Cerebrospinal fluid analysis of beta-amyloid, tau, and phosphorylated tau is frequently used in Europe. However, the use of various cut off values seriously hampers comparability and yields a potential threat to an interpretation and balanced use in clinical practice. We recommend that each laboratory establishes normative data and that multi-centered studies should be organized to explore the reasons for any differences. © 2009 EFNS.


Qiu W.W.Q.,Boston University | Qiu W.W.Q.,Alzheimer Disease Center | Lai A.,Boston University | Mon T.,Boston University | And 7 more authors.
American Journal of Geriatric Psychiatry | Year: 2014

Objective: The effect of angiotensin converting enzyme (ACE) inhibitors on Alzheimer disease (AD) remains unclear, with conflicting results reported. We studied the interaction of the Apolipoprotein E (ApoE) genotype and ACE inhibitors on AD. Methods: This was a cross-sectional study of homebound elderly with an AD diagnosis and documentation of medications taken. ApoE genotype was determined. Results: A total of 355 subjects with status on ApoE alleles and cognitive diagnoses were studied. The average age (mean SD) of this population was 73.3 8.3 years old, and 73% were female. Cross-sectionally, there was no difference in the number of AD cases between ApoE4 carriers and ApoE4 non-carriers or between ACE inhibitor users and non-users in the homebound elderly. ApoE4 carriers treated with ACE inhibitors, however, had more diagnoses of AD compared with those who did not have the treatment (28% versus 6%, p 0.01) or ApoE4 non-carriers treated with an ACE inhibitor (28% versus 10%, p 0.03). ACE inhibitor use was associated with AD diagnosis only in the presence of an E4 allele. Using multivariate logistic regression analysis, we found that in diagnosed AD cases there was a significant interaction between ApoE4 and ACE inhibitor use (odds ratio: 20.85; 95% confidence interval: 3.08-140.95; p 0.002) after adjusting for age, sex, ethnicity, and education. Conclusion: The effects of ACE inhibitors on AD may be different depending on ApoE genotype. A prospective study is needed to determine whether ACE inhibitor use accelerates or poorly delays AD development in ApoE4 carriers compared with ApoE4 non-carriers.


Kristofikova Z.,Alzheimer Disease Center | Patocka J.,University of South Bohemia | Ripova D.,Alzheimer Disease Center
Psychiatrie | Year: 2010

Although causes of Alzheimer disease are not known yet in detail, it appears that amyloid ß peptides can play a key role in the pathogenesis of the dementia. The toxicity of peptides is closely associated with their ability to oligomerize and aggregate or to create complexes with various endogenous molecules (e.g., with receptors, carriers, enzymes, oxysterols, etc.). However, mechanisms of their physiological interactions and the shift to pathological effects have not been yet elucidated. The experimental results indicate that the physiological actions of peptides are probably associated with the monomelic soluble L-isoform and mediated by stereospecific binding to corresponding molecule. Synthetic D-isoforms or reverse peptides are not effective in this respect. On the other hand, the toxic actions of aggregated L- and D-isoforms on membranes are very similar. In the study, the complexes of amyloid ß peptides and of R-/S-oxysterols are compared. Possible applications of naturally occurring enantiomers of oxysterols and of synthetic D-peptides in patients with Alzheimer disease are also discussed.


Kristofikova Z.,Alzheimer Disease Center | Ripova D.,Alzheimer Disease Center | Hegnerova K.,Academy of Sciences of the Czech Republic | Sirova J.,Alzheimer Disease Center | Homola J.,Academy of Sciences of the Czech Republic
Neurochemical Research | Year: 2013

It is suggested that intracellular tau protein (τ), when released extracellularly upon neuron degeneration, could evoke direct toxic effects on the cholinergic neurotransmitter system through muscarinic receptors and thus contribute to the pathogenesis of Alzheimer's disease. In this study, we evaluated the in vitro effects of six naturally occurring monomeric τ isoforms on rat hippocampal synaptosomal choline transporters CHT1 (large transmembrane proteins associated with high-affinity choline transport and vulnerable to actions of amyloid β peptides (Aβ) applied in vitro or in vivo). Some τ isoforms at nM concentrations inhibited choline transport in a dose- and time-dependent saturable manner (352 = 441 > 410 = 383 > 381 = 412) and effects were associated with changes in the Michaelis constant rather than in maximal velocity. Moreover, the actions of τ 352/441 were not influenced by previous depolarisation of synaptosomes or by previous depletion of membrane cholesterol. Specific binding of [3H]hemicholinium-3 was not significantly altered by τ 352/441 at higher nM concentrations. Results of in vitro tests on CHT1 transporters from cholesterol-depleted synaptosomes supported interactions between Aβ 1-40 and τ 352. In addition, we developed surface plasmon resonance biosensors to monitor complexes of Aβ 1-42 and τ 352 using a sandwich detection format. It seems, therefore, that protein τ, similar to Aβ peptides, can contribute to the pathogenesis of Alzheimer's disease through its actions on CHT1 transporters. However, the interaction mechanisms are quite different (τ probably exerts its effects through direct interactions of microtubule binding repeats with extracellular portions of the CHT1 protein without influencing the choline recognition site, Aβ rather through lipid rafts in the surrounding membranes). An N-terminal insert of τ is not necessary but the N-terminal projection domain plays a role. The developed biosensor will be used to detect Aβ-τ complexes in cerebrospinal fluid in order to evaluate them as prospective biomarkers of Alzheimer′s disease. © 2013 Springer Science+Business Media New York.


Kristofikova Z.,Alzheimer Disease Center | Kriz Z.,Masaryk University | Ripova D.,Alzheimer Disease Center | Koca J.,Masaryk University
Neurochemical Research | Year: 2012

Amyloid β peptides appear to play a role in physiological processes; however, they are also involved in the pathogenesis of Alzheimer disease. Their actions under normal conditions are probably mediated by soluble monomeric L-isoforms at low concentrations, perhaps via highly specific interactions. On the contrary, toxic effects of aggregated natural L-isoforms/synthetic D-isoforms on membranes are very similar, but synthetic reverse/random L-isoforms without pronounced aggregation properties are not toxic. Our previous work reported interactions of non-aggregated/aggregated L-isoforms of amyloid β peptides 1-40/1-42 with racemic 24-hydroxycholesterol. In this study, stereospecificity in the interactions of natural 24(S)hydroxycholesterol (cerebrosterol) or synthetic 24(R)hydroxycholesterol with soluble fragment 1-40 was evaluated by means of an in vitro test based on increased vulnerability of the hemicholinium-3 sensitive high-affinity choline uptake system in rat hippocampal cholesterol- depleted synaptosomes to the actions of amyloid β; computational simulations were also performed. Our results suggest that: (1) 24(S)hydroxycholesterol interacts with L-peptide 1-40 but not with the reverse L-peptide 40-1, (2) 24(R)hydroxycholesterol does not interact with L-peptide 1-40 or reverse 40-1, and (3) both enantiomers can probably interact with D-peptide 1-40. Therefore, the binding of 24(S)hydroxycholesterol is not fully stereospecific and the interaction could not reflect a physiological mechanism. Data from the computational simulation indicate that the hydrophobic core of the amyloid β molecule interacts with the hydrophobic part of 24(S)hydroxycholesterol, but no hydrogen bonds with high stability were found. Using this procedure, globular amyloid β could retain 24(S)hydroxy- cholesterol and thus contribute to its pathological accumulation in the brains of patients with Alzheimer disease. © Springer Science+Business Media, LLC 2011.


Kriz Z.,Masaryk University | Klusak J.,Masaryk University | Kristofikova Z.,Alzheimer Disease Center | Koca J.,Masaryk University
PLoS ONE | Year: 2013

Progressive cerebral deposition of amyloid beta occurs in Alzheimeŕs disease and during the aging of certain mammals (human, monkey, dog, bear, cow, cat) but not others (rat, mouse). It is possibly due to different amino acid sequences at positions 5, 10 and 13. To address this issue, we performed series of 100 ns long trajectories (each trajectory was run twice with different initial velocity distribution) on amyloid beta (1-42) with the human and rat amino acid sequence in three different environments: water with only counter ions, water with NaCl at a concentration of 0.15 M as a model of intracellular Na+ concentration at steady state, and water with NaCl at a concentration of 0.30 M as a model of intracellular Na+ concentration under stimulated conditions. We analyzed secondary structure stability, internal hydrogen bonds, and residual fluctuation. It was observed that the change in ionic strength affects the stability of internal hydrogen bonds. Increasing the ionic strength increases atomic fluctuation in the hydrophobic core of the human amyloid, and decreases the atomic fluctuation in the case of rat amyloid. The secondary structure analyses show a stable α-helix part between residues 10 and 20. However, C-terminus of investigated amyloids is much more flexible showing no stable secondary structure elements. Increasing ionic strength of the solvent leads to decreasing stability of the secondary structural elements. The difference in conformational behavior of the three amino acids at position 5, 10 and 13 for human and rat amyloids significantly changes the conformational behavior of the whole peptide. © 2013 Kříž et al.


PubMed | Alzheimer Disease Center
Type: Journal Article | Journal: Neurochemical research | Year: 2012

Amyloid peptides appear to play a role in physiological processes; however, they are also involved in the pathogenesis of Alzheimer disease. Their actions under normal conditions are probably mediated by soluble monomeric L-isoforms at low concentrations, perhaps via highly specific interactions. On the contrary, toxic effects of aggregated natural L-isoforms/synthetic D-isoforms on membranes are very similar, but synthetic reverse/random L: -isoforms without pronounced aggregation properties are not toxic. Our previous work reported interactions of non-aggregated/aggregated L-isoforms of amyloid peptides 1-40/1-42 with racemic 24-hydroxycholesterol. In this study, stereospecificity in the interactions of natural 24(S)hydroxycholesterol (cerebrosterol) or synthetic 24(R)hydroxycholesterol with soluble fragment 1-40 was evaluated by means of an in vitro test based on increased vulnerability of the hemicholinium-3 sensitive high-affinity choline uptake system in rat hippocampal cholesterol-depleted synaptosomes to the actions of amyloid ; computational simulations were also performed. Our results suggest that: (1) 24(S)hydroxycholesterol interacts with L-peptide 1-40 but not with the reverse L-peptide 40-1, (2) 24(R)hydroxycholesterol does not interact with L-peptide 1-40 or reverse 40-1, and (3) both enantiomers can probably interact with D-peptide 1-40. Therefore, the binding of 24(S)hydroxycholesterol is not fully stereospecific and the interaction could not reflect a physiological mechanism. Data from the computational simulation indicate that the hydrophobic core of the amyloid molecule interacts with the hydrophobic part of 24(S)hydroxycholesterol, but no hydrogen bonds with high stability were found. Using this procedure, globular amyloid could retain 24(S)hydroxycholesterol and thus contribute to its pathological accumulation in the brains of patients with Alzheimer disease.


PubMed | Alzheimer Disease Center
Type: Journal Article | Journal: Neurochemical research | Year: 2013

It is suggested that intracellular tau protein (), when released extracellularly upon neuron degeneration, could evoke direct toxic effects on the cholinergic neurotransmitter system through muscarinic receptors and thus contribute to the pathogenesis of Alzheimers disease. In this study, we evaluated the in vitro effects of six naturally occurring monomeric isoforms on rat hippocampal synaptosomal choline transporters CHT1 (large transmembrane proteins associated with high-affinity choline transport and vulnerable to actions of amyloid peptides (A) applied in vitro or in vivo). Some isoforms at nM concentrations inhibited choline transport in a dose- and time-dependent saturable manner (352=441>410=383>381=412) and effects were associated with changes in the Michaelis constant rather than in maximal velocity. Moreover, the actions of 352/441 were not influenced by previous depolarisation of synaptosomes or by previous depletion of membrane cholesterol. Specific binding of [3H]hemicholinium-3 was not significantly altered by 352/441 at higher nM concentrations. Results of in vitro tests on CHT1 transporters from cholesterol-depleted synaptosomes supported interactions between A 1-40 and 352. In addition, we developed surface plasmon resonance biosensors to monitor complexes of A 1-42 and 352 using a sandwich detection format. It seems, therefore, that protein , similar to A peptides, can contribute to the pathogenesis of Alzheimers disease through its actions on CHT1 transporters. However, the interaction mechanisms are quite different ( probably exerts its effects through direct interactions of microtubule binding repeats with extracellular portions of the CHT1 protein without influencing the choline recognition site, A rather through lipid rafts in the surrounding membranes). An N-terminal insert of is not necessary but the N-terminal projection domain plays a role. The developed biosensor will be used to detect A- complexes in cerebrospinal fluid in order to evaluate them as prospective biomarkers of Alzheimers disease.

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