1.
Fluorinated and iodinated (Z)-2-(4-(2-fluoroethoxy)benzylidene)-5-iodobenzofuran-3(2H)-one.
Authors
Source
Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2011.
2011 Nov 30 [updated 2011 Dec 28].
Excerpt
Fluorinated and iodinated (Z)-2-(4-(2-fluoroethoxy)benzylidene)-5-iodobenzofuran-3(2H)-one (compound 3), abbreviated as [18F]3 and [125I]3, respectively, is an aurone derivative synthesized by Watanabe et al. for single-photon emission computed tomography (SPECT) and positron emission tomography (PET) of Alzheimer’s disease (AD) by targeting β-amyloid (Aβ) plaques (1). AD is characterized in pathology by the presence of extracellular Aβ plaques, intraneuronal neurofibrillary tangles, and neuronal loss in the cerebral cortex (2, 3). Of them, Aβ deposit is the earliest neuropathological marker and is relatively specific to AD and closely related disorders. Aβ plaques are composed of abnormal paired helical filaments 5–10 nm in size. These filaments are largely made of insoluble Aβ peptides that are 40 or 42 amino acids in length (4). In recent years, molecular imaging by targeting the extracellular Aβ has been intensively investigated in attempts to detect early AD, assess Aβ content in vivo, determine the timing of anti-plaque therapy, and evaluate the therapeutic efficacy (4). Radiolabeled Aβ40 peptides were tested first, but they showed poor penetration ability to cross the blood–brain barrier (BBB) (4). Based on the fact that Aβ can be specifically stained in vitro with dyes of Congo red, chrysamine G, and thioflavin-T, an effort was made to develop imaging agents with these dyes. This effort, however, was in general unsuccessful because the bulky ionic groups of heteroatoms in these dyes prevent them from crossing the BBB (2). Importantly, a large class of derivatives (e.g., aminonaphthalenes, benzothiazoles, stilbenes, and imidazopyridines) was synthesized with these dyes as templates (4). Clinical and preclinical studies have shown that these derivatives not only possess a high binding affinity with Aβ plaques as their parent compounds, but also exhibit good penetration ability through the BBB and rapid washout from brain. Ono et al. first synthesized a class of radioiodinated flavone derivatives that present a high binding affinity with Aβ plaques and good penetration ability through the BBB (5). However, these flavone derivatives display poor clearance from the brain, which leads to a high brain background. The investigators then explored another class of flavonoids with aurone as the core structure (6, 7). Aurone is a heterocyclic chemical compound that contains a benzofuran element associated with a benzylidene linked in position 2 and a chalcone-like group being closed into a five-member ring. The aurone derivatives possess a nucleophilic group (NH2, NHMe, or NMe2) at the 4' position and a radioiodine at the 5 position. Although these aurone derivatives exhibit a strong binding affinity with Aβ (inhibition constant (K i) = 1.2–6.8 nM), high penetration ability through the BBB (1.9%−4.6% injected dose per gram tissue (ID/g) at 2 min), and a fast washout from the brain (0.3%−0.5% ID/g at 30 min), the pharmacokinetics of these compounds are less favorable for brain imaging than the pharmacokinetics of the agent [123I]IMPY (6-iodo-2-(4'-dimethylamino)phenyl-imidazo[1,2]pyridine), which is the only SPECT agent to be tested in humans to date (1, 8, 9). The investigators also modified the flavone and aurone derivatives by pegylating them with 1–3 units of ethylene glycol at the 4' position or by conjugating them with the chelating agent bis-amino-bis-thiol (BAT) (7). Favorable pharmacokinetics for brain imaging was observed for the pegylated derivatives ([18F]8(a–c)) but not for the BAT-chelated derivatives ([99mTc]BAT-FL and [99mTc]BAT-AR) (6, 7). This series of chapters summarizes the data obtained with flavone and aurone derivatives, including [125I]15, [125I]9, [125I]14, [125I]16, [125I]17, [99mTc]BAT-FL, [99mTc]BAT-AR, [18F]8(a-c), [125I]3, and [18F]3 (1, 6-8). This chapter presents the data obtained with [125I]3 and [18F]3 (1).
Sections
Radioiodinated (Z)-2-(4-(2-hydroxyethoxy)benzylidene)-5-iodobenzofuran-3(2H)-one.
Authors
Source
Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2011.
2011 Nov 30 [updated 2011 Dec 28].
Excerpt
Radioiodinated (Z)-2-(4-(2-hydroxyethoxy)benzylidene)-5-iodobenzofuran-3(2H)-one (compound 15), abbreviated as [125I]15, is an aurone derivative synthesized by Maya et al. for single-photon emission computed tomography(SPECT) of Alzheimer’s disease (AD) by targeting β-amyloid (Aβ) (1). The other four aurone derivatives include radioiodinated (Z)-2-(4-methoxybenzylidene)-5-iodobenzofuran-3(2H)-one (compound 9), (Z)-2-(4-hydroxybenzylidene)-5-iodobenzofuran-3(2H)-one (compound 14), (Z)-2-(4-(2-(2-hydroxyethoxy)ethoxy)benzylidene)-5-iodobenzofuran-3(2H)-one (compound 16), and (Z)-2-(4-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)benzylidene)-5-iodobenzofuran-3(2H)-one (compound 17), which are abbreviated as [125I]9, [125I]14, [125I]16, and [125I]17, respectively. AD is characterized in pathology by the presence of extracellular Aβ plaques, intraneuronal neurofibrillary tangles, and neuronal loss in the cerebral cortex (2, 3). Of them, Aβ deposit is the earliest neuropathological marker and is relatively specific to AD and closely related disorders. Aβ plaques are composed of abnormal paired helical filaments 5–10 nm in size. These filaments are largely made of insoluble Aβ peptides that are 40 or 42 amino acids in length (4). In recent years, molecular imaging by targeting the extracellular Aβ has been intensively investigated in attempts to detect early AD, assess Aβ content in vivo, determine the timing of anti-plaque therapy, and evaluate the therapeutic efficacy (4). Radiolabeled Aβ40 peptides were tested first, but they showed poor penetration ability to cross the blood–brain barrier (BBB) (4). Based on the fact that Aβ can be specifically stained in vitro with dyes of Congo red, chrysamine G, and thioflavin-T, an effort was made to develop imaging agents with these dyes. This effort, however, was in general unsuccessful because the bulky ionic groups of heteroatoms in these dyes prevent them from crossing the BBB (2). Importantly, a large class of derivatives (e.g., aminonaphthalenes, benzothiazoles, stilbenes, and imidazopyridines) was synthesized with these dyes as templates (4). Clinical and preclinical studies have shown that these derivatives not only possess a high binding affinity with Aβ plaques as their parent compounds, but also exhibit good penetration ability through the BBB and rapid washout from brain with low to no plaque deposits. Ono et al. first synthesized a class of radioiodinated flavone derivatives that present a high binding affinity with Aβ plaques and good penetration ability through the BBB (5). However, these flavone derivatives display poor clearance from the brain, which leads to a high brain background. The investigators then explored another class of flavonoids with aurone as the core structure (6, 7). Aurone is a heterocyclic chemical compound that contains a benzofuran element associated with a benzylidene linked in position 2 and a chalcone-like group being closed into a five-member ring. The aurone derivatives possess a nucleophilic group (NH2, NHMe, or NMe2) at the 4' position and a radioiodine at the 5 position. Although these aurone derivatives exhibit a strong binding affinity with Aβ (inhibition constant (K i) = 1.2–6.8 nM), high penetration ability through the BBB (1.9%−4.6% injected dose per gram tissue (ID/g) at 2 min), and a fast washout from the brain (0.3%−0.5% ID/g at 30 min), the pharmacokinetics of these compounds are less favorable for brain imaging than the pharmacokinetics of the agent [123I]IMPY (6-iodo-2-(4'-dimethylamino)phenyl-imidazo[1,2]pyridine), which is the only SPECT agent to be tested in humans to date (1, 8, 9). The investigators also modified the flavone and aurone derivatives by pegylating them with 1–3 units of ethylene glycol at the 4' position or by conjugating them with the chelating agent bis-amino-bis-thiol (BAT) (7). Favorable pharmacokinetics for brain imaging was observed for the pegylated derivatives ([18F]8(a–c)) but not for the BAT-chelated derivatives ([99mTc]BAT-FL and [99mTc]BAT-AR) (6, 7). This series of chapters summarizes the data obtained with flavone and aurone derivatives, including [125I]15, [125I]9, [125I]14, [125I]16, [125I]17, [99mTc]BAT-FL, [99mTc]BAT-AR, [18F]8(a–c), [125I]3, and [18F]3 (1, 6-8). This chapter presents the data obtained with [125I]15, [125I]9, [125I]14, [125I]16, and [125I]17 (1).
Sections
99mTc-Bis-amino-bis-thiol-conjugated 6-(3-bromopropoxy)-2-(4-(dimethylamino)phenyl)-4H-chromen-4-one and (Z)-5-(3-bromopropoxy)-2-(4-(dimethylamino)benzylidene)benzofuran-3(2H)-one.
Authors
Source
Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2011.
2011 Nov 30 [updated 2011 Dec 28].
Excerpt
99mTc-Bis-amino-bis-thiol (BAT)-conjugated 6-(3-bromopropoxy)-2-(4-(dimethylamino)phenyl)-4H-chromen-4-one and (Z)-5-(3-bromopropoxy)-2-(4-(dimethylamino)benzylidene)benzofuran-3(2H)-one, abbreviated as [99mTc]BAT-FL and [99mTc]BAT-AR, respectively, are flavone and aurone derivatives synthesized by Ono et al. for single-photon emission computed tomography (SPECT) of Alzheimer’s disease (AD) by targeting β-amyloid (Aβ) (1). AD is characterized in pathology by the presence of extracellular Aβ plaques, intraneuronal neurofibrillary tangles, and neuronal loss in the cerebral cortex (2, 3). Of them, Aβ deposit is the earliest neuropathological marker and is relatively specific to AD and closely related disorders. Aβ plaques are composed of abnormal paired helical filaments 5–10 nm in size. These filaments are largely made of insoluble Aβ peptides that are 40 or 42 amino acids in length (4). In recent years, molecular imaging by targeting the extracellular Aβ has been intensively investigated in attempts to detect early AD, assess Aβ content in vivo, determine the timing of anti-plaque therapy, and evaluate the therapeutic efficacy (4). Radiolabeled Aβ40 peptides were tested first, but they showed poor penetration ability to cross the blood–brain barrier (BBB) (4). Based on the fact that Aβ can be specifically stained in vitro with dyes of Congo red, chrysamine G, and thioflavin-T, an effort was made to develop imaging agents with these dyes. This effort, however, was in general unsuccessful because the bulky ionic groups of heteroatoms in these dyes prevent them from crossing the BBB (2). Importantly, a large class of derivatives (e.g., aminonaphthalenes, benzothiazoles, stilbenes, and imidazopyridines) was synthesized with these dyes as templates (4). Clinical and preclinical studies have shown that these derivatives not only possess a high binding affinity with Aβ plaques as their parent compounds, but also exhibit good penetration ability through the BBB and rapid washout from brain with low to no plaque deposits. Ono et al. first synthesized a class of radioiodinated flavone derivatives that present a high binding affinity with Aβ plaques and good penetration ability through the BBB (5). However, these flavone derivatives display poor clearance from the brain, which leads to a high brain background. The investigators then explored another class of flavonoids with aurone as the core structure (1, 6). Aurone is a heterocyclic chemical compound that contains a benzofuran element associated with a benzylidene linked in position 2 and a chalcone-like group closed into a five-member ring. The aurone derivatives possess a nucleophilic group (NH2, NHMe, or NMe2) at the 4' position and a radioiodine at the 5 position. Although these aurone derivatives exhibit a strong binding affinity with Aβ (inhibition constant (K i) = 1.2–6.8 nM), high penetration ability through the BBB (1.9%−4.6% injected dose per gram tissue (ID/g) at 2 min), and a fast washout from the brain (0.3%−0.5% ID/g at 30 min), the pharmacokinetics of these compounds are less favorable for brain imaging than the pharmacokinetics of the agent [123I]IMPY (6-iodo-2-(4'-dimethylamino)phenyl-imidazo[1,2]pyridine), which is the only SPECT agent to be tested in humans to date (7-9). The investigators also modified the flavone and aurone derivatives by pegylating them with 1–3 units of ethylene glycol at the 4' position or by conjugating them with the chelating agent bis-amino-bis-thiol (BAT). Favorable pharmacokinetics for brain imaging was observed for the pegylated derivatives ([18F]8(a–c)) but not for the BAT-chelated derivatives ([99mTc]BAT-FL and [99mTc]BAT-AR) (1, 6). This series of chapters summarizes the data obtained with flavone and aurone derivatives, including [125I]15, [125I]9, [125I]14, [125I]16, [125I]17, [99mTc]BAT-FL, [99mTc]BAT-AR, [18F]8(a–c), [125I]3, and [18F]3 (1, 6-8). This chapter presents the data obtained with [99mTc]BAT-FL and [99mTc]BAT-AR (1).
Sections
18F-Labeled fluoropegylated 6-fluoroethoxy-4'-dimethylaminoflavone, 6-(2-(2-fluoro-ethoxy)-ethoxy)-4'-dimethylaminoflavone, and 6-(2-(2-(2-fluoro-ethoxy)-ethoxy)ethoxy)-4'-dimethylaminoflavone.
Authors
Source
Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2011.
2011 Nov 30 [updated 2011 Dec 28].
Excerpt
18F-Labeled fluoropegylated 6-fluoroethoxy-4'-dimethylaminoflavone (compound 8a), 6-(2-(2-fluoro-ethoxy)-ethoxy)-4'-dimethylaminoflavone (compound 8b), and 6-(2-(2-(2-fluoro-ethoxy)-ethoxy)ethoxy)-4'-dimethylaminoflavone (compound 8c), abbreviated as [18F]8a, [18F]8b, and [18F]8c, respectively, are flavone derivatives synthesized by Ono et al. for positron emission tomography (PET) of Alzheimer’s disease (AD) by targeting β-amyloid (Aβ) (1). AD is characterized in pathology by the presence of extracellular Aβ plaques, intraneuronal neurofibrillary tangles, and neuronal loss in the cerebral cortex (2, 3). Of them, Aβ deposit is the earliest neuropathological marker and is relatively specific to AD and closely related disorders. Aβ plaques are composed of abnormal paired helical filaments 5–10 nm in size. These filaments are largely made of insoluble Aβ peptides that are 40 or 42 amino acids in length (4). In recent years, molecular imaging by targeting the extracellular Aβ has been intensively investigated in attempts to detect early AD, assess Aβ content in vivo, determine the timing of anti-plaque therapy, and evaluate the therapeutic efficacy (4). Radiolabeled Aβ40 peptides were tested first, but they showed poor penetration ability to cross the blood–brain barrier (BBB) (4). Based on the fact that Aβ can be specifically stained in vitro with dyes of Congo red, chrysamine G, and thioflavin-T, an effort was made to develop imaging agents with these dyes. This effort, however, was in general unsuccessful because the bulky ionic groups of heteroatoms in these dyes prevent them from crossing the BBB (2). Importantly, a large class of derivatives (e.g., aminonaphthalenes, benzothiazoles, stilbenes, and imidazopyridines) was synthesized with these dyes as templates (4). Clinical and preclinical studies have shown that these derivatives not only possess a high binding affinity with Aβ plaques as their parent compounds, but also exhibit good penetration ability through the BBB and rapid washout from brain with low to no plaque deposits. Ono et al. first synthesized a class of radioiodinated flavone derivatives that present a high binding affinity with Aβ plaques and good penetration ability through the BBB (5). However, these flavone derivatives display poor clearance from the brain, which leads to a high brain background. The investigators then explored another class of flavonoids with aurone as the core structure (1, 6). Aurone is a heterocyclic chemical compound that contains a benzofuran element associated with a benzylidene linked in position 2 and a chalcone-like group being closed into a five-member ring. The aurone derivatives possess a nucleophilic group (NH2, NHMe, or NMe2) at the 4' position and a radioiodine at the 5 position. Although these aurone derivatives exhibit a strong binding affinity with Aβ (inhibition constant (K i) = 1.2–6.8 nM), high penetration ability through the BBB (1.9%−4.6% injected dose per gram tissue (ID/g) at 2 min), and a fast washout from the brain (0.3%−0.5% ID/g at 30 min), the pharmacokinetics of these compounds are less favorable for brain imaging than the pharmacokinetics of the agent [123I]IMPY (6-iodo-2-(4'-dimethylamino)phenyl-imidazo[1,2]pyridine), which is the only SPECT agent to be tested in humans to date (7-9). The investigators also modified the flavone and aurone derivatives by pegylating them with 1–3 units of ethylene glycol at the 4' position or by conjugating them with the chelating agent bis-amino-bis-thiol (BAT). Favorable pharmacokinetics for brain imaging was observed for the pegylated derivatives ([18F]8(a–c)) but not for the BAT-chelated derivatives ([99mTc]BAT-FL and [99mTc]BAT-AR) (1, 6). This series of chapters summarizes the data obtained with flavone and aurone derivatives, including [125I]15, [125I]9, [125I]14, [125I]16, [125I]17, [99mTc]BAT-FL, [99mTc]BAT-AR, [18F]8(a–c), [125I]3, and [18F]3 (1, 6-8). This chapter presents the data obtained with [18F]8(a–c) (1).
Sections
Atomic Force Microscopy and MD Simulations Reveal Pore-Like Structures of All-D-Enantiomer of Alzheimer's β-Amyloid Peptide: Relevance to the Ion Channel Mechanism of AD Pathology.
Abstract
Alzheimer's disease (AD) is a protein misfolding disease characterized by a build-up of β-amyloid (Aβ) peptide as senile plaques, uncontrolled neurodegeneration, and memory loss. AD pathology is linked to the destabilization of cellular ionic homeostasis and involves Aβ peptide-plasma membrane interactions. In principle, there are two possible ways through which disturbance of the ionic homeostasis can take place: directly, where the Aβ peptide either inserts into the membrane and creates ion-conductive pores or destabilizes the membrane organization; or, indirectly, where the Aβ peptide interacts with existing cell membrane receptors. To distinguish between these two possible types of Aβ-membrane interactions, we took advantage of the biochemical tenet that ligand-receptor interactions are stereospecific; L amino acid peptides, but not their D counterparts, bind to cell membrane receptors. However, with respect to the ion channel-mediated mechanism, like L-amino acids, D-amino acid peptides will also form ion channel-like structures. Using atomic force microscopy (AFM) we imaged the structures of both D- and L enantiomers of the full length Aβ1-42when reconstituted in lipid bilayers. AFM imaging shows that both L- and D-Aβ isomers form similar channel-like structures. Molecular dynamics (MD) simulations support the AFM imaged 3D structures. Earlier we have shown that D-Aβ1-42 channels conduct ions similarly to their L-counter parts. Taken together, our results support the direct mechanism of Aβ ion channel-mediated destabilization of ionic homeostasis rather than the indirect mechanism through Aβ interaction with membrane receptors.
- PMID:
- 22217000
- [PubMed - as supplied by publisher]
Association between IgM Anti-Herpes Simplex Virus and Plasma Amyloid-BetaLevels.
Source
INSERM, U897, Bordeaux, France.
Abstract
OBJECTIVE:
Herpes simplex virus (HSV) reactivation has been identified as a possible risk factor for Alzheimer's disease (AD) and plasma amyloid-beta (Aβ) levels might be considered as possible biomarkers of the risk of AD. The aim of our study was to investigate the association between anti-HSV antibodies and plasma Aβ levels.
METHODS:
The study sample consisted of 1222 subjects (73.9 y in mean) from the Three-City cohort. IgM and IgG anti-HSV antibodies were quantified using an ELISA kit, and plasma levels of Aβ(1-40) and Aβ(1-42) were measured using an xMAP-based assay technology. Cross-sectional analyses of the associations between anti-HSV antibodies and plasma Aβ levels were performed by multi-linear regression.
RESULTS:
After adjustment for study center, age, sex, education, and apolipoprotein E-e4 polymorphism, plasma Aβ(1-42) and Aβ(1-40) levels were specifically inversely associated with anti-HSV IgM levels (β = -20.7, P = 0.001 and β = -92.4, P = 0.007, respectively). In a sub-sample with information on CLU- and CR1-linked SNPs genotyping (n = 754), additional adjustment for CR1 or CLU markers did not modify these associations (adjustment for CR1 rs6656401, β = -25.6, P = 0.002 for Aβ(1-42) and β = -132.7, P = 0.002 for Aβ(1-40;) adjustment for CLU rs2279590, β = -25.6, P = 0.002 for Aβ(1-42) and β = -134.8, P = 0.002 for Aβ(1-40)). No association between the plasma Aβ(1-42)-to-Aβ(1-40) ratio and anti-HSV IgM or IgG were evidenced.
CONCLUSION:
High anti-HSV IgM levels, markers of HSV reactivation, are associated with lower plasma Aβ(1-40) and Aβ(1-42) levels, which suggest a possible involvement of the virus in the alterations of the APP processing and potentially in the pathogenesis of AD in human.
- PMID:
- 22216291
- [PubMed - in process]
- PMCID: PMC3247269
Amyloid-β Oligomers in Cerebrospinal Fluid are Associated with Cognitive Decline in Patients with Alzheimer's Disease.
Source
Department of Cardiothoracic Surgery of the Martin-Luther-University Halle-Wittenberg, Halle, Germany.
Abstract
Oligomers of the amyloid-β peptide (Aβ) are thought to be the most toxic form of Aβ and are linked to the development of Alzheimer's disease (AD). Here, we used a flow cytometric approach for the detection and assessment of oligomers in cerebrospinal fluid (CSF) from AD patients and other neurological disorders. 30 CSF samples from patients suffering from AD (n = 14), non-demented controls (n = 12), and other neurological disorders (dementia with Lewy bodies, n = 2; vascular dementia, n = 1; primary progressive aphasia, n = 1) were analyzed for the presence of Aβ-oligomers by flow cytometry. The CSF levels of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-β (Aβ)42 were determined using ELISA. CSF Aβ-oligomer levels in AD patients were elevated in comparison to the non-AD group (p = 0.073). The ratio Aβ-oligomers/Aβ42 was significantly elevated in AD subjects compared to non-AD subjects (p = 0.001). Most important, there was a negative correlation between the amount of Aβ-oligomers and the Mini-Mental Status Exam score (r = -0.65; p = 0.013) in AD patients. The detection of Aβ-oligomers using flow cytometry analysis seems to be useful in assessing the stage of AD. This is a novel and important finding as none of the currently used CSF biomarkers are clearly associated with dementia severity.
- PMID:
- 22214781
- [PubMed - as supplied by publisher]
siRNA against presenilin 1 (PS1) down regulates amyloid beta 42 production in IMR-32 cells.
Abstract
ABSTRACT:
BACKGROUND:
One of the pathological hallmarks of Alzheimer's disease (AD) is the deposition of the ~4 kDa amyloidbeta protein (Abeta) within lesions known as senile plaques. Abeta is also deposited in the walls of cerebral blood vessels in many cases of AD. A substantial proportion of the Abeta that accumulates in the AD brain is deposited asAmyloid, which is highly insoluble, proteinaceous material with a beta-pleated-sheet conformation and deposited extracellularly in the form of 5-10 nm wide straight fibrils. As gamma-secretase catalyzes the final cleavage that releases the Abeta42 or 40 from amyloid beta -protein precursor (APP), therefore, it is a potential therapeutic target for the treatment of AD. gamma-Secretase cleavage is performed by a high molecular weight protein complex containing presenilins (PSs), nicastrin, Aph-1 and Pen-2. Previous studies have demonstrated that the presenilins (PS1 and PS2) are critical components of a large enzyme complex that performs gamma-secretase cleavage.
METHODS:
In this study we used RNA interference (RNAi) technology to examine the effects of small-interfering RNA (siRNA) against PS1 on expression levels of PS1 and Abeta42 in IMR-32 Cells using RTPCR, western blotting and immunofluorescence techniques.
RESULTS:
The results of the present study showed down regulation of PS1 and Abeta42 in IMR32 cells transfected with siRNA against PS1.
CONCLUSION:
Our results substantiate the concept that PS1 is involved in gamma-secretase activity and provides the rationale for therapeutic strategies aimed at influencing Abeta42 production.
- PMID:
- 22214483
- [PubMed - as supplied by publisher]
Cerebrospinal Fluid Levels of β-Amyloid 1-42, but Not of Tau, Are Fully Changed Already 5 to 10 Years Before the Onset of Alzheimer Dementia.
Source
Neuropsychiatric Clinic, Skåne University Hospital, S-20502 Malmö, Sweden. oskar.hansson@med.lu.se.
Abstract
CONTEXT:
Early detection of prodromal Alzheimer disease (AD) is important because new disease-modifying therapies are most likely to be effective when initiated during the early stages of disease.
OBJECTIVES:
To assess the ability of the cerebrospinal fluid (CSF) biomarkers total tau (T-tau), phosphorylated tau (P-tau), and β-amyloid 1-42 (Aβ42) to predict future development of AD dementia within 9.2 years in patients with mild cognitive impairment (MCI) and to compare CSF biomarkers between early and late converters to AD.
DESIGN:
A clinical study with a median follow-up of 9.2 years (range, 4.1-11.8 years).
SETTING:
Memory disorder clinic. Patients A total of 137 patients with MCI who underwent lumbar puncture at baseline. Main Outcome Measure Conversion to AD dementia.
RESULTS:
During follow-up, 72 patients (53.7%) developed AD and 21 (15.7%) progressed to other forms of dementia. At baseline, CSF Aβ42 levels were reduced and T-tau and P-tau levels were elevated in patients who converted to AD during follow-up compared with nonconverters (P < .001). Baseline CSF Aβ42 levels were equally reduced in patients with MCI who converted to AD within 0 to 5 years (early converters) compared with those who converted between 5 and 10 years (late converters). However, CSF T-tau and P-tau levels were significantly higher in early converters vs late converters. A baseline Aβ42:P-tau ratio predicted the development of AD within 9.2 years with a sensitivity of 88%, specificity of 90%, positive predictive value of 91%, and negative predictive value of 86%.
CONCLUSIONS:
Approximately 90% of patients with MCI and pathologic CSF biomarker levels at baseline develop AD within 9 to 10 years. Levels of Aβ42 are already fully decreased at least 5 to 10 years before conversion to AD dementia, whereas T-tau and P-tau seem to be later markers. These results provide direct support in humans for the hypothesis that altered Aβ metabolism precedes tau-related pathology and neuronal degeneration.
Obovatol improves cognitive functions in animal models for Alzheimer's disease.
Source
College of Pharmacy and MRC, Chungbuk National University, 12 Gaesin-dong, Heungduk-gu, Cheongju, Chungbuk, 361-763 South Korea Department of Food and Biotechnology, Chungju National University, 123 Geomdan-ri, Iryu-myeon, Chungju, Chungbuk, 380-702 South Korea KT&G Central Research Institute, Yuseong-gu, Daejeon, 305-805 South Korea Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, 305-333 South Korea.
Abstract
Etiology of Alzheimer's disease (AD) is obscure, but neuroinflammation and accumulation of β-amyloid (Aβ) are implicated in pathogenesis of AD. We have shown anti-inflammatory and neurotrophic properties of obovatol, a biphenolic compound isolated from Magnolia obovata. Here, we examined the effect of obovatol on cognitive deficits in two separate AD models; (1) mice that received intracerebroventricular (i.c.v.) infusion of Aβ(1-42) (2.0 μg/mouse) and (2) Tg2576 mice expressing mutant human amyloid precursor protein (APP; K670N, M671L). Injection of Aβ(1-42) into lateral ventricle caused memory impairments in the Morris water maze and passive avoidance tasks, being associated with neuroinflammation. Aβ(1-42) -induced abnormality was significantly attenuated by administration of obovatol. When we analyzed with Tg2576 mice, long-term treatment of obovatol (1 mg/kg/day for 3 months) significantly improved cognitive function. In parallel with the improvement, treatment suppressed astroglial activation, BACE1 expression and NF-κB activity in the transgenic mice. Furthermore, obovatol potently inhibited fibrillation of Aβin vitro in a dose-dependent manner, as determined by Thioflavin T fluorescence and electron microscopic analysis. In conclusion, our data demonstrated that obovatol prevented memory impairments in experimental AD models, which could be attributable to amelioration of neuroinflammation and amyloidogenesis by inhibition of NF-κB signaling pathway and anti-fibrillogenic activity of obovatol. © 2011 The Authors Journal of Neurochemistry© 2011 International Society for Neurochemistry.
Journal of Neurochemistry © 2011 International Society for Neurochemistry.
Altered CSF Orexin and α-Synuclein Levels in Dementia Patients.
Source
Molecular Memory Research Unit, The Wallenberg Lab, Lund University, Department of Clinical Sciences Malmö, Sweden.
Abstract
Neurodegenerative dementia, most frequently represented by Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), is often accompanied by altered sleeping patterns and excessive daytime sleepiness. Studies showing an association between the neuropeptide orexin and AD/DLB-related processes such as amyloid-β (Aβ)1-42 plaque formation, α-synuclein accumulation, and inflammation indicate that orexin might play a pathogenic role similar to the situation in narcolepsy. Our study of patients with AD (n = 26), DLB (n = 18), and non-demented controls (n = 24) shows a decrease in cerebrospinal fluid (CSF) orexin concentrations in DLB versus AD patients and controls. The observed differences in orexin levels were found to be specific to female DLB patients. We also show that the female DLB patients exclusively displayed lower levels of α-synuclein compared to AD patients and controls. Orexin was linked to α-synuclein and total-tau in female non-demented controls whereas associations between orexin and Aβ1-42concentrations were absent in all groups regardless of gender. Thus, the proposed links between orexin, Aβ, and α-synuclein pathology could not be monitored in CSF protein concentrations. Interestingly, α-synuclein was strongly correlated to the CSF levels of total-tau in all groups, suggesting α-synuclein to be an unspecific marker of neurodegeneration. We conclude that lower levels of CSF orexin are specific to DLB versus AD and appear unrelated to Aβ1-42 and α-synuclein levels in AD and DLB. Alterations in CSF orexin and α-synuclein levels may be related to gender which warrants further investigation.
Biomarkers associated with delirium in critically ill patients and their relation with long-term subjective cognitive dysfunction; indications for different pathways governing delirium in inflamed and non-inflamed patients.
Abstract
ABSTRACT:
INTRODUCTION:
Delirium occurs frequently in critically ill patients and is associated with disease severity and infection. Although several pathways for delirium have been described, biomarkers associated with delirium in ICU patients is not well studied. We examined plasma biomarkers in delirious and non-delirious patients and the role of these biomarkers on long-term cognitive function.
METHODS:
In an exploratory observational study we included 100 ICU patients with or without delirium and with ("inflamed") and without ("non-inflamed") infection/SIRS. Delirium was diagnosed using the confusion assessment method-ICU (CAM-ICU). Within 24 hours following the onset of delirium, blood was obtained for biomarker analysis. There were no differences in patient characteristics between delirious and non-delirious patients. To determine associations between biomarkers and delirium univariate and multivariate logistic regression analyses was performed. Eighteen months after ICU discharge, a cognitive failure questionnaire was distributed to the ICU survivors.
RESULTS:
In total 50 delirious and 50 non-delirious patients were included. We found that IL-8, MCP-1, PCT, cortisol and S100-beta were significantly associated with delirium in inflamed patients (N=46). In the non-inflamed group of patients (N=54) IL-8, IL-1ra, IL-10 ratio A-beta1-42/40 and ratio A-betaN-42/40 were significantly associated with delirium. In multivariate regression analysis IL-8 was independently associated (odds ratio 9.0; 95%CI 1.8-44.0) with delirium in inflamed patients and IL-10 (OR 2.6; 95%CI 1.1 - 5.9) and A-beta1-42/40 (OR 0.03; 95%CI 0.002 - 0.50) with delirium in non-inflamed patients. Furthermore, levels of several amyloid-beta forms, but not human Tau or S100-beta, were significantly correlated with self reported cognitive impairment 18 months after ICU discharge, while inflammatory markers were not correlated to impaired long-term cognitive function.
CONCLUSIONS:
In inflamed patients the proinflammatory cytokine IL-8 was associated with delirium. While in non-inflamed patients anti-inflammatory cytokine IL-10 and A-beta1-42/40 were associated with delirium. This suggests that the underlying mechanism governing the development of delirium in inflamed patients differs from that in non-inflamed patients. Finally, elevated levels of amyloid-beta correlate with long-term subjective cognitive impairment delirium may represent the first sign of a (subclinical) dementia process. Future studies need to confirm these results.
Fibrillar Amyloid-β1-42 Modifies Actin Organization Affecting the Cofilin Phosphorylation State: A Role for Rac1/cdc42 Effector Proteins and the Slingshot Phosphatase.
Source
Laboratory of Cellular and Molecular Neurosciences, University of Chile and International Center for Biomedicine (ICC), Santiago, Chile.
Abstract
The neuronal cytoskeleton regulates numerous processes that occur in normal homeostasis. Under pathological conditions such as those of Alzheimer's disease (AD), major alterations in cytoskeleton organization have been observed and changes in both microtubules and actin filaments have been reported. Many neurodegenerative consequences of AD are linked to the production and accumulation of amyloid peptides (Aβ) and their oligomers, produced from the internal cleavage of the amyloid-β protein precursor. We previously reported that fibrillar Aβ1-42 (fAβ) treatment of hippocampal neurons induced an increase in Rac1 and Cdc42 activities linking fAβ effects with changes in actin dynamics. Here we show fAβ-induces increased activity of PAK1 and cyclin-dependent kinase 5, and that p21-activated kinase (PAK1) activation targets the LIMK1-cofilin signaling pathway. Increased cofilin dephosphorylation under conditions of enhanced LIM-Kinase 1 (LIMK1) activity suggests that fAβ co-stimulates bifurcating pathways impacting cofilin phosphorylation. Overexpression of slingshot (SSH) prevents the augment of F-actin induced by fAβ after 24 h, suggesting that fAβ-induced changes in actin assembly involve both LIMK1 and SSH. These results suggest that fAb may alter the PAK1/LIMK1/cofilin axis and therefore actin organization in AD.
Promotion of β-amyloid production by C-reactive protein and its implications in the early pathogenesis of Alzheimer's disease.
Source
Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
Abstract
C-reactive protein (CRP) and β-amyloid protein (Aβ) are involved in the development of Alzheimer's disease (AD). However, the relationship between CRP and Aβ production is unclear. In vitro and in vivo experiments were performed to investigate the association of CRP with Aβ production. Using the rat adrenal pheochromocytoma cell line (PC12 cells) to mimic neurons, cytotoxicity was evaluated by cell viability and supernatant lactate dehydrogenase (LDH) activity. The levels of amyloid precursor protein (APP), beta-site APP cleaving enzyme (BACE-1), and presenilins (PS-1 and PS-2) were investigated using real-time polymerase chain reaction and Western blotting analysis. Aβ1-42 was measured by enzyme-linked immunosorbent assay. The relevance of CRP and Aβ as well as potential mechanisms were studied using APP/PS1 transgenic (Tg) mice. Treatment with 0.5-4.0μM CRP for 48h decreased cell viability and increased LDH leakage in PC12 cells. Incubation with CRP at a sub-toxic concentration of 0.2μM increased the mRNA levels of APP, BACE-1, PS-1, and PS-2, as well as Aβ1-42 production. CRP inhibitor reversed the CRP-induced upregulations of the mRNA levels of APP, BACE-1, PS-1, and PS-2, and the protein levels of APP, BACE-1, PS-1, and Aβ1-42, but did not reversed Aβ1-42 cytotoxicity. The cerebral levels of CRP and Aβ1-42 in APP/PS1 Tg mice were positively correlated, accompanied with the elevated mRNA expressions of serum amyloid P component (SAP), complement component 1q (C1q), and tumor necrosis factor-α (TNF-α). These results suggest that CRP cytotoxicity is associated with Aβ formation and Aβ-related markers expressions; CRP and Aβ were relevant in early-stage AD; CRP may be an important trigger in AD pathogenesis.
Copyright © 2011. Published by Elsevier Ltd.
Effect of N-homocysteinylation on physicochemical and cytotoxic properties ofamyloid β-peptide.
Source
Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
Abstract
Abstract Hyperhomocysteinemia has recently been identified as an important risk factor for Alzheimer's disease (AD). One of the potential mechanisms underlying harmful effects of homocysteine (Hcy) is site-specific acylation of proteins at lysine residues by homocysteine thiolactone (HCTL). The accumulation of amyloid β-peptide (Aβ) in the brain is a neuropathological hallmark of AD. In the present study we were interested to investigate the effects of N-homocysteinylation on the aggregation propensity and neurotoxicity of Aβ(1-42). By coupling several techniques, we demonstrated that the homocysteinylation of lysine residues increase the neurotoxicity of the Aβ peptide by stabilizing soluble oligomeric intermediates. STRUCTURED SUMMARY OF PROTEIN INTERACTIONS: A Beta 1-42 and A Beta 1-42bind by fluorescence technology (View interaction) A Beta 1-42 and A Beta 1-42bind by electron microscopy (View interaction).
Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
TLR2 Is a Primary Receptor for Alzheimer's Amyloid β Peptide To Trigger Neuroinflammatory Activation.
Source
Department of Neurology, University of the Saarland, 66421 Homburg/Saar, Germany;
Abstract
Microglia activated by extracellularly deposited amyloid β peptide (Aβ) act as a two-edged sword in Alzheimer's disease pathogenesis: on the one hand, they damage neurons by releasing neurotoxic proinflammatory mediators (M1 activation); on the other hand, they protect neurons by triggering anti-inflammatory/neurotrophic M2 activation and by clearing Aβ via phagocytosis. TLRs are associated with Aβ-induced microglial inflammatory activation and Aβ internalization, but the mechanisms remain unclear. In this study, we used real-time surface plasmon resonance spectroscopy and conventional biochemical pull-down assays to demonstrate a direct interaction between TLR2 and the aggregated 42-aa form of human Aβ (Aβ42). TLR2 deficiency reduced Aβ42-triggered inflammatory activation but enhanced Aβ phagocytosis in cultured microglia and macrophages. By expressing TLR2 in HEK293 cells that do not endogenously express TLR2, we observed that TLR2 expression enabled HEK293 cells to respond to Aβ42. Through site-directed mutagenesis of tlr2 gene, we identified the amino acids EKKA (741-744) as a critical cytoplasmic domain for transduction of inflammatory signals. By coexpressing TLR1 or TLR6 in TLR2-transgenic HEK293 cells or silencing tlrs genes in RAW264.7 macrophages, we observed that TLR2-mediated Aβ42-triggered inflammatory activation was enhanced by TLR1 and suppressed by TLR6. Using bone marrow chimeric Alzheimer's amyloid precursor transgenic mice, we observed that TLR2 deficiency in microglia shifts M1- to M2-inflammatory activation in vivo, which was associated with improved neuronal function. Our study demonstrated that TLR2 is a primary receptor for Aβ to trigger neuroinflammatory activation and suggested that inhibition of TLR2 in microglia could be beneficial in Alzheimer's disease pathogenesis.
Amyloid generation and dysfunctional immunoproteasome activation with disease progression in animal model of familial Alzheimer disease.
Source
Institut de Neuropatologia, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, Hospitalet de Llobregat; CIBERNED (Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas); Spain Dipartimento di Biologia Animale, Laboratorio di Biologia Cellulare e Neurobiologia, Università di Pavia, Pavia, Italy Laboratorio de Fisiología y Biofísica de Membranas, Departamento de Biología Animal & Instituto de Tecnologías Biomédicas, Universidad de La Laguna, Tenerife, Spain Departament de Medicina Experimental, Universitat de Lleida-IRBLleida, Lleida, Spain Centre de Genètica Mèdica i Molecular, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
Abstract
Double-transgenic APP/PS1 mice express a chimeric mouse/human amyloid precursor protein (APP) bearing the Swedish mutation (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9) both causative of familial Alzheimer disease (FAD). Transgenic mice show impaired memory and learning performance from the age of six months onwards. Double-transgenic APP/PS1 mice express altered APP and PS1 mRNAs and proteins, reduced BACE1 mRNA and normal BACE1 protein, all of which suggest a particular mechanism of amyloidogenesis when compared with sporadic AD. The first β-amyloid plaques in APP/PS1 mice appear at three months and they increase in number and distribution with disease progression in parallel with increased levels of brain soluble β-amyloid 1-42 and 1-40, but also with reduced 1-42/1-40 ratio with age. Amyloid deposition in plaques is accompanied by altered mitochondria and increased oxidative damage, post-translational modifications and accumulation of altered proteins at the dystrophic neurites surrounding plaques. Degradation pathways are also modified with disease progression including activation of the immunoproteasome together with variable alterations of the different protease activities of the ubiquitin-proteasome system. Present observations show modifications in the production of β-amyloid, and activation and malfunction of the subcellular degradation pathways that have general implications in the pathogenesis of AD and more particularly in specificities of FAD amyloidogenesis.
© 2011 The Authors; Brain Pathology © 2011 International Society of Neuropathology.
β-Amyloid (1-42) Levels in Cerebrospinal Fluid and Cerebral Atrophy in Mild Cognitive Impairment and Alzheimer's Disease.
Source
Section of Geriatric Psychiatry, INF 280, Heidelberg, Germany.
Abstract
BACKGROUND:
Recent studies consistently reported Alzheimer's disease (AD) and, to a lower extent, mild cognitive impairment (MCI) to be accompanied by reduced cerebrospinal fluid (CSF) levels of β-amyloid. However, how these changes are related to brain morphological alterations is so far only partly understood.
METHODS:
CSF levels of β-amyloid (1-42) were examined with respect to cerebral atrophy in 23 subjects with MCI, 16 patients with mild-to-moderateAlzheimer's disease (AD) and 15 age-matched controls by using magnetic resonance imaging and voxel-based morphometry (VBM).
RESULTS:
When contrasted with the controls, β-amyloid (1-42) levels were significantly lower (p < 0.05) in patients with MCI and even more so in the AD patients. This effect was significantly associated with reduced gray matter densities in both the right and left hippocampal head based on the results of a VBM analysis across the entire sample.
CONCLUSION:
Our finding confirms the results of previous studies and suggests that both the decrease in β-amyloid(1-42) and the development of hippocampal atrophy coincide in the disease process.
Neuregulin-1 protects against neurotoxicities induced by Swedish amyloidprecursor protein via the ErbB4 receptor.
Source
Department of Anatomy and Neuroscience, College of Medicine, Eulji University, Daejeon, Republic of Korea.
Abstract
Neuregulin-1 (NRG1) plays an important role in the development and plasticity of the brain and exhibits potent neuroprotective properties. However, little information on its role in Alzheimer's disease (AD) is known. The neuroprotective effect and mechanisms of NRG1 in SH-SY5Y cells overexpressing the Swedish mutant form of amyloidprecursor protein (Swe-APP) and primary cortical neuronal cells treated with amyloid beta peptide(1-42) (Aβ(1-42)) were investigated in this study. NRG1 attenuated Swe-APP- or Aβ(1-42)-induced lactate dehydrogenase (LDH) release in a concentration-dependent manner. The mitigating effects of NRG1 on neuronal cell death were blocked by ErbB4 inhibition, a key NRG1 receptor, which suggests a role of ErbB4 in the neuroprotective function of NRG1. Moreover, NRG1 reduced the number of Swe-APP- and Aβ(1-42)-induced TUNEL-positive SH-SY5Y cells and primary cortical neurons, respectively. NRG1 reduced the accumulation of reactive oxygen species and attenuated Swe-APP-induced mitochondrial membrane potential loss. NRG1 also induced the upregulation of the expression of the anti-apoptotic protein, Bcl-2, and decreased caspase-3 activation. Collectively, our results demonstrate that NRG1 exerts neuroprotective effects via the ErbB4 receptor, which suggests the neuroprotective potential of NRG1 in AD.
Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.
p75NTR is mainly responsible for Aβ toxicity but not for its internalization: a primary study.
Source
Department of Human Physiology and Centre for Neuroscience, Flinders University, GPO Box 2100, Adelaide, 5001, Australia, yuhlzjl@ccmu.edu.cn.
Abstract
Accumulating evidence indicates that the intraneuronal accumulation of beta-amyloid peptide (Aβ) is earlier than the formation of extraneuronal amyloid plaque but the mechanism of the accumulation remains unclear. p75NTR is a receptor for Aβ and interacts with Aβ in vitro and in vivo but whether p75NTR mediates Aβ internalization and intraneuronal accumulation is not known. In this study, we aim to determine if p75NTR mediates Aβ internalization, which might provide new insights into Aβ metabolism and toxicity. FRET analysis in PC12 cells showed that internalized Aβ was close to p75NTR. Aβ1-42 could be internalized in PC12 cells in a concentration-dependent manner but the antibody to the p75NTR extracellular domain did not prevent its internalization. Aβ1-42 could also be internalized in mouse neonatal cortical neurons and the deletion of p75NTR in these neurons did not prevent its internalization but prevented Aβ neurotoxicity. Cholesterol at 10 μM significantly increased Aβ1-42 internalization in PC12 cells. Internalized Aβ1-42 is mainly co-localized with Beclin-1 (a biomarker of autophagosomes) but not with endosomal and lysomal markers. p75NTR may not play a main role in Aβ internalization at the concentrations tested but is responsible for Aβ induced toxicity in primary neurons. Internalized Aβ is mainly sorted to autophagosomes for metabolism.
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