Beta Amyloid~Long-term oral administration of melatonin improves spatial learning and memory and protects against cholinergic degeneration in middle-aged Ts65Dn mice, a model of Down syndrome.
Ts65Dn mice (TS), the most commonly used model of Down syndrome (DS),
exhibit phenotypic characteristics of this condition. Both TS mice and
DS individuals present cognitive disturbances, age-related cholinergic
degeneration, and increased brain expression of β-amyloid
precursor protein (AβPP). These neurodegenerative processes may
contribute to the progressive cognitive decline observed in DS.
Melatonin is a pineal indoleamine that has been reported to reduce
neurodegenerative processes and improve cognitive deficits in various
animal models. In this study, we evaluated the potentially beneficial
effects of long-term melatonin treatment on the cognitive deficits,
cholinergic degeneration, and enhanced AβPP and β-amyloid
levels of TS mice. Melatonin was administered for 5 months to 5- to
6-month-old TS and control (CO) mice. Melatonin treatment improved
spatial learning and memory and increased the number of choline
acetyltransferase (ChAT)-positive cells in the medial septum of both TS
and CO mice. However, melatonin treatment did not significantly reduce
AβPP or β-amyloid
levels in the cortex or the hippocampus of TS mice. Melatonin
administration did reduce anxiety in TS mice without inducing
sensorimotor alterations, indicating that prolonged treatment with this
indoleamine is devoid of noncognitive behavioral side effects (e.g.,
motor coordination, sensorimotor abilities, or spontaneous activity).
Our results suggest that melatonin administration might improve the
cognitive abilities of both TS and CO mice, at least partially, by
reducing the age-related degeneration of basal forebrain cholinergic
neurons. Thus, chronic melatonin supplementation may be an effective
treatment for delaying the age-related progression of cognitive
deterioration found in DS.
Beta Amyloid~Specific binding of DNA to aggregated forms of Alzheimer's Disease amyloid peptides.
Anomalous protein aggregation is closely associated to age-related
mental illness. Extraneuronal plaques, mainly composed of aggregated amyloid peptides, are considered as hallmarks of Alzheimer's Disease. According to the amyloid cascade hypothesis, this disease starts as a consequence of an abnormal processing of the amyloid precursor protein resulting in an excess of amyloid peptides. Nuclear localization of amyloid peptide aggregates together with amyloid-DNA
interaction, have been repeatedly reported. In this paper we have used
Surface Plasmon Resonance and Electron Microscopy to study the structure
and behavior of different peptides and proteins, including
β-lactoglobulin, bovine serum albumin, myoglobin, histone, casein and
the amyloid-β
peptides related to Alzheimer's disease Aβ(25-35) and Aβ(1-40). The main
purpose of this study is to investigate whether proneness to DNA
interaction is a general property displayed by aggregated forms of
proteins, or it is an interaction specifically related to the aggregated
forms of those particular proteins and peptides related to
neurodegenerative diseases. Our results reveal that those aggregates
formed by amyloid
peptides show a particular proneness to interact with DNA. They are the
only aggregated structures capable of binding DNA, and show more
affinity for DNA than for other polyanions as heparin and polyglutamic
acid, therefore strengthening the hypothesis that amyloid peptides may, by means of interaction with nuclear DNA, contribute to the onset of Alzheimer Disease.
Beta Amyloid~Identification of potential bivalent inhibitors from natural compounds for acetylcholinesterase through in silico screening using multiple pharmacophores.
The symptomatic cure observed in the treatment of Alzheimer's disease
(AD) by FDA approved drugs could possibly be due to their specificity
against the active site of acetylcholinesterase (AChE) and not by
targeting its pathogenicity. The AD pathogenicity involved in AChE
protein is mainly due to amyloid beta
peptide aggregation, which is triggered specifically by peripheral
anionic site (PAS) of AChE. In the present study, a workflow has been
developed for the identification and prioritization of potential
compounds that could interact not only with the catalytic site but also
with the PAS of AChE. To elucidate the essential structural elements of
such inhibitors, pharmacophore models were constructed using PHASE,
based on a set of fifteen best known AChE inhibitors. All these models
on validation were further restricted to the best seven. These were
transferred to PHASE database screening platform for screening 89,425
molecules deposited at the "ZINC natural product database". Novel lead
molecules retrieved were subsequently subjected to molecular docking and
ADME profiling. A set of 12 compounds were identified with high
pharmacophore fit values and good predicted biological activity scores.
These compounds not only showed higher affinity for catalytic residues,
but also for Trp86 and Trp286, which are important, at PAS of AChE. The
knowledge gained from this study, could lead to the discovery of
potential AChE inhibitors that are highly specific for AD treatment as
they are bivalent lead molecules endowed with dual binding ability for
both catalytic site and PAS of AChE
Beta Amyloid~Classification of Amyloid-Positivity in Controls: Comparison of Visual Read and Quantitative Approaches.
An important research application of amyloid imaging with positron emission tomography (PET) is detection of the earliest evidence of fibrillar amyloid-beta (Aβ) deposition. Use of amyloid
PET for this purpose, requires a reproducible method for defining a
cutoff that separates individuals with no significant Aβ deposition from
those in which Aβ deposition has begun. We previously reported the
iterative outlier approach (IO) for the analysis of Pittsburgh
Compound-B (PiB) PET data. Developments in amyloid
imaging since the initial report of IO have led us to re-examine the
generalizability of this method. IO was developed using full-dynamic
atrophy-corrected PiB PET data obtained from a group of control subjects
with a fairly distinct separation between PiB-positive [PiB(+)] and
PiB-negative [PiB(-)] subjects. METHODS: We tested the performance of IO
using late-summed tissue ratio data with atrophy correction or with an
automated template method without atrophy correction and tested the
robustness of the method when applied to a cohort of older subjects in
which separation between PiB(+) and PiB(-) subjects was not so distinct.
RESULTS: The IO method did not perform consistently across analyses and
performed particularly poorly when separation was less clear. We found
that a sparse k-means (SKM) cluster analysis approach performed
significantly better; performing more consistently across methods and
subject cohorts. We also compared SKM to a consensus visual read
approach and found very good correspondence. Conclusion The visual read
and SKM methods, applied together, may optimize the identification of
early Aβ deposition. These methods have the potential to provide a
standard approach to the detection of PiB-positivity that is
generalizable across centers.
Beta amyloid~Acetylcholine and antibodies against the acetylcholine receptor protect neurons and astrocytes against beta-amyloid toxicity.
Aggregated amyloid-β
causes pathological changes in mixed cultures of neurons and astrocytes
such as sporadic cytoplasmic intracellular Ca(2+)-signalling, increase
in reactive oxygen species production and cell death. Some of the toxic
effects of amyloid-β
are mediated through the interaction of the peptide with α7-type
nicotinic acetylcholine receptors at the cell surface. Here we
demonstrated that affinity purified antibodies to synthetic fragment
173-193 of the α7-subunit of the nAChR are able to protect cells from amyloid-β induced cell death. The antibodies had no effect on the amyloid-β induced calcium signal in astrocytes. However, they significantly reduced amyloid-β
induced and NADPH oxidase mediated ROS production. Modulation of the
NADPH oxidase activity by either the antibodies, the receptor agonist
acetylcholine or the antagonist of the α7-type nicotinic acetylcholine
receptors α-bungarotoxin was vital in inhibiting both amyloid-β
induced ROS production, caspase 3 cleavage as well as cell death. The
uncovered details of the mechanism underlying the action of antibodies
to α7-type nicotinic acetylcholine receptors gives additional insight
into the involvement of this receptor in Alzheimer's disease pathology
and provides a new approach to anti-Alzheimer's Disease vaccine design.
α(2)-Macroglobulin (α(2)M) is an extracellular chaperone that inhibits
amorphous and fibrillar protein aggregation. The reaction of α(2)M with
proteases results in an 'activated' conformation, where the proteases
become covalently-linked within the interior of a cage-like structure
formed by α(2)M. This study investigates, for the first time, the effect
of activation on the ability of α(2)M to inhibit amyloid
formation of Aβ(1-42) and I59T human lysozyme and shows that
protease-activated α(2)M can act via two distinct mechanisms: (i) by
trapping proteases still able to degrade polypeptide chains and (ii) by a
chaperone action that prevents misfolded clients from continuing along
the amyloid forming pathway. STRUCTURED SUMMARY OF PROTEIN INTERACTIONS: A beta 1-42andA beta
1-42bindbyfluorescence technology(View interaction)159T lysozymeand159T
lysozymebindbylight scattering(View interaction)159T lysozymeand159T
lysozymebindbyfluorescence technology(View
interaction)Alpha-lactalbuminandAlpha-lactalbuminbindbyfluorescence
technology(View interaction)159T lysozymeand159T lysozymebindbyelectron
microscopy(View interaction)A beta 1-42andA beta 1-42bindbyelectron microscopy(View interaction
Beta Amyloid~Protease-activated alpha-2-macroglobulin can inhibit amyloid formation via two distinct mechanisms.
α(2)-Macroglobulin (α(2)M) is an extracellular chaperone that inhibits
amorphous and fibrillar protein aggregation. The reaction of α(2)M with
proteases results in an 'activated' conformation, where the proteases
become covalently-linked within the interior of a cage-like structure
formed by α(2)M. This study investigates, for the first time, the effect
of activation on the ability of α(2)M to inhibit amyloid
formation of Aβ(1-42) and I59T human lysozyme and shows that
protease-activated α(2)M can act via two distinct mechanisms: (i) by
trapping proteases still able to degrade polypeptide chains and (ii) by a
chaperone action that prevents misfolded clients from continuing along
the amyloid forming pathway. STRUCTURED SUMMARY OF PROTEIN INTERACTIONS: A beta 1-42andA beta
1-42bindbyfluorescence technology(View interaction)159T lysozymeand159T
lysozymebindbylight scattering(View interaction)159T lysozymeand159T
lysozymebindbyfluorescence technology(View
interaction)Alpha-lactalbuminandAlpha-lactalbuminbindbyfluorescence
technology(View interaction)159T lysozymeand159T lysozymebindbyelectron
microscopy(View interaction)A beta 1-42andA beta 1-42bindbyelectron microscopy(View interaction
Beta Amyloid~Synthesis and evaluation of oxime derivatives as modulators for amyloid beta-induced mitochondrial dysfunction.
Starting from quinuclidinyl oxime 1 identified by preliminary screening,
a series of azacycles-containing oxime derivatives was synthesized.
Their mPTP blocking activities were evaluated by a JC-1 assay, measuring
the change of mitochondrial membrane potential. The inhibitory activity
of nine compounds against amyloid beta-induced
mPTP opening was comparable or even superior to that of piracetam.
Among them, 12d effectively maintained mitochondrial function and cell
viabilities on the ATP assay, the MTT assay, and the ROS assay. In
addition, it exhibited favorable in vitro stability and pharmacokinetic
characteristics, which hold a promise for further development of AD
therapeutics.
Beta Amylid~Synthesis and evaluation of oxime derivatives as modulators for amyloid beta-induced mitochondrial dysfunction.
Starting from quinuclidinyl oxime 1 identified by preliminary
screening, a series of azacycles-containing oxime derivatives was
synthesized. Their mPTP blocking activities were evaluated by a JC-1
assay, measuring the change of mitochondrial membrane potential. The
inhibitory activity of nine compounds against amyloid beta-induced
mPTP opening was comparable or even superior to that of piracetam.
Among them, 12d effectively maintained mitochondrial function and cell
viabilities on the ATP assay, the MTT assay, and the ROS assay. In
addition, it exhibited favorable in vitro stability and pharmacokinetic
characteristics, which hold a promise for further development of AD
therapeutics.
Copyright © 2012 Elsevier Masson SAS. All rights reserved.
Copyright © 2012 Elsevier Masson SAS. All rights reserved.
Beta Amyloid~β-hairpin-mediated nucleation of polyglutamine amyloid formation.
The conformational preferences of polyglutamine (polyQ) sequences are of
major interest because of their central importance in the expanded CAG
repeat diseases that include Huntington's disease (HD). Here we explore
the response of various biophysical parameters to the introduction of
β-hairpin motifs within polyQ sequences. These motifs (trpzip,
disulfide, d-Pro-Gly, Coulombic attraction, l-Pro-Gly) enhance formation
rates and stabilities of amyloid
fibrils with degrees of effectiveness well-correlated with their known
abilities to enhance β-hairpin formation in other peptides. These
changes led to decreases in the critical nucleus for amyloid
formation from a value of n* = 4 for a simple, unbroken Q(23) sequence
to approximate unitary n* values for similar length polyQs containing
β-hairpin motifs. At the same time, the morphologies, secondary
structures, and bioactivities of the resulting fibrils were essentially
unchanged from simple polyQ aggregates. In particular, the signature
pattern of SSNMR (13)C Gln resonances that appears to be unique to polyQ
amyloid is
replicated exactly in fibrils from a β-hairpin polyQ. Importantly, while
β-hairpin motifs do produce enhancements in the equilibrium constant
for nucleation in aggregation reactions, these K(n*) values remain quite
low (~ 10(-10)) and there is no evidence for significant embellishment
of β-structure within the monomer ensemble. The results indicate an
important role for β-turns in the nucleation mechanism and structure of
polyQ amyloid and have implications for the nature of the toxic species in expanded CAG repeat diseases.
Beta Amyloid ~Oligomers, fact or artefact? SDS-PAGE induces dimerization of β-amyloid in human brain samples.
The formation of low-order oligomers of β-amyloid
(Aβ) within the brain is widely believed to be a central component of
Alzheimer's disease (AD) pathogenesis. However, despite advances in
high-throughput and high-resolution techniques such as xMAP and mass
spectrometry (MS), investigations into these oligomeric species have
remained reliant on low-resolution Western blots and enzyme-linked
immunosorbent assays. The current investigation compared Aβ profiles
within human cortical tissue using sodium dodecyl sulphate (SDS)
polyacrylamide gel electrophoresis (PAGE), xMAP and surface enhanced
laser desorption/ionization time-of-flight MS and found that whilst
there was significant correlation across the techniques regarding levels
of monomeric Aβ, only SDS-PAGE was capable of detecting dimeric
isoforms of Aβ. The addition of synthetic di-tyrosine cross-linked
Aβ(1-40)Met(35)(O) to the AD tissue demonstrated that the MS methodology
was capable of observing dimeric Aβ at femto-molar concentrations, with
no noticeable effect on monomeric Aβ levels. Focus turned to the
association between SDS-PAGE and levels of observable dimeric Aβ within
the AD brain tissue. These investigations revealed that increased levels
of dimeric Aβ were observed with increasing concentrations of SDS in
the sample buffer. This finding was subsequently confirmed using
synthetic Aβ(1-42) and suggests that SDS was inducing the formation of
dimeric Aβ. The findings that SDS promotes Aβ dimerization have
significant implications for the putative role of low-order oligomers in
AD pathogenesis and draw into question the utility of oligomeric Aβ as a
therapeutic target.
Beta Amyloid~Computational modeling of the effects of amyloid-beta on release probability at hippocampal synapses.
The role of amyloid beta
(Aβ) in brain function and in the pathogenesis of Alzheimer's disease
(AD) remains elusive. Recent publications reported that an increase in
Aβ concentration perturbs pre-synaptic release in hippocampal neurons.
In particular, it was shown in vitro that Aβ is an endogenous regulator
of synaptic transmission at the CA3-CA1 synapse, enhancing its release
probability. How this synaptic modulator influences neuronal output
during physiological stimulation patterns, such as those elicited in
vivo, is still unknown. Using a realistic model of hippocampal CA1
pyramidal neurons, we first implemented this Aβ-induced enhancement of
release probability and validated the model by reproducing the
experimental findings. We then demonstrated that this synaptic
modification can significantly alter synaptic integration properties in a
wide range of physiologically relevant input frequencies (from 5 to 200
Hz). Finally, we used natural input patterns, obtained from CA3
pyramidal neurons in vivo during free exploration of rats in an open
field, to investigate the effects of enhanced Aβ on synaptic release
under physiological conditions. The model shows that the CA1 neuronal
response to these natural patterns is altered in the increased-Aβ
condition, especially for frequencies in the theta and gamma ranges.
These results suggest that the perturbation of release probability
induced by increased Aβ can significantly alter the spike probability of
CA1 pyramidal neurons and thus contribute to abnormal hippocampal
function during AD.
Beta Amyloid~Aggregation and neurotoxicity of recombinant alpha-synuclein aggregates initiated by dimerization.
Aggregation and neurotoxicity of recombinant alpha-synuclein aggregates initiated by dimerization.
Abstract
ABSTRACT:
BACKGROUND: Aggregation of the alpha-Synuclein (alpha-Syn) protein, amyloid fibril formation and progressive neurodegeneration are the neuropathological hallmarks of Parkinson's Disease (PD). However, a detailed mechanism of alpha-Syn aggregation/fibrillogenesis and the exact nature of toxic oligomeric species produced during amyloid formation process are still unknown.
RESULTS:
In this study, the rates of alpha-Syn aggregation were compared for the recombinant wild-type (WT) alpha-Syn and a structurally relevant chimeric homologous protein containing an inducible Fv dimerizing domain (alpha-SynFv), capable to form dimers in the presence of a divalent ligand (AP20187). In the presence of AP20187, we report a rapid random coil intobeta-sheet conformational transformation of alpha-SynFv within 24 h, whereas WT alpha-Syn showed 24 h delay to achievebeta-sheet structure after 48 h. Fluorescence ANS and ThT binding experiments demonstrate an accelerated oligomer/amyloidformation of dimerized alpha-SynFv, compared to the slower oligomerization and amyloidogenesis of WT alpha-Syn or alpha-SynFv without dimerizer AP20187. Both alpha-SynFv and alpha-Syn pre-fibrillar aggregates internalized cells and induced neurotoxicity when injected into the hippocampus of wild-type mice. These recombinant toxic aggregates further converted into non-toxic amyloids which were successfully amplified by protein misfolding cyclic amplification method, providing the first evidence for the in vitro propagation of synthetic alpha-Syn aggregates.
CONCLUSIONS:
Together, we show that dimerization is important for alpha-Syn conformational transition and aggregation. In addition, alpha-Syn dimerization can accelerate the formation of neurotoxic aggregates and amyloid fibrils which can be amplified in vitro. A detailed characterization of the mechanism of alpha-Syn aggregation/amyloidogenesis and toxicity is crucial to comprehend Parkinson's disease pathology at the molecular level.
Beta Amyloid~IAPP aggregation and cellular toxicity are inhibited by 1,2,3,4,6-penta-O-galloyl-β-d-glucose.
IAPP aggregation and cellular toxicity are inhibited by 1,2,3,4,6-penta-O-galloyl-β-d-glucose.
Source
Department of Chemistry and Biochemistry, Loyola Marymount University , Los Angeles, CA , USA , and.
Abstract
Abstract The polyphenol, 1,2,3,4,6-penta-O-galloyl-β-d-glucose (PGG) has been found to exhibit a host of positive pharmacologic activities, including anti-cancer and anti-diabetic. Little is known about the mode of action of PGG in yielding these positive activities. We show here that PGG is a potent inhibitor of IAPP (islet amyloid polypeptide, amylin) aggregation. Preventing the initial aggregation event of IAPP is one strategy for slowing, and possibly preventing, the toxic effects of IAPP oligomeric intermediates. Equal molar ratios of PGG to IAPP substantially reduced the ability of IAPP to bind thioflavin T. Atomic force microscopy revealed that PGG prevented amyloid-based fiber formation under rigorous conditions conducive to forming IAPP aggregates. PGG was also found to protect PC12 rat cells from toxic IAPP. PGG was compared to the knownamyloid inhibitors (and structural relatives); tannic acid and gallic acid. In every test, PGG was far superior to tannic and gallic acids at inhibiting amyloid aggregation. These results indicate that PGG is a potent inhibitor of IAPP amyloid aggregation and a potential lead molecule for development of an amyloid inhibiting therapeutic.
- PMID:
- 23339420
- [PubMed - as supplied by publisher]
Beta Amyloid~Single Molecule Characterization of the Interactions between Amyloid-β Peptides and the Membranes of Hippocampal Cells.
Single Molecule Characterization of the Interactions between Amyloid-β Peptides and the Membranes of Hippocampal Cells.
Narayan P, Ganzinger KA, McColl J, Weimann L, Meehan S, Qamar S, Carver JA, Wilson MR, St George-Hyslop P, Dobson CM,Klenerman D.
Source
Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge, United Kingdom CB2 1EW.
Abstract
Oligomers of the 40 and 42 residue amyloid-β peptides (Aβ40 and Aβ42) have been implicated in the neuronal damage and impaired cognitive function associated with Alzheimer's disease. However, little is known about the specific mechanisms by which these misfolded species induce such detrimental effects on cells. In this work, we use single-molecule imaging techniques to examine the initial interactions between Aβ monomers and oligomers and the membranes of live cells. This highly sensitive method enables the visualization of individual Aβ species on the cell surface and characterization of their oligomerization state, all at biologically relevant, nanomolar concentrations. The results indicate that oligomers preferentially interact with cell membranes, relative to monomers and that the oligomers become immobilized on the cell surface. Additionally, we observe that the interaction of Aβ species with the cell membrane is inhibited by the presence of ATP-independent molecular chaperones. This study demonstrates the power of this methodology for characterizing the interactions between protein aggregates and the membranes of live neuronal cells at physiologically relevant concentrations and opens the door to quantitative studies of the cellular responses to potentially pathogenic oligomers.
Beta Amyloid~MR Microscopy of Human Amyloid-β Deposits: Characterization of Parenchymal Amyloid, Diffuse Plaques, and Vascular Amyloid.
MR Microscopy of Human Amyloid-β Deposits: Characterization of Parenchymal Amyloid, Diffuse Plaques, and Vascular Amyloid.
Nabuurs RJ, Natté R, de Ronde FM, Hegeman-Kleinn I, Dijkstra J, van Duinen SG, Webb AG, Rozemuller AJ, van Buchem MA, van der Weerd L.
Source
Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
Abstract
Cerebral deposits of amyloid-β peptides (Aβ) form the neuropathological hallmarks of Alzheimer's disease (AD) and cerebralamyloid angiopathy (CAA). In the brain, Aβ can aggregate as insoluble fibrils present in amyloid plaques and vascular amyloid, or as diffuse plaques consisting of mainly non-fibrillar Aβ. Previously, magnetic resonance imaging (MRI) has been shown to be capable of detecting individual amyloid plaques, not only via the associated iron, but also Aβ itself has been suggested to be responsible for a decrease in the image intensity. In this current study we aim to investigate the MRI properties of the different cerebral Aβ deposits including diffuse plaques and vascular amyloid. Postmortem 60-μm-thick brain sections of AD, CAA, and Down's syndrome patients, known to contain Aβ, were studied. High resolution T2*- and T2-weighted MRI scans and quantitative relaxation maps were acquired using a microcoil on a Bruker 9.4T MRI system. Specific MRI characteristics of each type of Aβ deposit were examined by co-registration of the MRI with Congo Red and Aβ-immunostainings of the same sections. Our results show that only fibrillar Aβ, present in both vascular and parenchymal amyloid, induced a significant change in T2* and T2 values. However, signal changes were not as consistent for all of the vessels affected by CAA, irrespective of possible dyshoric changes. In contrast, the non-fibrillar diffuse plaques did not create any detectable MRI signal changes. These findings are relevant for the interpretation and further development of (quantitative) MRI methods for the detection and follow-up of AD and CAA.
eta Amyloid~1-42 β-Amyloid peptide requires PDK1/nPKC/Rac 1 pathway to induce neuronal death.
1-42 β-Amyloid peptide requires PDK1/nPKC/Rac 1 pathway to induce neuronal death.
Manterola L, Hernando-Rodríguez M, Ruiz A, Apraiz A, Arrizabalaga O, Vellón L, Alberdi E, Cavaliere F, Lacerda HM, Jimenez S, Parada LA, Matute C, Zugaza JL.
Source
Biodonostia Institute, Hospital Donostia, P Doctor Begiristain, Donostia, Spain.
Abstract
1-42 β-Amyloid (Aβ(1-42)) peptide is a key molecule involved in the development of Alzheimer's disease. Some of its effects are manifested at the neuronal morphological level. These morphological changes involve loss of neurites due to cytoskeleton alterations. However, the mechanism of Aβ(1-42) peptide activation of the neurodegenerative program is still poorly understood. Here, Aβ(1-42) peptide-induced transduction of cellular death signals through the phosphatidylinositol 3-kinase (PI3K)/phosphoinositol-dependent kinase (PDK)/novel protein kinase C (nPKC)/Rac 1 axis is described. Furthermore, pharmacological inhibition of PDK1 and nPKC activities blocks Rac 1 activation and neuronal cell death. Our results provide insights into an unsuspected connection between PDK1, nPKCs and Rac 1 in the same signal-transduction pathway and points out nPKCs and Rac 1 as potential therapeutic targets to block the toxic effects of Aβ(1-42) peptide in neurons.
Beta Amyloid~Added Diagnostic Value of (11)C-PiB-PET in Memory Clinic Patients with Uncertain Diagnosis.
Added Diagnostic Value of (11)C-PiB-PET in Memory Clinic Patients with Uncertain Diagnosis.
Source
Memory Disorders Research Group, Department of Neurology, Nuclear Medicine and PET, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Abstract
INTRODUCTION:
The added diagnostic value of (11)C-PiB-PET for the assessment of the accumulation of corticalbeta-amyloid in memory clinic patients with uncertain diagnosis remains undetermined.
METHODS:
All patients who underwent PiB-PET at the Copenhagen Memory Clinic between March 2008 and November 2011 were included in this uncontrolled, retrospective study. The standard diagnostic evaluation program included physical and neurological examination, cognitive and functional assessment, a cranial CT or MRI, functional imaging and cerebrospinal fluid sampling. Based on anonymized case reports, three experienced clinicians reached a consensus diagnosis and rated their confidence in the diagnosis before and after disclosure of PiB-PET ratings. PiB-PET scans were rated as either positive or negative.
RESULTS:
A total of 57 patients (17 females, 30 males; age 65.7 years, range 44.2-82.6) were included in the study. Twenty-seven had a positive PiB-PET scan. At the first diagnostic evaluation, 16 patients were given a clinical Alheimer's disease diagnosis (14 PiB positive). Of the 57 patients, 13 (23%) were diagnostically reclassified after PiB-PET ratings were disclosed. The clinicians' overall confidence in their diagnosis increased in 28 (49%) patients.
CONCLUSION:
PiB-PET adds to the specialist clinical evaluation and other supplemental diagnostic investigations in the diagnostic classification of patients with uncertain diagnosis in a specialized memory clinic.
Beta Amyloid~Association of BACE1 Gene Polymorphism with Cerebellar Volume but Not Cognitive Function in Normal Individuals.
Association of BACE1 Gene Polymorphism with Cerebellar Volume but Not Cognitive Function in Normal Individuals.
Source
Department of Psychiatry, Taipei Veterans General Hospital, Taipei, ROC.
Abstract
AIMS:
β-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a biological and positional candidate gene for Alzheimer's disease (AD). Previous studies found that BACE1-null mice had impaired performance on cognition and neurodegeneration during the aging process. Additionally, a synonymous polymorphism of BACE1 (rs638405) in exon 5 has been reported to be associated with risk for AD. We hypothesized that this BACE1 gene variant might influence regional brain volumes and cognitive tests in normal individuals.
METHODS:
Participants were 330 normal volunteers between 21 and 92 years of age (mean age 56.3 ± 22.0 years; 191 males, 139 females). Cognitive tests (the Mini-Mental State Examination and Digit Spans), magnetic resonance imaging, and genotyping of BACE1 rs638405 were examined for each subject. The differences in regional gray matter (GM) volumes between G homozygotes and C-allele carriers were tested using optimized voxel-based morphometry.
RESULTS:
Compared to C-allele carriers, G homozygotes exhibited significantly larger GM volumes in the left cerebellar culmen and right cerebellar lingual area, but no significant differences on cognitive function tests.
CONCLUSION:
The findings suggest that the BACE1 rs638405 polymorphism may affect cerebellar morphology, but not cognitive function in healthy humans
Beta Amyloid~Conformation-dependent oligomers in cerebrospinal fluid of presymptomatic familial Alzheimer's disease mutation carriers.
Conformation-dependent oligomers in cerebrospinal fluid of presymptomatic familial Alzheimer's disease mutation carriers.
Source
Mary S. Easton Center for Alzheimer's Disease Research at UCLA, Calif., USA.
Abstract
BACKGROUND/AIMS:
Oligomerization of amyloid beta (Aβ) is a hypothesized step in the formation of plaques in Alzheimer's disease (AD) but has been difficult to demonstrate in vivo in humans. As persons destined to develop familial AD (FAD) due to fully penetrant autosomal dominant mutations are essentially certain to develop the disease, they provide the opportunity to identify oligomers during the presymptomatic stage of the disease.
METHODS:
We measured levels of Aβ(42) using a conventional immunoassay and prefibrillar, fibrillar, and annular protofibrillar oligomers using polyclonal conformation-dependent antibodies in the cerebrospinal fluid (CSF) of 7 persons at risk for inheriting FAD mutations. Levels of oligomers were compared between FAD mutation carriers and noncarriers.
RESULTS:
Compared to 2 noncarriers, annular protofibrillar oligomers were elevated, prefibrillar and fibrillar oligomers trended towards elevation and Aβ(42) monomer trended towards being decreased in 5 FAD mutation carriers.
CONCLUSION:
Our data provide evidence for an identifiable elevation of CSF oligomers during the presymptomatic phase of FAD.
Beta Amyloid ~ Conformation-dependent oligomers in cerebrospinal fluid of presymptomatic familial Alzheimer's disease mutation carriers.
Conformation-dependent oligomers in cerebrospinal fluid of presymptomatic familial Alzheimer's disease mutation carriers.
Source
Mary S. Easton Center for Alzheimer's Disease Research at UCLA, Calif., USA.
Abstract
BACKGROUND/AIMS:
Oligomerization of amyloid beta (Aβ) is a hypothesized step in the formation of plaques in Alzheimer's disease (AD) but has been difficult to demonstrate in vivo in humans. As persons destined to develop familial AD (FAD) due to fully penetrant autosomal dominant mutations are essentially certain to develop the disease, they provide the opportunity to identify oligomers during the presymptomatic stage of the disease.
METHODS:
We measured levels of Aβ(42) using a conventional immunoassay and prefibrillar, fibrillar, and annular protofibrillar oligomers using polyclonal conformation-dependent antibodies in the cerebrospinal fluid (CSF) of 7 persons at risk for inheriting FAD mutations. Levels of oligomers were compared between FAD mutation carriers and noncarriers.
RESULTS:
Compared to 2 noncarriers, annular protofibrillar oligomers were elevated, prefibrillar and fibrillar oligomers trended towards elevation and Aβ(42) monomer trended towards being decreased in 5 FAD mutation carriers.
CONCLUSION:
Our data provide evidence for an identifiable elevation of CSF oligomers during the presymptomatic phase of FAD.
- PMID:
- 23341831
- [PubMed]
Beta Amyloid~[Progress of researches on mechanisms of acupuncture intervention of Alzheimer's disease].
[Progress of researches on mechanisms of acupuncture intervention of Alzheimer's disease].
[Article in Chinese]
Source
Teaching and Study Section of Anatomy, Basic Medical College, Shanghai University of Chinese Medicine, Shanghai 201203, China. zhujing0208@163.com
Abstract
Alzheimer's disease (AD) is one of the major diseases threatening the aged people's health. In the present paper, the authors reviewed development of studies on acupuncture treatment of AD from: 1) regulating release of neurotransmitters (cholinergic, amino-acids and monoamine neurotransmitters), 2) protecting cerebral neurons from apoptosis (anti-oxidative stress, improving synaptic plasticity, and suppressing apoptosis), 3) improving levels of neurotrophic factors, 4) regulating hippocampal intracellular signaling, 5) inhibiting inflammatory reactions of the brain tissue, 6) adjusting the level of abnormal proteins (microtubule-associated protein, beta-amyloid), and 7) up-regulating the level of autophagy activity. However, current experimental studies can not completely answer clinical questions due to limited model designs and complicated pathological mechanisms of AD. Many findings of biological indexes need being verified further. Reasonable therapeutic regimens of acupuncture formulated according to syndrome differentiation will help improving clinical curative effect and the corresponding research on new therapeutic targets may be helpful to our understanding about the mechanism of acupuncture.
Beta Amyloid~Effect of Helical Conformation and Side-Chain Structure on γ-Secretase Inhibition by β-Peptide Foldamers: Insight into Substrate Recognition.
Effect of Helical Conformation and Side-Chain Structure on γ-Secretase Inhibition by β-Peptide Foldamers: Insight into Substrate Recognition.
Imamura Y, Umezawa N, Osawa S, Shimada N, Higo T, Yokoshima S, Fukuyama T, Iwatsubo T, Kato N, Tomita T, Higuchi T.
Abstract
Substrate-selective inhibition or modulation of the activity of γ-secretase, which is responsible for the generation of amyloid-β peptides, might be an effective strategy for prevention and treatment of Alzheimer's disease. We have shown that helical β-peptide foldamers are potent and specific inhibitors of γ-secretase. Here we report identification of target site of the foldamers by using a photoaffinity probe. The photoprobe directly and specifically labeled the N-terminal fragment of presenilin 1, in which the initial substrate docking site is predicted to be located. We also optimized the foldamer structure by preparing a variety of derivatives and obtained two highly potent foldamers by incorporation of a hydrophilic and neutral functional group into the parent structure. The class of side-chain functional group and the position of incorporation were both important for γ-secretase-inhibitory activity. The substrate selectivity of the inhibitory activity was also quite sensitive to the class of side chain group incorporated.
Beta Amyloid ~ Copper and heme-mediated Abeta toxicity: redox chemistry, Abeta oxidations and anti-ROS compounds.
Copper and heme-mediated Abeta toxicity: redox chemistry, Abeta oxidations and anti-ROS compounds.
Source
CNRS, LCC (Laboratoire de Chimie de Coordination), 205 route de Narbonne, BP 44099, F-31077 Toulouse Cedex 4 (France). Université de Toulouse, UPS, INPT, F-31077 Toulouse Cedex 4 (France). peter.faller@lcc-toulouse.fr.
Abstract
Oxidative stress mediated by reactive oxygen or nitrogen species (ROS/RNS) seems to be implicated in several diseases including neurodegenerative ones. In one of them, namely Alzheimer's disease, there is a large body of evidence that the aggregation of the peptide amyloid-beta (Abeta) is implicated in the generation of the oxidative stress. Redox active metal ions play a key role in oxidative stress, either in the production of ROS/RNS by enzymes or loosely bound metals or in the protection against ROS, mostly as catalytic centers in enzymes. In Alzheimer's disease, it is thought that metals (mostly Cu, Fe and heme) can bind to amyloid-beta and that such systems are involved in the generation of oxidative stress. In the present article, we review the role of ROS/RNS produced by redox active Cu ions and Heme compounds in the context of the amyloidcascade. We focus on (i) the coordination chemistry of Cu and heme to Abeta; (ii) the role of the corresponding Abeta adducts in the (catalytic) production of ROS/RNS; (iii) the subsequent degradation of Abeta by these reactive species and (iv) the use of antioxidants, in particular metal sequestering compounds and direct antioxidants like polyphenols as a therapeutic strategies.
- PMID:
- 23339309
- [PubMed - as supplied by publisher]
eta Anyloid ~ Insights into A β aggregation: A molecular dynamics perspective.
Insights into A β aggregation: A molecular dynamics perspective.
Source
Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93105-9510. shea@chem.ucsb.edu.
Abstract
This article reviews recent molecular dynamics simulations of the Alzheimer's amyloid- protein, the primary component of the amyloid plaques found in the brain of Alzheimer's patients. Different simulation techniques, and their application to the study of monomeric, oligomeric, and fibrillar species is discussed. This review highlights how simulations have acted as an invaluable complement to experiment, providing atomistically detailed structural information about monomer, oligomer, and fibrillar structures, as well as mechanistic insights into the aggregation process of amyloid- protein in the absence and presence of toxicity and aggregation inhibitors.
Beta Amyloid ~ Aggregation and neurotoxicity of recombinant alpha-synuclein aggregates initiated by dimerization.
Aggregation and neurotoxicity of recombinant alpha-synuclein aggregates initiated by dimerization.
Abstract
ABSTRACT:
BACKGROUND: Aggregation of the alpha-Synuclein (alpha-Syn) protein, amyloid fibril formation and progressive neurodegeneration are the neuropathological hallmarks of Parkinson's Disease (PD). However, a detailed mechanism of alpha-Syn aggregation/fibrillogenesis and the exact nature of toxic oligomeric species produced during amyloid formation process are still unknown.
RESULTS:
In this study, the rates of alpha-Syn aggregation were compared for the recombinant wild-type (WT) alpha-Syn and a structurally relevant chimeric homologous protein containing an inducible Fv dimerizing domain (alpha-SynFv), capable to form dimers in the presence of a divalent ligand (AP20187). In the presence of AP20187, we report a rapid random coil intobeta-sheet conformational transformation of alpha-SynFv within 24 h, whereas WT alpha-Syn showed 24 h delay to achievebeta-sheet structure after 48 h. Fluorescence ANS and ThT binding experiments demonstrate an accelerated oligomer/amyloidformation of dimerized alpha-SynFv, compared to the slower oligomerization and amyloidogenesis of WT alpha-Syn or alpha-SynFv without dimerizer AP20187. Both alpha-SynFv and alpha-Syn pre-fibrillar aggregates internalized cells and induced neurotoxicity when injected into the hippocampus of wild-type mice. These recombinant toxic aggregates further converted into non-toxic amyloids which were successfully amplified by protein misfolding cyclic amplification method, providing the first evidence for the in vitro propagation of synthetic alpha-Syn aggregates.
CONCLUSIONS:
Together, we show that dimerization is important for alpha-Syn conformational transition and aggregation. In addition, alpha-Syn dimerization can accelerate the formation of neurotoxic aggregates and amyloid fibrils which can be amplified in vitro. A detailed characterization of the mechanism of alpha-Syn aggregation/amyloidogenesis and toxicity is crucial to comprehend Parkinson's disease pathology at the molecular level.
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