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Amyloid β peptide (Aβ) is a key player in the development of Alzheimer’s disease (AD). It is the primary component of senile plaques in AD patients and is also found in soluble forms. Cholinergic activity mediated by α7 nicotinic receptors has been shown to be affected by Aβ soluble forms. To shed light into the molecular mechanism of this effect, we explored the direct actions of oligomeric Aβ 140 and Aβ 142 on human α7 by fluorescence spectroscopy and single-channel recordings. Fluorescence measurements using the conformational sensitive probe crystal violet (CrV) revealed that in the presence of Aβ α7 undergoes concentration-dependent conformational changes. Exposure of α7 to 100 pM Aβ changes CrV K D towards that of the desensitized state. However, α7 is still reactive to high carbamylcholine (Carb) concentrations. These observations are compatible with the induction of active/desensitized states as well as of a novel conformational state in the presence of both Aβ and Carb. At 100 nM Aβ, α7 adopts a resting-state-like structure which does not respond to Carb, suggesting stabilization of α7 in a blocked state. In real time, we found that Aβ is capable of eliciting α7 channel activity either in the absence or presence of the positive allosteric modulator (PAM) PNU-120596. Activation by Aβ is favored at picomolar or low nanomolar concentrations and is not detected at micromolar concentrations. At high Aβ concentrations, the mean duration of activation episodes elicited by ACh in the presence of PNU-120596 is significantly reduced, an effect compatible with slow open-channel block. We conclude that Aβ directly affects α7 function by acting as an agonist and a negative modulator. Whereas the capability of low concentrations of Aβ to activate α7 could be beneficial, the reduced α7 activity in the presence of higher Aβ concentrations or its long exposure may contribute to the cholinergic signaling deficit and may be involved in the initiation and development of AD. Fil: Lasala, Matías Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina Fil: Fabiani, Camila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina Fil: Corradi, Jeremias. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina Fil: Antollini, Silvia Susana. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina Fil: Bouzat, Cecilia Beatriz. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina

We report microsecond timescale ligand field molecular dynamics simulations of the copper complexes of three known mutants of the amyloid-β peptide, E22G, E22Q and E22K, alongside the naturally occurring sequence. We find that all three mutants lead to formation of less compact structures than the wild-type: E22Q is the most similar to the native peptide, while E22G and especially E22K are markedly different in size, shape and stability. Turn and coil structures dominate all structures studied but subtle differences in helical and β-sheet distribution are noted, especially in the C-terminal region. The origin of these changes is traced to disruption of key salt bridges: in particular, the Asp23-Lys28 bridge that is prevalent in the wild-type is absent in E22G and E22K, while Lys22 in the latter mutant forms a strong association with Asp23. We surmise that the drastically different pattern of salt bridges in the mutants lead to adoption of a different structural ensemble of the peptide backbone, and speculate that this might affect the ability of the mutant peptides to aggregate in the same manner as known for the wild-type., Theoretical chemistry, Molecular dynamics, Copper, Salt bridges, Amyloid peptide

BACKGROUND: Cerebrospinal fluid (CSF) biomarkers are increasingly used to diagnose Alzheimer's disease (AD). However, important methodological and technical remain regarding measurement variability between kit providers and users. We compared the Lumipulse fully automated assays with the manual INNOTEST assays (both from Fujirebio Europe NV, Gent, Belgium) on a clinically representative sample of patients and controls. METHODS: CSF samples of 156 patients were used to quantify Amyloïd Aβ1-42 peptide (Aβ1-42) and Total-Tau (T-Tau) protein by chemiluminescent enzyme-immunoassay (Lumipulse). Patients were divided into several subgroups: Alzheimer (AD = 44), mild-cognitive impairment (MCI = 23), other dementias (OD = 36), non-dementing neurological conditions (ND = 11), and controls (CTRL = 42). Clinical cut-offs were determined by comparing AD and CTRL with ROC curves for the two markers and their related ratio (T-Tau/Aβ1-42). Subgroups of 58 (for phosphorylated-Tau) and 115 samples (for Aβ1-42 and T-Tau) were used to evaluate the concordance of this analyzer with the INNOTEST assays. RESULTS: Lumipulse and INNOTEST assays showed good concordance for all markers, but systematic bias was observed justifying the need to redefine new clinical cut-offs. To discriminate AD from CTRL subjects, T-Tau/Aβ1-42 ratio was the best biomarker, with a cut-off value of 1.12 (sensitivity 81.8% and specificity 92.9%). Similar clinical performances were observed for the Lumipulse and Innotests assays on the subsample of 115 subjects. CONCLUSIONS: Our results demonstrate that the Lumipulse Aβ1-42 and T-Tau assays show good analytical and clinical performances in the context of patient evaluation referred to a memory clinic. Automated analyzers should be preferred for the measurement of CSF AD biomarkers to reduce inter- and intra-laboratory variability.

Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. Histopathologically, AD presents with two hallmarks: neurofibrillary tangles (NFTs), and aggregates of amyloid β peptide (Aβ) both in the brain parenchyma as neuritic plaques, and around blood vessels as cerebral amyloid angiopathy (CAA). According to the vascular hypothesis of AD, vascular risk factors can result in dysregulation of the neurovascular unit (NVU) and hypoxia. Hypoxia may reduce Aβ clearance from the brain and increase its production, leading to both parenchymal and vascular accumulation of Aβ. An increase in Aβ amplifies neuronal dysfunction, NFT formation, and accelerates neurodegeneration, resulting in dementia. In recent decades, therapeutic approaches have attempted to decrease the levels of abnormal Aβ or tau levels in the AD brain. However, several of these approaches have either been associated with an inappropriate immune response triggering inflammation, or have failed to improve cognition. Here, we review the pathogenesis and potential therapeutic targets associated with dysfunction of the NVU in AD.

Cerebrovascular insufficiency appears years prior to clinical symptoms in Alzheimer’s disease. The soluble, highly toxic amyloid-β species, generated from the amyloidogenic processing of amyloid precursor protein, are known instigators of the chronic cerebrovascular insufficiency observed in both Alzheimer’s disease patients and transgenic mouse models. We have previously demonstrated that pioglitazone potently reverses cerebrovascular impairments in a mouse model of Alzheimer’s disease overexpressing amyloid-β. In this study, we sought to characterize the effects of amyloid-β overproduction on the cerebrovascular proteome; determine how pioglitazone treatment affected the altered proteome; and analyze the relationship between normalized protein levels and recovery of cerebrovascular function. Three-month-old wildtype and amyloid precursor protein mice were treated with pioglitazone- (20 mg/kg/day, 14 weeks) or control-diet. Cerebral arteries were surgically isolated, and extracted proteins analyzed by gel-free and gel-based mass spectrometry. 193 cerebrovascular proteins were abnormally expressed in amyloid precursor protein mice. Pioglitazone treatment rescued a third of these proteins, mainly those associated with oxidative stress, promotion of cerebrovascular vasocontractile tone, and vascular compliance. Our results demonstrate that amyloid-β overproduction perturbs the cerebrovascular proteome. Recovery of cerebrovascular function with pioglitazone is associated with normalized levels of key proteins in brain vessel function, suggesting that pioglitazone-responsive cerebrovascular proteins could be early biomarkers of Alzheimer’s disease., yes

The growing interest for peptide therapeutics calls for new strategies to determine the physico-chemical properties responsible for the interactions of peptides with the environment. This study reports about the lipophilicity of two fragments of the amyloid β-peptide, Aβ 25-35 and Aβ 12-28. Firstly, computational studies showed the limits of log D(7.4)oct in describing the lipophilicity of medium-sized peptides. Chromatographic lipophilicity indexes (expressed as log k', the logarithm of the retention factor) were then measured in three different systems to highlight the different skills of Aβ 25-35 and Aβ 12-28 in giving interactions with polar and apolar environments. CD studies were also performed to validate chromatographic experimental conditions. Results show that Aβ 12-28 has a larger skill in promoting hydrophobic and electrostatic interactions than Aβ 25-35. This finding proposes a strategy to determine the lipophilicity of peptides for drug discovery purposes but also gives insights in unraveling the debate about the aminoacidic region of Aβ responsible for its neurotoxicity.

Among diseases whose cure is still far from being discovered, Alzheimer’s disease (AD) has been recognized as a crucial medical and social problem. A major issue in AD research is represented by the complexity of involved biochemical pathways, including the nature of protein misfolding, which results in the production of toxic species. Considering the involvement of (mis)folding processes in AD aetiology, targeting molecular chaperones represents a promising therapeutic perspective. This review analyses the connection between AD and molecular chaperones, with particular attention toward the most important heat shock proteins (HSPs) as representative components of the human chaperome: Hsp60, Hsp70 and Hsp90. The role of these proteins in AD is highlighted from a biological point of view. Pharmacological targeting of such HSPs with inhibitors or regulators is also discussed.

Soluble Abeta oligomers are widely recognised as the toxic forms responsible for triggering AD and Abeta receptors are hypothesized to represent the first step in a neuronal cascade leading to dementia. Cellular prion protein (PrP) has been reported as a high-affinity binder of Ab oligomers. The interactions of PrP with both Ab 42 and the highly toxic N-truncated pyroglutamylated species (AbpE3-42) are here investigated, at a molecular level, by means of ThT fluorescence, NMR and TEM. We demonstrate that soluble PrP binds both Ab42 and AbpE3-42, preferentially interacting with oligomeric species and delaying fibril formation. Residue level analysis of Ab42 oligomerization process reveals, for the first time, that PrP is able to differently interact with the forming oligomers, depending on the aggregation state of the starting Ab42 sample. A distinct behavior is observed for Ab42 N-terminal and C-terminal residues, suggesting that PrP protects Ab42 N-tail from entangling on the mature NMR invisible fibril, consistent with the hypothesis that Ab42 N-tail is the locus of interaction with PrP. PrP/AbpE3-42 interactions are here reported for the first time. All interaction data are validated and complemented by cellular tests performed on Wt and PrP-silenced neuronal cell lines, clearly showing PrP dependent Ab oligomer cell internalization and toxicity. The ability of soluble PrP to compete for Ab oligomers binding with membrane-anchored PrP bears relevance for studies of druggable pathways.

Insulin degrading enzyme (IDE) plays key roles in degrading peptides vital in type two diabetes, Alzheimer's, inflammation, and other human diseases. However, the process through which IDE recognizes peptides that tend to form amyloid fibrils remained unsolved. We used cryoEM to understand both the apo- and insulin-bound dimeric IDE states, revealing that IDE displays a large opening between the homologous ~55 kDa N- and C-terminal halves to allow selective substrate capture based on size and charge complementarity. We also used cryoEM, X-ray crystallography, SAXS, and HDX-MS to elucidate the molecular basis of how amyloidogenic peptides stabilize the disordered IDE catalytic cleft, thereby inducing selective degradation by substrate-assisted catalysis. Furthermore, our insulin-bound IDE structures explain how IDE processively degrades insulin by stochastically cutting either chain without breaking disulfide bonds. Together, our studies provide a mechanism for how IDE selectively degrades amyloidogenic peptides and offers structural insights for developing IDE-based therapies.

Protein misfolding and abnormal assembly could lead to aggregates such as oligomer, proto-fibril, mature fibril, and senior amyloid plaques, which are associated with the pathogenesis of many amyloid diseases. These irreversible amyloid aggregates typically form in vivo and researchers have been endeavoring to find new modulators to invert the aggregation propensity in vitro, which could increase understanding in the mechanism of the aggregation of amyloid protein and pave the way to potential clinical treatment. Graphene oxide (GO) was shown to be a good modulator, which could strongly control the amyloidosis of Aβ (33-42). In particular, quartz crystal microbalance (QCM), circular dichroism (CD) spectroscopy, and atomic force microscopy (AFM) measurements revealed the size-dependent manner of GO on modulating the assembly of amyloid peptides, which could be a possible way to regulate the self-assembled nanostructure of amyloid peptide in a predictable manner.

Aluminium is reported to play an important role in the aetiology, pathogenesis and development of Alzheimer's disease (AD). Black tea (BT, Camellia sinensis, family – Theaceae) represents approximately 78% of total consumed tea in the world and possesses neuroprotective properties under conditions like hypoxia, ischaemia and Parkinson's disease. This research aimed to evaluate neuroprotective effect of black tea extract (BTE) on the cognitive deficits, activity of acetylcholinesterase (AChE), levels and activities of oxidant–antioxidant indices (thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx)), expressions of β amyloid 1–42 (Aβ1–42) synthesis related (amyloid precursor protein (APP), β and γ secretases) and apoptotic markers (Bax, Bcl-2, cyto c, caspases 3, 8 and 9) in hippocampus and cortex of aluminium chloride (AlCl3) induced AD rats. Chronic AlCl3 administration (100 mg/kg body weight i.p.) in Wistar rats for 60 days significantly enhanced the AChE activity, memory impairment, oxidative damage, Aβ burden and apoptosis markers. Co-administration of BTE to AlCl3 rats for 60 days significantly ameliorated the aluminium induced pathological changes. Thus, it is suggested that the anti-Alzheimer role of BTE may be attributed mainly to the active components present in black tea.

Membrane-assisted amyloid formation is implicated in human diseases, and many of the aggregating species accelerate amyloid formation and induce cell death. While structures of membrane-associated intermediates would provide tremendous insights into the pathology and aid in the design of compounds to potentially treat the diseases, it has not been feasible to overcome the challenges posed by the cell membrane. Here, we use NMR experimental constraints to solve the structure of a type-2 diabetes related human islet amyloid polypeptide intermediate stabilized in nanodiscs. ROSETTA and MD simulations resulted in a unique β-strand structure distinct from the conventional amyloid β-hairpin and revealed that the nucleating NFGAIL region remains flexible and accessible within this isolated intermediate, suggesting a mechanism by which membrane-associated aggregation may be propagated. The ability of nanodiscs to trap amyloid intermediates as demonstrated could become one of the most powerful approaches to dissect the complicated misfolding pathways of protein aggregation.

Protein misfolding and aggregation have been associated with the onset of neurodegenerative disorders. Recent studies demonstrate that the aggregation process can result in a high diversity of protein conformational states, however the identity of the specific species responsible for the cellular damage is still unclear. Here, we use yeast as a model to systematically analyse the intracellular effect of expressing 21 variants of the amyloid-ß-peptide, engineered to cover a continuous range of intrinsic aggregation propensities. We demonstrate the existence of a striking negative correlation between the aggregation propensity of a given variant and the oxidative stress it elicits. Interestingly, each variant generates a specific distribution of protein assemblies in the cell. This allowed us to identify the aggregated species that remain diffusely distributed in the cytosol and are unable to coalesce into large protein inclusions as those causing the highest levels of oxidative damage. Overall, our results indicate that the formation of large insoluble aggregates may act as a protective mechanism to avoid cellular oxidative stress., Graphical abstract fx1 The scheme represents three different scenarios that can occur in a yeast cell upon Aβ42-GFP peptide expression. Scenario I: Soluble Aβ42-GFP species that neither form protein inclusions, nor diffuse aggregates, are not dangerous for the cell; Scenario II: Aβ42-GFP species that do not form protein inclusions but form diffuse aggregates, which can cause intracellular oxidative stress, are hazardous for the cell; Scenario III: Aβ42-GFP species that form protein inclusions are not deleterious for the cell, suggesting that the formation of these big aggregates acts as a protective strategy against oxidative stress., Highlights • Aβ42 peptides aggregation propensity negatively correlates with intracellular oxidative stress. • Low aggregation propensity Aβ42 variants accumulate as cytosolic diffuse aggregates instead of protein inclusions. • Diffuse aggregates are the major elicitors of oxidative stress. • Protein inclusion formation is a protective strategy against oxidative damage.

By combining NMR spectroscopy, transmission electron microscopy, and circular dichroism we have identified the structural determinants involved in the interaction of green tea catechins with Aβ1-42, PrP106-126, and ataxin-3 oligomers. The data allow the elucidation of their mechanism of action, showing that the flavan-3-ol unit of catechins is essential for interaction. At the same time, the gallate moiety, when present, seems to increase the affinity for the target proteins. These results provide important information for the rational design of new compounds with anti-amyloidogenic activity and/or molecular tools for the specific targeting of amyloid aggregates in vivo.

Alzheimer's disease is a neurodegenerative pathology strongly correlated to aging. Its symptoms are characterized by an impaired short term memory process in the early stages of the disease and later on by a loss of all type of memory process. There is actually no cure for this pathology. At the histo-pathological levels, the disease show an accumulation of aggregated proteins in the brain (called amyloid protein) in the intra or extra cellular space, which act as a disruptor of the normal neuronal function and activity. Thus, most of the therapeutic approach to treat the disease aim at removing those proteins aggregates from the brain. However, some of the Alzheimer's disease characteristics could be melded with normal aging : One such case is the global decrease of the proteostasis mechanism in the cell which normally happen in normal brain. The assumption made during this work is that the recovery of these mechanisms impaired by age would constitute a credible therapeutic approach, complementary to the other existing approaches to the complex disease that is Alzheimer's disease. Following this hypothesis I was interested in the role and regulation of one of the major system controlling proteostasis: the UPR (unfolded protein response), and particulary to the XBP-1s transcription factor , considered one of the master regulator of this cellular network; La maladie d'Alzheimer est une pathologie neurodégénérative progressive liée à l'âge qui détériore premièrement les fonctions liées aux mémoires de travail et épisodiques, avant de s'étendre à l'ensemble des procédures mémorielles dans les stades plus avancés. L'ensemble des traitements existant à ce jour sont palliatifs. Au niveau histologique, la maladie d'Alzheimer est caractérisée par l'accumulation extra- et intracellulaire de différentes protéines agrégées (appelées amyloïde) dans les tissus cérébraux, entrainant des dysfonctions importantes du circuit neuronal. De fait, la majorité des approches thérapeutiques en développement consistent à tenter de réduire ou supprimer ces agrégats protéiques. Cependant, la maladie d'Alzheimer étant étroitement corrélée au vieillissement, certaines de ses caractéristiques biologiques sont parfois confondues avec celles du vieillissement non pathologique. L'une de ces caractéristiques est la diminution des différents mécanismes liés à l'homéostasie protéique (protéostasie). L'hypothèse réalisée au cours de mes travaux est que le rétablissement de ces mécanismes diminués par l'âge constituerait une approche thérapeutique crédible, complémentaire aux approches actuelles, à la pathologie complexe qu'est la maladie d'Alzheimer. C'est en suivant cette optique que je me suis intéressé au rôle et à la régulation de l'un des systèmes majeusr du contrôle de la protéostasie : l'UPR (unfolded protein response), et en particulier au facteur de transcription XBP-1s, considéré comme l'une des pièces maîtresses de ce réseau de signalisation cellulaire

Alzheimer’s disease is a disease affecting many cellular and molecular targets and therefore requires a search for therapeutic multi-target molecules. Polyphenols presenting multiple pharmacological effects seem to be more efficient. Our findings demonstrated that trans ε-viniferin, a natural polyphenol, both induced the disaggregation of Aβ42 peptide and rescued inflammation on murine primary neuronal cultures. Moreover, it goes through the blood brain barrier and decreases inflammation and size of amyloid plaques in APPswePS1dE9 mice.; La maladie d’Alzheimer est caractérisée par plusieurs altérations cellulaires et moléculaires contre lesquelles il serait nécessaire de trouver un médicament multicible. Les polyphénols présentant de multiples effets pharmacologiques ont été utilisés dans ce projet. Il a ainsi été mis en évidence que dans un modèle cellulaire de la maladie d’Alzheimer, la trans ε-viniférine présentait des propriétés anti-inflammatoires et de désagrégation du peptide β-amyloïde (Aβ) supérieures à celles du resvératrol. La trans ε-viniférine a également un effet anti-inflammatoire dans un modèle murin de la maladie d’Alzheimer et atténue la formation des dépôts amyloïdes. Elle pourrait donc être une molécule thérapeutique multicible pertinente.

Protein aggregation is linked to many pathological conditions, including several neurodegenerative diseases. The aggregation propensities of proteins are thought to be controlled to a large extent by the physicochemical properties encoded in the primary sequence. We have previously exploited a set of amyloid β peptide (Aβ42) variants exhibiting a continuous gradient of intrinsic aggregation propensities to demonstrate that this rule applies in vivo in bacteria. In the present work we have characterized the behavior of these Aβ42 mutants when expressed in yeast. In contrast to bacteria, the intrinsic aggregation propensity is gated by yeast, in such a way that this property correlates with the formation of intracellular inclusions only above a specific aggregation threshold. Proteins displaying solubility levels above this threshold escape the inclusion formation pathway. In addition, the most aggregation-prone variants are selectively cleared by the yeast quality control degradation machinery. Thus, both inclusion formation and proteolysis target the same aggregation-prone variants and cooperate to minimize the presence of these potentially dangerous species in the cytosol. The demonstration that sorting to these pathways in eukaryotes is strongly influenced by protein primary sequence should facilitate the development of rational approaches to predict and hopefully prevent in vivo protein deposition.

APPswe/PS1dE9 and Tg2576 are very common transgenic mouse models of Alzheimer's disease (AD), used in many laboratories as tools to research the mechanistic process leading to the disease. In order to augment our knowledge about the amyloid-β (Aβ) isoforms present in both transgenic mouse models, we have developed two chromatographic methods, one acidic and the other basic, for the characterization of the Aβ species produced in the brains of the two transgenic mouse models. After immunoprecipitation and micro-liquid chromatography-electrospray ionization mass spectrometry/mass spectrometry, 10 species of Aβ, surprisingly all of human origin, were detected in the brain of Tg2576 mouse, whereas 39 species, of both murine and human origin, were detected in the brain of the APP/PS1 mouse. To the best of our knowledge, this is the first study showing the identification of such a high number of Aβ species in the brain of the APP/PS1 transgenic mouse, whereas, in contrast, a much lower number of Aβ species were identified in the Tg2576 mouse. Therefore, this study brings to light a relevant phenotypic difference between these two popular mice models of AD.

Background Alzheimer’s disease (AD) is the most common form of neurodegenerative disorder that leads to a decline in cognitive function. In AD, aggregates of amyloid β peptide precede the accumulation of neurofibrillary tangles, both of which are hallmarks of the disease. The great majority (>90 %) of the AD cases are not originated from genetic defects, therefore supporting the central roles of epigenetic modifications that are acquired progressively during the life span. Strong evidences have indicated the implication of epigenetic modifications, including histone modification and DNA methylation, in AD. Recent studies revealed that 5-hydroxymethylcytosine (5hmC) is dynamically regulated during neurodevelopment and aging. Results We show that amyloid peptide 1–42 (Aβ1-42) could significantly reduce the overall level of 5hmC in vitro. We found that the level of 5hmC displayed differential response to the pathogenesis in different brain regions, including the cortex, cerebellum, and hippocampus of APP-PSEN1 double transgenic (DTg) mice. We observed a significant decrease of overall 5hmC in hippocampus, but not in cortex and cerebellum, as the DTg mice aged. Genome-wide profiling identified differential hydroxymethylation regions (DhMRs) in DTg mice, which are highly enriched in introns, exons and intergenic regions. Gene ontology analyses indicated that DhMR-associated genes are highly enriched in multiple signaling pathways involving neuronal development/differentiation and neuronal function/survival. Conclusions 5hmC-mediated epigenetic regulation could potentially be involved in the pathogenesis of AD. Electronic supplementary material The online version of this article (doi:10.1186/s12864-016-2731-1) contains supplementary material, which is available to authorized users.

International audience; Oxidative stress is considered as an important factor and an early event in the etiology of Alzheimer's disease (AD). Cu bound to the peptide amyloid-β (Aβ) is found in AD brains, and Cu-Aβ could contribute to this oxidative stress, as it is able to produce in vitro H2O2 and HO. in the presence of oxygen and biological reducing agents such as ascorbate. The mechanism of Cu-Aβ-catalyzed H2O2 production is however not known, although it was proposed that H2O2 is directly formed from O2 via a 2-electron process. Here, we implement an electrochemical setup and use the specificity of superoxide dismutase-1 (SOD1) to show, for the first time, that H2O2 production by Cu-Aβ in the presence of ascorbate occurs mainly via a free O2.− intermediate. This finding radically changes the view on the catalytic mechanism of H2O2 production by Cu-Aβ, and opens the possibility that Cu-Aβ-catalyzed O2.− contributes to oxidative stress in AD, and hence may be of interest.

Background: For long time Alzheimer's disease has been attributed to a cholinergic deficit. More recently, it has been considered dependent on the accumulation of the amyloid beta peptide (Aβ), which promotes neuronal loss and impairs neuronal function. Results/methodology: In the present study, using biophysical and biochemical experiments we tested the hypothesis that in addition to its role as a neurotransmitter, acetylcholine may exert its action as an anti-Alzheimer agent through a direct interaction with Aβ. Conclusion: Our data provide evidence that acetylcholine favors the soluble peptide conformation and exerts a neuroprotective effect against the neuroinflammatory and toxic effects of Aβ. The present paper paves the way toward the development of new polyfunctional anti-Alzheimer therapeutics capable of intervening on both the cholinergic transmission and the Aβ aggregation.

Citation: Yu SS, Tang X, Ho Y-S, Chang RC-C and Chiu K (2016) Links between the Brain and Retina: The Effects of Cigarette Smoking-Induced Age-Related Changes in Alzheimer’s Disease and Macular Degeneration. Front. Neurol. 7:119. doi: 10.3389/fneur.2016.00119 Links between the Brain and Retina: The Effects of Cigarette Smoking-induced Age-Related Changes in Alzheimer’s Disease and Macular Degeneration

Amyloid-β peptide (Aβ) is the major component of amyloid deposits found in the brain tissue of Alzheimer patients. The tendency of amyloid peptide to form amyloid plaques is known to be related to the features of the plasma membrane. Flavonoids, a group of naturally occurring molecules, exert beneficial properties to human health thanks to their antioxidant property; this property depends on their capacity to interact and permeate the cell membrane lipid bilayer. In the present research we report an Electron Paramagnetic Resonance (EPR) investigation of 2-dioleoyl- sn -glycero-3-phosphocholine (DOPC) membranes interacting with the β-amyloid fragment Aβ(25-35), in the presence of flavonoids rutin, quercetin, naringin and naringenin. Our results, evidencing a flavonoid-dependent rigidifying effect of the bilayer, may provide the molecular basis to explain the known neuroprotective effect of flavonoid compounds.

The detection of amyloid precursor protein isoform 770 (APP770) was achieved with the use of total internal reflection ellipsometry (TIRE) in a direct immunoassay format with DE2 monoclonal antibodies raised against the β amyloid peptide 1-16 (Aβ 1-16) which is a part of APP770. DE2 antibodies were immobilised on the surface of gold by electrostatic binding to a layer of (poly)allylamine hydrochloride (PAH) via an intermediate layer of Protein G molecules. TIRE spectra were recorded after adsorption (binding) of every molecular layer in a sequence of PAH, Protein G, DE2, and APP770. A noticeable increase in the adsorbed layer thickness was obtained upon binding of APP770 molecules from its solution of unknown concentration in Complete Medium, a complex mixture containing other proteins. For a purpose of TIRE biosensor calibration, complementary quartz crystal microbalance (QCM) measurements were utilised and allowed the evaluation of surface concentrations of DE2 and APP770 of 1.08.1011 cm-2 and 4.73.1012 cm-2, respectively.