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Objective: To explore the mechanism of olfactory three needle therapy on Parkinson's disease dementia (PDD) by observing its effects on expression of apolipoprotein E (ApoE)、glial fibrillary acidic protein (GFAP) and related core pathology substrates in the hippocampus of PDD model mice. Method: Male C57BL/6 mice were randomly divided into four groups: control group (Control), sham operation group (Sham), model group (Model) and acupuncture electrotherapy group (AE), with 10 mice in each group. The PD model was established by injecting 6-OHDA into the medial forebrain tract (MFB) and PDD mice were selected. After successful modeling and selection, the AE group received "olfactory three needle" electroacupuncture treatment. After 14 days of intervention, Morris water maze test and shuttle box test were used to evaluate the learning and memory ability of mice in each group. Hematoxylin-eosin (HE) staining was used to observe the pathological changes of hippocampal CA1 region. Western blotting was used to detect the expression of αsyn, Aβ and ApoE proteins in hippocampal CA1 region. The colocation rate of ApoE and GFAP in hippocampal CA1 region was observed by double immunofluorescence markers. Result: Compared with Model group, the AE group exhibited a shortened escape latency in water maze (P< 0.01), increased platform crossing (P<0.05), increased active escape times of shuttle box (P<0.05), and reduced the average total time of electric stimulation (P<0.01). In the Model group, the neurons in the hippocampal CA1 area were sparsely arranged and showed signs of degeneration and necrosis; and cell nuclei were small, hyperchromatic and had unclear structures, indicating the appearance of nuclear pyrosis. In contrast, the AE group showed significant improvements in neuronal pathology, with most cells regularly arranged, round and large nuclei, lightly stained and clearly shaped. Compared with the Model group, the expression levels of αsyn, Aβ, ApoE protein and the colocalization rate of ApoE and GFAP in hippocampal CA1 region in AE group were decreased (P<0.01, P<0.01, P<0.01, P<0.05). Conclusion: The "Olfactory three needle" acupuncture can improve the cognitive ability and restore the morphological structure and function of neurons in PDD mice. The mechanism may be related to the inhibition of ApoE expression in astrocytes and the reduction of α-syn and Aβ deposition in hippocampal CA1 region. [ABSTRACT FROM AUTHOR]

Dysfunctional phenotype of microglia, the primary brain immune cells, may aggravate Alzheimer's disease (AD) pathogenesis by releasing proinflammatory factors, such as nitric oxide (NO). The endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) are bioactive lipids increasingly recognised for their essential roles in regulating microglial activity both under normal and AD-driven pathological conditions. To investigate the possible impact of chronic exposure to β-amyloid peptides (Aβ) on the microglial endocannabinoid signalling, we characterised the functional expression of the endocannabinoid system on neonatal microglia isolated from wild-type and Tg2576 mice, an AD-like model, which overexpresses Aβ peptides in the developing brain. We found that Aβ-exposed microglia produced 2-fold more 2-AG than normal microglia. Accordingly, the expression levels of diacylglycerol lipase-α (DAGLα) and monoacylglycerol lipase (MAGL), the main enzymes responsible for synthesising and hydrolysing 2-AG, respectively, were consistently modified in Tg2576 microglia. Furthermore, compared to wild-type cells, transgenic microglia basally showed increased expression of the cannabinoid 2 receptor, typically upregulated in an activated proinflammatory phenotype. Indeed, following inflammatory stimulus, Aβ-exposed microglia displayed an enhanced production of NO, which was abolished by pharmacological inhibition of DAGLα. These findings suggested that exposure to Aβ polarises microglial cells towards a pro-AD phenotype, possibly by enhancing 2-AG signalling. [ABSTRACT FROM AUTHOR]

Abstract Background Excessive aggregation of β-amyloid peptides (Aβ) is regarded as the hallmark of Alzheimer’s disease. Exploring the underlying mechanism regulating Aβ aggregation remains challenging and investigating aggregation events of Aβ in the presence and absence of metallic ions at molecular level would be meaningful in elucidating the role of metal cations on interactions between Aβ molecules. In this study, chemical self-assembled monolayer (SAM) method was employed to fabricate monolayer of β-amyloid peptides Aβ42 on gold substrate with a bolaamphiphile named 16-Mercaptohexadecanoic acid (MHA). Firstly, the samples of gold substrate (blank control), the MHA-modified substrate, and the Aβ42-modified substrate were detected by X-ray photoelectron spectroscopy (XPS) to track the self-assembly process. Aggregation behaviors of Aβ42 before and after metallic ions (Zn2+, Ca2+, Al3+) treatment were monitored by atomic force microscopy (AFM) and the interaction between Aβ42 and metallic ions (Zn2+, Ca2+, Al3+) was investigated by surface-enhanced Raman Scattering (SERS). Results The XPS spectra of binding energy of gold substrate (blank control), the MHA-modified substrate, and the Aβ42-modified substrate are well fitted with the corresponding monolayer’s composition, which indicates that Aβ42 monolayer is well formed. The recorded surface morphology of different experimental groups obtained by AFM showed markedly different nanostructures, indicating occurrence of aggregation events between Aβ42 molecules after adding metal ions to the solution. Compared to the control group, the presence of metallic ions resulted in the increased size of surface structures on the observed 3D topography. Besides, the intermolecular rupture force of Aβ42 increased with the addition of metallic ions. Further study by SERS showed that the Raman strength of Aβ42 changes significantly after the metal cation treatment. A considerable part of the amide bonds interacts with metal cations, leading to a structural change, which is characterized by the weakened β-fold Raman peak. Conclusion The AFM imaging results suggest that aggregation events occurred between Aβ42 molecules with the addition of metal cations. In addition, the results of force tests indicate that the presence of metallic ions could promote adhesion between Aβ42 molecules, which is likely to be the trigger for aggregation behavior of Aβ42. Furthermore, the effect of metallic cations on the conformational change of Aβ42 studied by SERS supported the results obtained by AFM. Taken together, the results showed that the presence of substoichiometric metal cations promotes aggregation behavior between Aβ42 molecules on the substrate at pH 7.4.

Background: Excessive aggregation of β-amyloid peptides (Aβ) is regarded as the hallmark of Alzheimer's disease. Exploring the underlying mechanism regulating Aβ aggregation remains challenging and investigating aggregation events of Aβ in the presence and absence of metallic ions at molecular level would be meaningful in elucidating the role of metal cations on interactions between Aβ molecules. In this study, chemical self-assembled monolayer (SAM) method was employed to fabricate monolayer of β-amyloid peptides Aβ42 on gold substrate with a bolaamphiphile named 16-Mercaptohexadecanoic acid (MHA). Firstly, the samples of gold substrate (blank control), the MHA-modified substrate, and the Aβ42-modified substrate were detected by X-ray photoelectron spectroscopy (XPS) to track the self-assembly process. Aggregation behaviors of Aβ42 before and after metallic ions (Zn2+, Ca2+, Al3+) treatment were monitored by atomic force microscopy (AFM) and the interaction between Aβ42 and metallic ions (Zn2+, Ca2+, Al3+) was investigated by surface-enhanced Raman Scattering (SERS).Results: The XPS spectra of binding energy of gold substrate (blank control), the MHA-modified substrate, and the Aβ42-modified substrate are well fitted with the corresponding monolayer's composition, which indicates that Aβ42 monolayer is well formed. The recorded surface morphology of different experimental groups obtained by AFM showed markedly different nanostructures, indicating occurrence of aggregation events between Aβ42 molecules after adding metal ions to the solution. Compared to the control group, the presence of metallic ions resulted in the increased size of surface structures on the observed 3D topography. Besides, the intermolecular rupture force of Aβ42 increased with the addition of metallic ions. Further study by SERS showed that the Raman strength of Aβ42 changes significantly after the metal cation treatment. A considerable part of the amide bonds interacts with metal cations, leading to a structural change, which is characterized by the weakened β-fold Raman peak.Conclusion: The AFM imaging results suggest that aggregation events occurred between Aβ42 molecules with the addition of metal cations. In addition, the results of force tests indicate that the presence of metallic ions could promote adhesion between Aβ42 molecules, which is likely to be the trigger for aggregation behavior of Aβ42. Furthermore, the effect of metallic cations on the conformational change of Aβ42 studied by SERS supported the results obtained by AFM. Taken together, the results showed that the presence of substoichiometric metal cations promotes aggregation behavior between Aβ42 molecules on the substrate at pH 7.4. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders have been shown to exhibit substantial interconnectedness with circadian rhythmicity. Alzheimer’s patients exhibit high degradation of the suprachiasmatic nucleus (SCN), the central endogenous circadian timekeeper, and Parkinson’s patients have highly disrupted peripheral clock gene expression. Disrupted sleep patterns are highly evident in patients with neurodegenerative diseases; fragmented sleep has been shown to affect tau-protein accumulation in Alzheimer’s patients, and rapid eye movement (REM) behavioral disorder is observed in a significant amount of Parkinson’s patients. Although numerous studies exist analyzing the mechanisms of neurodegeneration and circadian rhythm function independently, molecular mechanisms establishing specific links between the two must be explored further. Thus, in this review, we explore the possible intersecting molecular mechanisms between circadian rhythm and neurodegeneration, with a particular focus on Parkinson’s disease. We provide evidence for potential influences of E3 ligase and poly adenosine diphosphate (ADP-ribose) polymerase 1 (PARP1) activity on neurodegenerative pathology. The cellular stress and subsequent DNA damage signaling imposed by hyperactivity of these multiple molecular systems in addition to aberrant circadian rhythmicity lead to extensive protein aggregation such as α-synuclein pre-formed fibrils (α-Syn PFFs), suggesting a specific molecular pathway linking circadian rhythmicity, PARP1/E3 ligase activity, and Parkinson’s disease.

Enrichment of neurally derived extracellular vesicles of several cell‐types from plasma for protein quantification longitudinally in living patients with Alzheimer's disease has permitted the development of a tentative temporal framework of initiating events, progression mechanisms, and amplification processes. Interactions of beta‐amyloid peptides with an elevated level of their normal prion protein dendritic receptor and of phospho‐tau species with their synaptogyrin‐3 synaptic vesicle receptor replace excessive production and accumulation of neuropathic proteins as the major initiating events. Synaptic dysfunction and microvascular angiopathy are confirmed as early progression mechanisms of decreased neuronal network connectivity, hypoxia, altered blood‐brain barrier, and neurocellular degeneration. Neurally derived extracellular vesicle protein abnormalities also reveal a range of later amplification processes that encompasses insulin resistance, lysosomal defects, decreased survival factors, increased reactive oxygen species, and excessive neuroinflammation. New potential therapeutic targets also are suggested as well as the likely timing of their pathogenic engagement. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders have been shown to exhibit substantial interconnectedness with circadian rhythmicity. Alzheimer's patients exhibit high degradation of the suprachiasmatic nucleus (SCN), the central endogenous circadian timekeeper, and Parkinson's patients have highly disrupted peripheral clock gene expression. Disrupted sleep patterns are highly evident in patients with neurodegenerative diseases; fragmented sleep has been shown to affect tau-protein accumulation in Alzheimer's patients, and rapid eye movement (REM) behavioral disorder is observed in a significant amount of Parkinson's patients. Although numerous studies exist analyzing the mechanisms of neurodegeneration and circadian rhythm function independently, molecular mechanisms establishing specific links between the two must be explored further. Thus, in this review, we explore the possible intersecting molecular mechanisms between circadian rhythm and neurodegeneration, with a particular focus on Parkinson's disease. We provide evidence for potential influences of E3 ligase and poly adenosine diphosphate (ADP-ribose) polymerase 1 (PARP1) activity on neurodegenerative pathology. The cellular stress and subsequent DNA damage signaling imposed by hyperactivity of these multiple molecular systems in addition to aberrant circadian rhythmicity lead to extensive protein aggregation such as α-synuclein pre-formed fibrils (α-Syn PFFs), suggesting a specific molecular pathway linking circadian rhythmicity, PARP1/E3 ligase activity, and Parkinson's disease. [ABSTRACT FROM AUTHOR]

Abnormal accumulation of β‐amyloid (Aβ) peptide aggregates in the brain is a major hallmark of Alzheimer's disease (AD). Aβ aggregates interfere with neuronal communications, ultimately causing neuronal damage and brain atrophy. Much effort has been made to develop AD treatments that suppress Aβ aggregate formation, thereby attenuating Aβ‐induced neurotoxicity. Here, the design of Aβ nanodepletors consisting of ultralarge mesoporous silica nanostructures and anti‐Aβ single‐chain variable fragments, with the goal of targeting and eliminating aggregative Aβ monomers, is reported. The Aβ nanodepletors impart a notable decline in Aβ aggregate formation, resulting in significant mitigation of Aβ‐induced neurotoxicity in vitro. Furthermore, stereotaxic injections of Aβ nanodepletors into the brain of an AD mouse model system successfully suppress Aβ plaque formation in vivo up to ≈30%, suggesting that Aβ nanodepletors can serve as a promising antiamylodoisis material. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is nowadays the prominent cause of senile dementia. This pathology is characterized by aggregation of neurofibrillary tangles in cells and by the accumulation of amyloid plaques in the brain. Noteworthy, a phosphorylated protein (tau protein) and a peptide presenting two overlapping sequences of 40 or 42 residues named β-amyloid peptides 1–40 (Aβ 1–40) and 1–42 (Aβ 1–42), respectively, were related to such deleterious phenomena. Singularly, the neurotoxicity was primarily attributed to the amyloid peptide Aβ 1–42 form due to its capacity to fold into beta-sheets rendering it insoluble thus causing subsequent aggregation and accumulation in vivo. Regarding AD diagnosis relying on mass spectrometry, Aβ 1–42 and/or Aβ 1–40 were considered as relevant biomarkers being measured in cerebrospinal fluids (CSF), blood and urine. Under that context, we aimed at implementing an innovative method to evidence the depletion of circulating Aβ 1–42 amyloid peptide compared to the shorter Aβ 1–40 form indicating a pathologic state. We investigated Surface-Assisted Laser Desorption/Ionization Mass Spectrometry (SALDI-MS) in order to monitor the Aβ 1–42/Aβ 1–40 ratio without any prior sample treatment or enrichment. Taking into account that β-amyloid peptide and 1–42 can aggregate into beta-sheets depending on the experimental conditions, specific attention was devoted to sample integrity monitoring performed by circular dichroism experiments during SALDI-MS method development. [Display omitted] • Si nanoneedles or nanowires modified with Ag, Cu and TiO 2 were designed as SALDI-MS chip and characterized. • Nanostructured surfaces enhance desorption/ionization efficiency. • AB peptides 1–40 and 1–42 in standard solution can be sensitively and rapidly identified by SALDI-MS, MSI and EDX. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is one of the most common age-associated pathologies, which inevitably leads to dementia and death. The aggregation of β-amyloid (Aβ) peptides on plaques in brain tissue is strongly associated with AD. The possible link between aluminum and AD still remains controversial. In this work, the aggregation of Aβ40 induced by Al(III) was investigated with the use of the fluorescence quenching method, UV–visible and circular dichroism spectroscopies as well as the atomic force microscopy technique. The results demonstrated that Al(III) induced the transformation of the initial random coil structure to the β-sheet configuration in the Aβ40 peptides. These structural changes facilitated the aggregation of Aβ40. Also, the binding constant was calculated with the use of the multivariate curve resolution-alternating least squares (MCR-ALS) chemometrics method. [ABSTRACT FROM AUTHOR]

Co-aggregation involving different amyloidogenic sequences has been emphasized recently in the modified amyloid cascade hypothesis. Yet, molecular-level interactions between two predominant β-amyloid peptide sequences, Aβ 40 and Aβ 42 , in the fibrillation process in membrane-mimicked environments remain unclear. Here, we report biophysical evidence that demonstrates the molecular-level interactions between Aβ 40 and Aβ 42 at the membrane-associated conucleation stage using dynamic nuclear polarization-enhanced solid-state NMR spectroscopy. These residue-specific contacts are distinguished from those reported in mature fibrils formed by either Aβ 40 or Aβ 42 . Meanwhile, site-specific interactions between Aβ and lipid molecules and modulation of microsecond-time-scale lipid dynamics are observed, which may be responsible for the more rapid and significant membrane content leakage compared to that with Aβ 40 alone.

Background: Alzheimer's disease (AD), is a progressive neurodegenerative disease that is characterized by cognitive loss. Most researchers believe that aggregation and accumulation of β-amyloid peptides (Aβ) in brain cells are the central pathological hallmark of this disease.Methods: Based on the amyloid hypothesis, a 10 amino acids β-sheet breaker peptide HPYD (His-Lys-Gln-Leu-Pro-Phe-Tyr-Glu-Glu-Asp) was designed according to the structure and sequence of the previous designed peptide H102. Accelerated stability test, thioflavine T (ThT) fluorescence spectral analysis and transmission electron microscopy (TEM) imaging were performed to detect the stability and inhibitory effects on the aggregation of Aβ1−42 by H102 and HPYD. FITC-labeled HPYD was first tested to determine whether it could be transferred along the olfactory pathway to the brain after nasal administration to mice. Subsequently, the Morris Water Maze (MWM) test for behavioral analysis was used to investigate the learning and memory ability of APP/PS1 transgenic mice by HPYD. Immunohistochemistry and western blot analysis was performed to determine the role of HPYD on Aβ and APP protein levels. In addition, microarray analysis was used to evaluate the effect of HPYD on gene expression in AD mouse models.Results: Our in vitro results demonstrated that HPYD had enhanced stability and inhibitory effects on Aβ1−42 aggregation compared to H102. HPYD could be delivered into the brain through nasal administration and improved the learning and memory ability in APP/PS1 transgenic mouse models by reducing Aβ and APP protein levels. In addition, microarray analyses suggested that several genes related to the inflammatory pathway, AD and gluco-lipid metabolism were dysregulated and could be restored to almost normal levels after HPYD administration to mice.Conclusions: Our results demonstrated that HPYD could be a potential therapeutic drug candidate for the treatment of AD.

Background: Alzheimer's disease (AD), is a progressive neurodegenerative disease that is characterized by cognitive loss. Most researchers believe that aggregation and accumulation of β-amyloid peptides (Aβ) in brain cells are the central pathological hallmark of this disease. Methods: Based on the amyloid hypothesis, a 10 amino acids β-sheet breaker peptide HPYD (His-Lys-Gln-Leu-Pro-Phe-Tyr-Glu-Glu-Asp) was designed according to the structure and sequence of the previous designed peptide H102. Accelerated stability test, thioflavine T (ThT) fluorescence spectral analysis and transmission electron microscopy (TEM) imaging were performed to detect the stability and inhibitory effects on the aggregation of Aβ1-42 by H102 and HPYD. FITC-labeled HPYD was first tested to determine whether it could be transferred along the olfactory pathway to the brain after nasal administration to mice. Subsequently, the Morris Water Maze (MWM) test for behavioral analysis was used to investigate the learning and memory ability of APP/PS1 transgenic mice by HPYD. Immunohistochemistry and western blot analysis was performed to determine the role of HPYD on Aβ and APP protein levels. In addition, microarray analysis was used to evaluate the effect of HPYD on gene expression in AD mouse models. Results: Our in vitro results demonstrated that HPYD had enhanced stability and inhibitory effects on Aβ1-42 aggregation compared to H102. HPYD could be delivered into the brain through nasal administration and improved the learning and memory ability in APP/PS1 transgenicmousemodels by reducing Aβ and APP protein levels. In addition, microarray analyses suggested that several genes related to the inflammatory pathway, AD and gluco-lipid metabolism were dysregulated and could be restored to almost normal levels after HPYD administration to mice. Conclusions: Our results demonstrated that HPYD could be a potential therapeutic drug candidate for the treatment of AD. [ABSTRACT FROM AUTHOR]

Non-specific disruption of cellular membranes induced by aggregation of exogeneous β-amyloid (Aβ) peptides is considered a viable pathological mechanism in Alzheimer's disease (AD). The solid-state nuclear magnetic resonance (ssNMR) spectroscopy has been widely applied in model liposomes to provide important insights on the molecular interactions between membranes and Aβ aggregates. Yet, the feasibility of in-cell ssNMR spectroscopy to probe Aβ-membrane interactions in native cellular environments has rarely been tested. Here we report the application of in-cell 31P ssNMR spectroscopy on live mouse neuroblastoma Neuro-2a (N2a) cells under moderate magic angle spinning (MAS) conditions. Both cell viability and cytoplasmic membrane integrity are retained for up to six hours under 5 kHz MAS frequency at 277 K, which allow applications of direct-polarization 31P spectroscopy and 31P spin-spin (T 2) relaxation measurements. The 31P T 2 relaxation time constant of N2a cells is significantly increased compared with the model liposome prepared with comparable major phospholipid compositions. With the addition of 5 μM 40-residue Aβ (Aβ 1 – 40) peptides, the 31P T 2 relaxation is instantly accelerated. This work demonstrates the feasibility of using in-cell 31P ssNMR to investigate the Aβ-membrane interactions in the biologically relevant cellular system. [Display omitted] • Neuro-2a cells maintain viability and integrity for six hours under moderate magic angle spinning conditions. • 31P NMR spectroscopy revealed partial resolution for the glycerol- and lyso-phospholipid resonance peaks. • 31P T 2 relaxation is significantly slower in N2a cell samples compared with model phospholipid vesicles. • 31P T 2 relaxation is slightly more rapid with the exogeneous β-amyloid peptides. [ABSTRACT FROM AUTHOR]

Background: Detection of retinal β-amyloid (Aβ) peptide accumulation is a novel diagnostic method for Alzheimer’s disease (AD), but there is, as yet, no conclusive evidence of its accuracy.Aim: To identify the diagnostic accuracy of pathological retinal Aβ detection for AD by a meta-analytic approach.Methods: Electronic and reference searches were conducted to identify studies related to the diagnostic effects of retinal Aβ detection in AD that met pre-defined inclusion criteria. The QUADAS-2 tool was employed to assess the risk of bias, and Review Manager plus the Open Meta-Analyst were used to perform the data analysis.Results: From 493 unduplicated reports, five studies with small sample sizes were included in this review. Six staining methods were employed. The eligible studies showed extremely broad ranges of sensitivity (0 to 1.00) and specificity (0.50 to 1.00) with substantial heterogeneity. The estimates of positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) were also extremely varied (from 0.71 to 11.57 for PLR, from 0.04 to 1.11 for NLR, and from 0.69 to 297.00 for DOR).Conclusions: The limited number of eligible studies and their methodological heterogeneity make it impossible to come to a conclusion whether pathological retinal Aβ detection is an effective diagnostic tool for AD. More studies, especially large surveys investigating retina Aβ load with quantitative methods among consecutive or random samples, are needed to determine the accuracy of Aβ detection for diagnosing AD.

We examined the potential protective effect of BDNF against β-amyloid-induced neurotoxicity in vitro and in vivo in rats. In neuronal cultures, BDNF had specific and dose–response protective effects on neuronal toxicity induced by Aβ1–42 and Aβ25–35. It completely reversed the toxic action induced by Aβ1–42 and partially that induced by Aβ25–35. These effects involved TrkB receptor activation since they were inhibited by K252a. Catalytic BDNF receptors (TrkB.FL) were localized in vitro in cortical neurons (mRNA and protein). In in vivo experiments, Aβ25–35 was administered into the indusium griseum or the third ventricle and several parameters were measured 7 days later to evaluate potential Aβ25–35/BDNF interactions, i.e. local measurement of BDNF release, number of hippocampal hilar cells expressing SRIH mRNA and assessment of the corpus callosum damage (morphological examination, pyknotic nuclei counting and axon labeling with anti-MBP antibody). We conclude that BDNF possesses neuroprotective properties against toxic effects of Aβ peptides.

Background: Detection of retinal β-amyloid (Ab) peptide accumulation is a novel diagnostic method for Alzheimer's disease (AD), but there is, as yet, no conclusive evidence of its accuracy. Aim: To identify the diagnostic accuracy of pathological retinal Ab detection for AD by a meta-analytic approach. Methods: Electronic and reference searches were conducted to identify studies related to the diagnostic effects of retinal Ab detection in AD that met pre-defined inclusion criteria. The QUADAS-2 tool was employed to assess the risk of bias, and Review Manager plus the Open Meta-Analyst were used to perform the data analysis. Results: From 493 unduplicated reports, five studies with small sample sizes were included in this review. Six staining methods were employed. The eligible studies showed extremely broad ranges of sensitivity (0-1.00) and specificity (0.50-1.00) with substantial heterogeneity. The estimates of positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) were also extremely varied (from 0.71 to 11.57 for PLR, from 0.04 to 1.11 for NLR, and from 0.69 to 297.00 for DOR). Conclusions: The limited number of eligible studies and their methodological heterogeneity make it impossible to come to a conclusion whether pathological retinal Ab detection is an effective diagnostic tool for AD. More studies, especially large surveys investigating retina Ab load with quantitative methods among consecutive or random samples, are needed to determine the accuracy of Ab detection for diagnosing AD. [ABSTRACT FROM AUTHOR]

In astroglial cells β-amyloid peptides (βA) induce a reactive phenotype and increase expression of NO synthase. Here we show that treatment of rat brain astrocytes with βA decreases their capacity to accumulate cyclic GMP (cGMP) in response to NO as a result of a decreased expression of soluble guanylyl cyclase (sGC) at the protein and mRNA levels. Potentiation of βA-induced NO formation by interferon-γ did not result in a larger decrease in cGMP formation and inhibition of NO synthase failed to reverse down-regulation of sGC, indicating that NO is not involved. The βA effect was prevented by the protein synthesis inhibitor cycloheximide. Intracerebral βA injection also decreased sGC β1 subunit mRNA levels in adult rat hippocampus and cerebellum. A loss of sGC in reactive astrocytes surrounding β-amyloid plaques could be a mechanism to prevent excess signalling via cGMP at sites of high NO production.

Alzheimer and Parkinson diseases are associated with cholinergic neuron loss and deterioration of bone mineral density. Gene therapy through either gene transfer, CRISPR gene editing, or CRISPR gene modulation holds the potential to cure Alzheimer and Parkinson diseases. The emerging role of weight-bearing exercise in the prevention of, and care for, osteoporosis, obesity, and diabetes has been previously recognized. Moreover, endurance exercise offers a viable alternative to reduce amyloid peptides deposits while increasing bone mineral density in Alzheimer and Parkinson patients. β-amyloid peptides, α-synuclein, and tau aggregates start building up two decades before the onset of Alzheimer and Parkinson diseases. Therefore, an early intervention program for the detection of these deposits is required to prevent or delay the onset of these diseases. This article spots light on the potential of gene therapy for Alzheimer and Parkinson diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In the present work, a new electrochemical strategy for the sensitive and specific detection of soluble β-amyloid Aβ(1-40/1-42) peptides in a rat model of Alzheimer's disease (AD) is described. In contrast to previous antibody-based methods, β-amyloid(1-40/1-42) was quantified based on its binding to gelsolin, a secretory protein present in the cerebrospinal fluid (CSF) and plasma. The level of soluble β-amyloid peptides in the CSF and various brain regions were found with this method to be lower in rats with AD than in normal rats. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the effect of ginsenoside compound K on β-amyloid (Aβ) peptide clearance in primary astrocytes. Aβ degradation in primary astrocytes was determined using an intracellular Aβ clearance assay. Aggregated LC3 in astrocyte cells, which is a marker for the level of autophagy, was detected using laser scanning confocal microscope. The effect of compound K on the mammalian target of rapamycin (mTOR)/autophagy pathway was determined using western blot analysis, and an enzyme-linked immunosorbent assay was used for Aβ detection. The results demonstrated that compound K promoted the clearance of Aβ and enhanced autophagy in primary astrocytes. In addition, it was found that phosphorylation of mTOR was inhibited by compound K, which may have contributed to the enhanced autophagy. In conclusion, compound K promotes Aβ clearance by enhancing autophagy via the mTOR signaling pathway in primary astrocytes. [ABSTRACT FROM AUTHOR]

Abstract: β-Amyloid (Aβ)-induced toxicity and oxidative stress have been postulated to play critical roles in the pathogenic mechanism of Alzheimer disease (AD). We investigated the in vivo ability of a mitochondria-targeted antioxidant, MitoQ, to protect against Aβ-induced toxicity and oxidative stress in a Caenorhabditis elegans model overexpressing human Aβ. Impairment of electron transport chain (ETC) enzymatic activity and mitochondrial dysfunction are early features of AD. We show that MitoQ extends lifespan, delays Aβ-induced paralysis, ameliorates depletion of the mitochondrial lipid cardiolipin, and protects complexes IV and I of the ETC. Despite its protective effects on lifespan, healthspan, and ETC function, we find that MitoQ does not reduce DCFDA fluorescence, protein carbonyl levels or modulate steadystate ATP levels or oxygen consumption rate. Moreover, MitoQ does not attenuate mitochondrial DNA (mtDNA) oxidative damage. In agreement with its design, the protective effects of MitoQ appear to be targeted specifically to the mitochondrial membrane and our findings suggest that MitoQ may have therapeutic potential for Aβ- and oxidative stress-associated neurodegenerative disorders, particularly AD. [Copyright &y& Elsevier]

Background: The use of dried blood spots on filter paper is well documented as an affordable and practical alternative to classical venous sampling for various clinical needs. This technique has indeed many advantages in terms of collection, biological safety, storage, and shipment. Amyloid β (Aβ) peptides are useful cerebrospinal fluid (CSF) biomarkers for Alzheimer disease diagnosis. However, Aβ determination is hindered by preanalytical difficulties in terms of sample collection and stability in tubes. Methods: We compared the quantification of Aβ peptides (1-40, 1-42, and 1-38) by simplex and multiplex ELISA, following either a standard operator method (liquid direct quantification) or after spotting CSF onto dried matrix paper card. Results: The use of dried matrix spot (DMS) overcame preanalytical problems and allowed the determination of Aβ concentrations that were highly commutable (Bland-Altman) with those obtained using CSF in classical tubes. Moreover, we found a positive and significant correlation (r2=0.83, Pearson coefficient p=0.0329) between the two approaches. Conclusions: This new DMS method for CSF represents an interesting alternative that increases the quality and efficiency in preanalytics. This should enable the better exploitation of Aβ analytes for Alzheimer's diagnosis. [ABSTRACT FROM AUTHOR]

Highlights: [•] Amyloid β deposits appear in 3-month-old APPswe/PS1dE9 mice. [•] Amyloid deposition was accompanied by a fall in soluble and membrane-bound Aβ levels. [•] Insoluble levels of Aβ peptides in the brain correlate inversely with plasma Aβ levels. [•] Plasma Aβ levels could be developed as possible biomarkers of cerebral amyloidosis in transgenic mice of AD. [Copyright &y& Elsevier]

Background and Aims: β-amyloid-induced inflammation has been implicated in the early pathologic events in neurodegenerative diseases. The anti-inflammation potential of genistein (GEN) had been proved recently in our previous studies. We undertook this study to investigate the effects of GEN on inflammation induced by β-amyloid25-35 treatment and the possible molecular mechanisms in C6 glial cells. Methods: C6 cells were pre-incubated with GEN for 2 h followed by the incubation with β-amyloid 25-35 (Aβ25-35) for another 24 h. Inflammatory factors were detected by ELISA. The mRNA and protein expression of nuclear factor κB (NF-κB) p65 was measured using RT-PCR and Western blot, respectively. After inhibiting the NF-κBp65 mRNA expression by using short interfering RNAs (siRNAs) technique, the changes of inflammatory factors levels were detected again. Results: GEN inhibited the production of inflammatory factors induced by Aβ25-35 treatment. Aβ25-35 treatment had no effect on the mRNA expression of NF-κBp65 but upregulated the protein expression of NF-κBp65. However, this upregulation effect on NF-κBp65 protein expression was alleviated by GEN pretreatment. After inhibiting NF-κBp65 mRNA expression by using siRNA technique, the effects of Aβ25-35 or GEN on the inflammatory factor generation were inhibited. Conclusions: These results indicated that GEN exhibited anti-inflammatory effects through regulating NF-κB signaling pathway in Aβ25-35-treated C6 glial cells. [Copyright &y& Elsevier]

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Insulin-like growth factor 1 (IGF-1) stimulates α-secretase processing of amyloid precursor protein (APP) and decreases Aβ production. Little is known about the relationship between IGF-1 and β-site amyloid precursor protein cleaving enzyme 1 (BACE-1), the protease essential for the production of β-amyloid peptides (Aβ). Here, we investigated the effect of IGF-1 on BACE-1 in PC12 cells. Quantitative polymerase chain reaction analysis and western blot showed that treatment of cells with IGF-1 significantly decreased the levels of BACE-1 mRNA and protein. Furthermore, IGF-1 increased the phosphorylation of Akt and ERK1/2. The presence of the phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002 and the mitogen-activated protein kinase kinases (MEK) inhibitor PD98059 blocked the effect of IGF-1 on BACE-1. Our data indicated that IGF-1-induced reduction of BACE-1 might involve the PI3-K/Akt and MAPK/ERK1/2 signaling pathways. [ABSTRACT FROM AUTHOR]

Abstract: Gold nanoparticles (Au NPs) were functionalized by cysteine (Cys), β-amyloid peptides (Cys 0 Aβ 1-28 , Cys 0 Aβ 1-40 , Aβ 1-42 ) and a pentapeptide fragment (Leu-Pro-Phe-Phe-Asp-OH (LPFFD-OH)). Optical absorption spectra of these systems were recorded and the plasmon resonance maximum values (λ max) of the UV–vis spectra together with the transmission electron microscopy (TEM) images were also analysed. Both TEM images and the appearance of a new absorption band between ∼720 and 750nm in the visible spectra of the Au–cysteine and Au–LPFFD-OH systems most probably indicate that upon addition of these molecules to Au NPs-containing aqueous dispersions formation of aggregates is occurred. The wavelength shift between the two observed absorption bands in cysteine- and pentapeptide-modified Au NPs systems are Δλ =185 and 193nm, respectively. These results suggest that the monodisperse spherical gold nanoparticles were arranged to chained structure due to the effect of these molecules. For confirmation of the binding of citrate and cysteine onto the plasmonic metal surface 1H NMR measurements were also performed. 1H NMR results may suggest that the citrate layer on the metal surface is replaced by cysteine leading to a formation of organic double layer structure. In the presence of β-amyloid peptides the aggregation was not observed, especially in the Au–Cys0Aβ1-40 and Au–Aβ1-42 systems, however compared to the cysteine or LPFFD-OH-containing gold dispersion with Cys0Aβ1-28 measurable less aggregation were occurred. The spectral parameters clearly suggest that Aβ1-42 can attach or bind to the surface of gold nanoparticles via both the apolar and the N-donors containing side-chains of amino acids and no aggregation in the colloidal gold dispersion was observed. [Copyright &y& Elsevier]

Abstract: Objective: Genistein (GEN), a principal component of soybean isoflavones, might possess the neuroprotective role through its antioxidant activity. However, the detailed mechanisms are unknown yet. The purpose of this study was to investigate whether GEN could alleviate oxidative damage induced by β-amyloid peptides 25–35 (Aβ25–35) in PC12 cells. Methods: The PC12 cells were pre-incubated with or without GEN for 2h following incubation with Aβ25–35 for another 24h. MTT was used to assess the cell viability. Hoechst 33342 staining was applied to determine the apoptotic cells. Confocal laser scanning microscopy was implemented to examine the reactive oxygen species (ROS) levels. Mitochondrial membrane potential (MMP) was measured by flow cytometry. Reduced and oxidized glutathione (GSH/GSSG) ratio was analyzed by using assay kits. Western blot analysis was performed to assess the proteins expression of NF-E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and γ-glutamylcysteine synthetase (γ-GCS). Results: GEN attenuated the cytotoxicity and partially prevented apoptosis induced by Aβ25–35. GEN dramatically attenuated ROS levels induced by Aβ25–35 in PC12 cells. In addition, GEN significantly reversed the reduction of MMP caused by Aβ25–35 to maintain the normal levels of the cells. The GSH/GSSG ratio in GEN pretreated groups significantly increased compared to the groups without GEN pretreatment. GEN reversed Aβ25–35 induced down regulation of the protein expression of γ-GCS, Nrf2 and HO-1. Conclusion: GEN could alleviate the oxidative stress caused by Aβ25–35 treatment and maintain redox balance in PC12 cells, which might be associated with the regulation of Nrf2/HO-1 signal pathway. [Copyright &y& Elsevier]

Abstract: Metabolic and functional studies of the amyloid precursor protein (APP) in platelets have advanced our understanding of Alzheimer''s disease (AD). Here we report that human platelets contain Aβ peptides, process and secrete them constitutively. Platelets generate formerly unkown Aβ-species by differential processing of APP. Release of Aβ peptides were also increased by platelet activation with thrombin, indicating the existence of a regulated exocytotic pathway. We showed that Aβ-levels, Aβ-processing patterns and Aβ-release kinetics were regulated by thrombin. In controls, release of Aβ peptide species (Aβ 1-40/42 and 1-37/38/39/) continued for more than 4h, while thrombin activated cells ceased secretion after 1h at large. Treatment of platelets with prostaglandine 2 slowed this process down. Intracellular Aβ peptide concentrations decreased steadily until no peptides could be detected after 20h (control) or after 4h (thrombin) in cultured platelets. [Copyright &y& Elsevier]

In this paper a hypothesis that some special signals (“key-signals” excito-amino acids, β-amyloid peptides and α-synuclein) are not only involved in information handling by the neuronal circuits, but also trigger out substantial structural and/or functional changes in the Central Nervous System (CNS) is introduced. This forces the neuronal circuits to move from one stable state towards a new state, but in doing so these signals became potentially dangerous. Several mechanisms are put in action to protect neurons and glial cells from these potentially harmful signals. However, in agreement with the Red Queen Theory of Ageing (Agnati et al. in Acta Physiol Scand 145:301–309, ), it is proposed that during ageing these neuroprotective processes become less effective while, in the meantime, a shortage of brain plasticity occurs together with an increased need of plasticity for repairing the wear and tear of the CNS. The paper presents findings supporting the concept that such key-signals in instances such as ageing may favour neurodegenerative processes in an attempt of maximizing neuronal plasticity. [ABSTRACT FROM AUTHOR]

Abstract: The human peptide rhAβ1–42 was effectively produced through a novel expression system and purification procedure. The peptide rhAβ1–42 was successfully expressed in Pichia pastoris, the methylotrophic yeast that has never been used as host. The cDNA encoding full-length hAβ1–42 was synthesized with yeast bias codons and cloned into the pPICZαA vector in frame with the yeast α-factor secretion signal under the transcriptional control of the AOX1 promoter and integrated into the secreting expression organism P. pastoris strain X33. Production of rhAβ1–42 through fermentation was further optimized and scaled up in an 80L fermentor. Secreted rhAβ1–42 was purified using a two-step purification scheme: SP Sepharose ion exchange chromatography and source™ 30 RPC. The purification procedure is fast and efficient and reached a recovery of >93% without loss of activity. The purified rhAβ1–42 was confirmed by Western blotting analysis and N-terminals amino sequencing analysis. This efficient and cost-effective expression system facilitates large-scale production and purification for recombinant rhAβ1–42. [Copyright &y& Elsevier]

Abstract: We examined the potential protective effect of BDNF against β-amyloid-induced neurotoxicity in vitro and in vivo in rats. In neuronal cultures, BDNF had specific and dose–response protective effects on neuronal toxicity induced by Aβ1–42 and Aβ25–35. It completely reversed the toxic action induced by Aβ1–42 and partially that induced by Aβ25–35. These effects involved TrkB receptor activation since they were inhibited by K252a. Catalytic BDNF receptors (TrkB.FL) were localized in vitro in cortical neurons (mRNA and protein). In in vivo experiments, Aβ25–35 was administered into the indusium griseum or the third ventricle and several parameters were measured 7 days later to evaluate potential Aβ25–35/BDNF interactions, i.e. local measurement of BDNF release, number of hippocampal hilar cells expressing SRIH mRNA and assessment of the corpus callosum damage (morphological examination, pyknotic nuclei counting and axon labeling with anti-MBP antibody). We conclude that BDNF possesses neuroprotective properties against toxic effects of Aβ peptides. [Copyright &y& Elsevier]

Abstract: Alzheimer''s disease (AD) is a neurodegenerative condition involving accumulation of the β-amyloid peptide, Aβ1–42. Previously we have shown that amyloid peptides (Aβ1–42, Aβ1–40) have different actions on the three major brain nicotinic acetylcholine receptor (nAChR) subtypes (α7, α4β2 and α3β4). The methionine in position 35 of Aβ (M35) has been shown to be important in the toxicity of Aβ and the 25–35 fragment can mimic some of the actions of the Aβ1–42 peptide. However, the extent to which this mutant and the fragment mimic subtype selectivity is unknown. Two-electrode voltage-clamp electrophysiology has been used to study the actions on α7, α4β2 and α3β4 recombinant nAChRs expressed in Xenopus laevis oocytes of full length Aβ1–42, and Aβ peptide fragments, scrambled peptides, and the Aβ1–42 peptide containing mutations of the methionine in position 35. The Aβ25–35 fragment did not display subunit specificity. Aβ1–42 with an M35C mutation showed similar subtype-specificity to wild-type Aβ1–42. However, Aβ1–42 with an M35V substitution reduced the peak amplitude of ACh-induced currents recorded from α4β2 nAChRs, but did not affect those recorded from α7 or α3β4. These results indicate that the amino acid in position 35 of Aβ1–42 is an important determinant of the subtype-specificity of this peptide on human recombinant α7, α4β2 and α3β4 nAChRs and that the 25–35 fragment fails to mimic all of the actions of the full-length peptide. [Copyright &y& Elsevier]

Alzheimer's disease (AD) is the most common form of brain dementia characterized by the accumulation of β-amyloid peptides (Aβ) and loss of forebrain cholinergic neurons. Aβ accumulation and aggregation are thought to contribute to cholinergic neuronal degeneration, in turn causing learning and memory deficits, but the specific targets that mediate Aβ neurotoxicity remain elusive. Recently, accumulating lines of evidence have demonstrated that Aβ directly modulates the function of neuronal nicotinic acetylcholine receptors (nAChRs), which leads to the new hypothesis that neuronal nAChRs may serve as important targets that mediate Aβ neurotoxicity. In this review, we summarize current studies performed in our laboratory and in others to address the question of how Aβ modulates neuronal nAChRs, especially nAChR subunit function. [ABSTRACT FROM AUTHOR]

Fibril formation by the Alzheimer's β-amyloid (Aβ) peptide in brain tissue is integral to the Alzheimer's disease pathology. Understanding the conformational properties and the mechanisms triggering aggregation of the Aβ peptides, at an atomic level of detail, is of crucial importance for the design of effective therapeutic agents against this disease. In this work, the conformational transitions and dynamic properties of an amyloidogenic peptide fragment (Aβ10-35) were studied by molecular dynamics simulations in systems modeling infinite dilution and the presence of macromolecular crowding agents (CA). The model system consists of the peptide described with an atomistic force field, the CA represented by inert, quasi-hard spheres and a continuum solvent model. This combined model allowed the simulations to be extended to 100 ns each. Simulations were carried out starting from a completely extended structure, a β-strand structure, and four nuclear magnetic resonance structures in dilute aqueous solution. For all structures, two additional simulations were performed that included the inert CA in the solution and occupied approx 30 and 40% of the volume, respectively. For two of the nuclear magnetic resonance structures, additional simulations were carried out with 35% volume fraction of CA to further examine the diffusive behavior of the peptide. The peptide adopted a collapsed coil conformation in all simulations. The results of the simulations in dilute solution showed reasonable qualitative agreement with experimental and other simulation results, whereas the presence of volume excluding agents resulted in some distinct changes in properties (e.g., an increase in the appearance of transient β-structure or decreases in diffusivity with increasing CA concentration). At the same time, internal motion such as order parameter or atomic root mean square fluctuations showed less systematic responses to volume exclusion. [ABSTRACT FROM AUTHOR]

Two-electrode voltage-clamp electrophysiology has been used to study the actions of two amyloid peptides (Aβ1–42, Aβ1–40) on α7, α4β2 and α3β4 recombinant human neuronal nicotinic acetylcholine receptors (nicotinic AChRs), heterologously expressed in Xenopus laevis oocytes.The application of Aβ1–42 or Aβ1–40 (1 pM–100 nM) for 5 s does not directly activate expressed human α7, α4β2 or α3β4 nicotinic AChRs.Aβ1–42 and Aβ1–40 are antagonists of α7 nicotinic AChRs. For example, 10 nM Aβ1–42 and Aβ1–40 both reduced the peak amplitude of currents recorded (3 mM ACh) to 48±5 and 45±10% (respectively) of control currents recorded in the absence of peptide. In both the cases the effect is sustained throughout a 30 min peptide application and is poorly reversible.Aβ1–42 and Aβ1–40 (10 nM) enhance currents recorded in response to ACh (3 mM) from oocytes expressing α4β2 nicotinic AChRs by 195±40 and 195±41% respectively. This effect is transient, reaching a peak after 3 min and returning to control values after a 24 min application of 10 nM Aβ1–42. We observe an enhancement of 157±22% of control ACh-evoked current amplitude in response to 100 nM Aβ1–42 recorded from oocytes expressing α4β2 nicotinic AChRs.Aβ1–42 and Aβ1–40 (10 nM) were without antagonist actions on the responses of α3β4 nicotinic AChRs to ACh (1 nM–3 mM).British Journal of Pharmacology (2005) 146, 964–971. doi:10.1038/sj.bjp.0706403; published online 26 September 2005 [ABSTRACT FROM AUTHOR]

In astroglial cells β-amyloid peptides (βA) induce a reactive phenotype and increase expression of NO synthase. Here we show that treatment of rat brain astrocytes with βA decreases their capacity to accumulate cyclic GMP (cGMP) in response to NO as a result of a decreased expression of soluble guanylyl cyclase (sGC) at the protein and mRNA levels. Potentiation of βA-induced NO formation by interferon-γ did not result in a larger decrease in cGMP formation and inhibition of NO synthase failed to reverse down-regulation of sGC, indicating that NO is not involved. The βA effect was prevented by the protein synthesis inhibitor cycloheximide. Intracerebral βA injection also decreased sGC β1 subunit mRNA levels in adult rat hippocampus and cerebellum. A loss of sGC in reactive astrocytes surrounding β-amyloid plaques could be a mechanism to prevent excess signalling via cGMP at sites of high NO production. [Copyright &y& Elsevier]

Intracellular localization of novel human brain carboxypeptidase B (HBCPB) was investigated in human hippocampus, using immunohistochemistry by confocal laser microscopy and biochemical purification of the homogenate by density gradient ultracentrifugation. The former revealed that the majority of HBCPB was expressed in the endoplasmic reticulum, in which the HBCPB-specific C14-module immunoreactivity was colocalized with GRP78 immunoreactivity, a stress 70 heat shock protein specifically expressed in the endoplasmic reticulum. The latter showed that anti-C14-module immunoreactivity and prepro-HBCPB immunoreactivity were both enriched in the microsome fraction, especially in that of the endoplasmic reticulum-density fraction of normal human hippocampal homogenates from various sources. However, HBCPB prepared from human hippocampus showed exopeptidase activity for synthetic beta-amyloid 1-42 peptide, in which A beta X-42 C-terminus immunoreactivity was decreased in a fashion dose-dependent of the amount of the protease added. These findings indicate that HBCPB, which is expressed in the endoplasmic reticulum of a group of neuronal perikarya, may play an important physiological role in degradation of beta-amyloid 1-42, which is specifically generated in the endoplasmic reticulum of human and rodent neurons and is also regarded as the most pathogenic and aggregatable species among all beta-amyloid peptides. Keywords: Alzheimer's disease, beta-amyloid peptides, endoplasmic reticulum, exopeptidase, human brain carboxypeptidase B, secretase [ABSTRACT FROM AUTHOR]

Over the past few years, molecular biological research has considerably deepened our understanding of the pathophysiological basis of Alzheimer's dementia (AD). Although different genetic origins of the disease have been identified, all of the findings point to a common terminal sequence in familial AD. This consists of an increased production of beta-amyloid peptides from beta-amyloid precursor protein. For the cases of sporadic AD, which far outweigh the number of cases of familial AD, an impaired catabolism of the beta-amyloid peptides may also be pathophysiologically decisive according to the latest findings. Research into the molecular level of AD makes it possible to identify points of attack for rational drug treatment of the disease, while molecular markers of AD are increasingly being used as a part of early and differential neurochemical diagnostics. [ABSTRACT FROM AUTHOR]

Abstract: Alzheimer''s disease (AD) is the most common degenerative disease in the elderly that is a severe threat to human health. In this paper, we report a simple but efficient electrochemical method to probe into the interaction between β-amyloid peptides and bilayer lipid membrane for revealing the toxic mechanism of AD. For this study, a supported bilayer lipid membrane is firstly modified on an electrode surface as the mimic of cell membrane, which can induce significant steric hindrance to prohibit the electrochemical probe [Fe(CN)6]3−/4− approaching the electrode. However, after incubation of the modified electrode with Aβ peptides, a noticeable electrochemical response of [Fe(CN)6]3−/4− can be obtained on the lipid membrane modified electrode, indicating the formation of ion channels in the lipid membrane. Further experimental results show that the peak current of [Fe(CN)6]3−/4− increases along with Aβ peptides concentration and incubation time. Meanwhile, the electrochemical response can be inhibited by (−)-epigallocatechin gallate, an inhibitor of the aggregation of Aβ peptides. Therefore, electrochemical technique might provide a convenient and powerful approach for in vitro studies of protein-misfolding diseases. [Copyright &y& Elsevier]

Keywords: -amyloid peptides; Alzheimer's disease; nanodepletors; scFv; silica nanostructures EN -amyloid peptides Alzheimer's disease nanodepletors scFv silica nanostructures 1 1 1 04/16/20 20200414 NES 200414 In article number 1910475, Elena A. Rozhkova, Chan Beum Park, Joonseok Lee, and co-workers design A nanodepletors constructed from ultralarge mesoporous silica nanostructures and anti-A single chain variable fragments, which effectively capture monomeric A peptides, inhibit A aggregate formation, and attenuate A -mediated cytotoxicity. The A -targeting and clearing capabilities of the A nanodepletors allow drastic reduction of the number of A plaques in vivo, presenting high therapeutic potential towards Alzheimer's disease treatments. -amyloid peptides, Alzheimer's disease, nanodepletors, scFv, silica nanostructures. [Extracted from the article]

Environmental exposure to lead (Pb) is reported to associate with the development of Alzheimer's disease, where the formation of β‐amyloid peptides (APs) of (1‐40), (1‐42), and (25‐35) is considered as the major risk factor. In this context, we aimed at investigating the effect of epigallocatechin gallate (EGCG), a major flavonoid polyphenol available in green tea, in mitigating the individual and combined toxicity generated by Pb and β‐APs in terms of oxidative stress and apoptosis in human neuronal cells. SH‐SY5Y cells were exposed to Pb and β‐APs of (1‐40) and (25‐35) individually and in different combinations in the presence and absence of EGCG. The results indicated that EGCG mitigated both Pb‐ and β‐AP‐induced oxidative stress in scavenging reactive oxygen species and apoptosis by improving the expression levels of Bax and bcl2 and inhibiting annexin V and caspase‐3. Thus, our study shows that EGCG protects SH‐SY5Y cells against the cytotoxicity induced by Pb and β‐APs by decreasing oxidative stress and inhibiting apoptosis. [ABSTRACT FROM AUTHOR]

Disruption of the synaptic plasma membrane (SPM) induced by the aggregation of β-amyloid (Aβ) peptides has been considered as a potential mechanism for the neurotoxicity of Aβ in Alzheimer's disease (AD). However, the molecular basis of such membrane disruption process remains unclear, mainly because of the severe systematic heterogeneity problem that prevents the high-resolution studies. Our previous studies using a two-component phosphatidylcholine (PC)/phosphatidylglycerol (PG) model liposome showed the presence of Aβ-induced membrane disruptions that were either on the pathway or off the pathway of fibril formation. The present study focuses on a more biologically relevant model membrane with compositions that mimic the outer leaflet of SPMs. The main findings are: (1) the two competing membrane disruption effects discovered in PC/PG liposomes and their general peptide-to-lipid-molar-ratio dependence persist in the more complicated membrane models; (2) the SPM-mimic membrane promotes the formation of certain "on-fibrillation-pathway" intermediates with higher α-helical structural population, which lead to more rapid and significant of membrane content leakage; (3) although the "on-fibrillation-pathway" intermediate structures show dependence on membrane compositions, there seems to be a common final fibril structure grown from different liposomes, suggesting that there may be a predominant fibril structure for 40-residue Aβ (i.e. Aβ 40 ) peptides in biologically-relevant membranes. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy., (Copyright © 2018. Published by Elsevier B.V.)

The amyloid-β peptides (Aβ40 and Aβ42) feature prominently in the synaptic dysfunction and neuronal loss associated with Alzheimer's disease (AD). This has been proposed to be due either to interactions between Aβ and cell surface receptors affecting cell signaling, or to the formation of calcium-permeable channels in the membrane that disrupt calcium homeostasis. In both mechanisms the cell membrane is the primary cellular structure with which Aβ interacts. Aβ concentrations in human bodily fluids are very low (pM-nM) rendering studies of the size, composition, cellular binding sites and mechanism of action of the oligomers formed in vivo very challenging. Most studies, therefore, have utilized Aβ oligomers prepared at micromolar peptide concentrations, where Aβ forms oligomeric species which possess easily observable cell toxicity. Such toxicity has not been observed when nM concentrations of peptide are used in the experiment highlighting the importance of employing physiologically relevant peptide concentrations for the results to be of biological significance. In this paper single-molecule microscopy was used to monitor Aβ oligomer formation and diffusion on a supported lipid bilayer at nanomolar peptide concentrations. Aβ monomers, the dominant species in solution, tightly associate with the membrane and are highly mobile whereas trimers and higher-order oligomers are largely immobile. Aβ dimers exist in a mixture of mobile and immobile states. Oligomer growth on the membrane is more rapid for Aβ40 than for the more amyloidogenic Aβ42 but is largely inhibited for a 1:1 Aβ40:Aβ42 mixture. The mechanism underlying these Aβ40-Aβ42 interactions may feature in Alzheimer's pathology., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is a progressive neurodegenerative disease with no clinically accepted treatment to cure or halt its progression. The Food and Drug Administration has approved drugs (e.g., rivastigmine, donepezil, galantamine, and memantine) that at best provide marginal benefits, thus emphasizing the urgent need to explore other molecular entities as future drug candidates for AD. Looking at the wide pharmaceutical applications of heterocyclic compounds and particularly those containing benzofuran and indole ring systems, these molecular frameworks have drawn special attention from medicinal chemists for further evaluation in numerous diseases. This article focuses on the history and recent advances of benzofuran- and indole-based compounds as inhibitors of butyrylcholinesterase, acetylcholinesterase, γ-secretase, β-secretase, tau misfolding, and β-amyloid aggregation., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

β-Amyloid (Aβ) aggregation is causally linked to neuronal pathology in Alzheimer's disease; therefore, several small molecules, antibodies, and peptides have been tested as anti-Aβ agents. We developed two compounds based on the Aβ-binding domain of transthyretin (TTR): a cyclic peptide cG8 and an engineered protein mTTR, and compared them for therapeutically relevant properties. Both mTTR and cG8 inhibit fibrillogenesis of Aβ, with mTTR inhibiting at a lower concentration than cG8. Both inhibit aggregation of amylin but not of α-synuclein. They both bind more Aβ aggregates than monomer, and neither disaggregates preformed fibrils. cG8 retained more of its activity in the presence of biological materials and was more resistant to proteolysis than mTTR. We examined the effect of mTTR or cG8 on Aβ binding to human neurons. When mTTR was co-incubated with Aβ under oligomer-forming conditions, Aβ morphology was drastically changed and Aβ-cell deposition significantly decreased. In contrast, cG8 did not affect morphology but decreased the amount of Aβ deposited. These results provide guidance for further evolution of TTR-mimetic anti-amyloid agents., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Scope: Dietary cholesterol has been shown to play a role in the development of Alzheimer's disease (AD). It is proposed that oxysterol especially 27-hydroxycholesterol (27-OHC) may play a potential role in β-amyloid peptides (Aβ) production and accumulation during AD progression., Methods and Results: To investigate the mechanisms of dietary cholesterol and 27-OHC on learning and memory impairment, male Sprague-Dawley rats are fed with cholesterol diet with or without 27-OHC synthetase inhibitor (anastrozole) injection. The levels of cholesterol, 27-OHC, 24-hydroxycholesterol (24S-OHC), 7α-hydroxycholesterol, and 7β-hydroxycholesterol in plasma are determined; apolipoprotein A (ApoA), apolipoprotein B (ApoB), HDL-cholesterol (HDL-C), and LDL-cholesterol (LDL-C) in plasma or brain; CYP27A1 and CYP7A1 in liver and CYP46A1 and CYP7B1 in brain; cathepsin B, cathepsin D, and acid phosphatase in lysosome; and Aβ1-40 and Aβ1-42 in brain. Results show increased levels of 27-OHC (p < 0.01), LDL-C (p < 0.01), and ApoB (p < 0.01), and decreased level of HDL-C (p < 0.05) in plasma, upregulated CYP27A1 (p < 0.01) and CYP7A1 (p < 0.01) expression in liver, altered lysosomal function, and increased level of Aβ in brain (p < 0.05)., Conclusions: This study indicates that the mechanisms of dietary cholesterol on learning and memory impairment may be involved in cholesterol metabolism and lysosome function with the increase of plasma 27-OHC, thus resulting in Aβ formation and accumulation., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Model phospholipid liposomes have been utilized widely to study the molecular interactions between peptides and membrane bilayers. In the mechanistic study of Alzheimer's disease (AD), disruption of neuronal cell membranes has been considered as a major contribution for the β-amyloid (Aβ) peptides' neurotoxicity. However, clear interpretation of the Aβ-induced cellular membrane at high-resolution level is challenging because of the co-existence of multiple pathways. Here we present the generation of simplified model liposome systems that will facilitate the in-depth mechanistic studies. Protocols for the preparation of model liposomes and the characterization of individual membrane disruption effects will be described.