Amyloid Peptide Aβ Research Articles

Stability of Aβ11-40 Trimers with Parallel and Antiparallel β-Sheet Organizations in a Membrane-Mimicking Environment by Replica Exchange Molecular Dynamics Simulation.

The aggregation of the amyloid (Aβ) peptide of 39-43 amino acids into plaques is observed in the brain of Alzheimer's disease (AD) patients, but the mechanisms underlying the neurotoxicity of Aβ oligomers are still elusive. One suggested initial mechanism is related to the implications of amyloid membrane interactions, but characterization of these assemblies is challenging by experimental means. In this study, we have explored the stability of a trimer of Aβ11-40 in parallel and antiparallel β-sheet structures for the wild-type sequence and its F20W mutant in a dipalmitoylphosphatidylcholine membrane using atomistic replica exchange molecular dynamic simulations. We show that both the U-shape organization and the assembly of β-hairpins are maintained in the membrane and are resistant to the mutation F20W. In contrast the models are destabilized by the F19P mutation. Overall, our results indicate that these two assemblies represent minimal seeds or nuclei for the formation of either amyloid fibrils, a variety of β-barrel pores, or various aggregates for many Aβ sequences in a membrane-mimicking environment.

Traffic-related air pollutants (TRAP-PM) promote neuronal amyloidogenesis through oxidative damage to lipid rafts

Traffic-related air pollution particulate matter (TRAP-PM) is associated with increased risk of Alzheimer Disease (AD). Rodent models respond to nano-sized TRAP-PM (nPM) with increased production of amyloid Aβ peptides, concurrently with oxidative damage. Because pro-Aβ processing of the amyloid precursor protein (APP) occurs on subcellular lipid rafts, we hypothesized that oxidative stress from nPM exposure would alter lipid rafts to favor Aβ production. This hypothesis was tested with J20 mice and N2a cells transgenic for hAPPswe (familial AD). Exposure of J20-APPswe mice to nPM for 150 h caused increased lipid oxidation (4-HNE) and increased the pro-amyloidogenic processing of APP in lipid raft fractions in cerebral cortex; the absence of these changes in cerebellum parallels the AD brain region selectivity for Aβ deposits. In vitro, nPM induced similar oxidative responses in N2a-APPswe cells, with dose-dependent production of NO, oxidative damage (4-HNE, 3NT), and lipid raft alterations of APP with increased Aβ peptides. The antioxidant N-acetyl-cysteine (NAC) attenuated nPM-induced oxidative damage and lipid raft alterations of APP processing. These findings identify neuronal lipid rafts as novel targets of oxidative damage in the pro-amyloidogenic effects of air pollution.

Effects of natural compounds on conformational properties and hairpin formation of amyloid-β42 monomer: docking and molecular dynamics simulation study

The β42 amyloid peptides (Aβ) are identified as a candidate target for Alzheimer’s drugs. Phenolic compounds can bind to the Aβ and inhibit amyloid formation. However, the inhibitory mechanism of phenolic compounds remains unclear. In this study, the molecular dynamic simulation and docking program were used to characterize the molecular details of inhibitory mechanism of the phenolic compounds. Our Results show that the phenolic compounds can bind to hydrophobic region in Aβ42 monomer and alter hydrophobic interactions network at Aβ42 which play a key role in β-sheet formation. The cluster analysis and interactions network analysis were used to probe conformational changes in Aβ42. In most populated clusters of Aβ42-phenolic compounds complexes, the sheet structures were not observed or reduced. It seems that the binding of phenolic compounds can induce larger conformational diversity for amyloid peptide and changes conformational properties of amyloid peptide. The phenolic compounds can deform β-Hairpin structure of Aβ by destabilizing salt bridges E22-K28 and D23-K28 which can alter the conformation of Aβ42 in aqueous solution. These findings are in accordance with experimental results, to some extent give a molecular level interpretation for the inhibitory mechanism of phenolic compounds .In addition, this study may add important new details to the inhibitory mechanism of Alzheimer’s drug.Communicated by Ramaswamy H. Sarma

Development of Kinase Inactive PD173955 Analogues for Reducing Production of Aβ Peptides

Compound 3a, DV2-103, is a kinase inactive analogue of a potent Abl1/Src kinase inhibitor, PD173955, 2. Both compounds, 2 and 3a, are known to reduce production of beta amyloid (Aβ) peptide in cells and animal models. We have now prepared and evaluated a series of PD-173955 analogues, several of which reduced Aβ production potently. This occurs in cells expressing human full-length amyloid precursor protein (APP) and not in cells expressing APP β-C terminal fragment (APP-C99), suggesting that the kinase inactive analogues strongly affect β-secretase (BACE1) cleavage of APP, similarly to Gleevec. A combination of the kinase inactive analogues of PD173955 with a BACE1 inhibitor (BACEi), namely, BACE IV, strongly reduced Aβ levels in cells, as noted previously with Gleevec and analogues. Several potent compounds also penetrated and accumulated in mouse brain in high nanomolar to low micromolar concentration.

The Rho kinase inhibitor fasudil attenuates Aβ1-42-induced apoptosis via the ASK1/JNK signal pathway in primary cultures of hippocampal neurons.

Alzheimer's disease (AD), a chronic, progressive, neurodegenerative disorder, is the most common type of dementia. Beta amyloid (Aβ) peptide aggregation and phosphorylated tau protein accumulation are considered as one of the causes for AD. Our previous studies have demonstrated the neuroprotective effect of the Rho kinase inhibitor fasudil, but the mechanism remains elucidated. In the present study, we examined the effects of fasudil on Aβ1-42 aggregation and apoptosis and identified the intracellular signaling pathways involved in these actions in primary cultures of mouse hippocampal neurons. The results showed that fasudil increased neurite outgrowth (52.84%), decreased Aβ burden (46.65%), Tau phosphorylation (96.84%), and ROCK-II expression. In addition, fasudil reversed Aβ1-42-induced decreased expression of Bcl-2 and increases in caspase-3, cleaved-PARP, phospho-JNK(Thr183/Tyr185), and phospho-ASK1(Ser966). Further, fasudil decreased mitochondrial membrane potential and intracellular calcium overload in the neurons treated with Aβ1-42. These results suggest that inhibition of Rho kinase by fasudil reverses Aβ1-42-induced neuronal apoptosis via the ASK1/JNK signal pathway, calcium ions, and mitochondrial membrane potential. Fasudil could be a drug of choicefor treatment of Alzheimer's disease.

A fresh look into background electrolyte selection for capillary electrophoresis-laser induced fluorescence of peptides and proteins.

This study reports a reinvestigation of background electrolyte selection strategy for performance improvement in CE-LIF of peptides and proteins. This strategy is based on the employment of high concentrations of organic species in BGE possessing high buffer capacity and low specific conductivity in order to ensure excellent stacking preconcentration and separation resolution of fluorescently tagged peptides and proteins. Unlike universal UV detection, the use of such BGEs at high concentrations does not lead to degradation of LIF detection signals at the working excitation and emission wavelengths. At the same buffer ionic strength, pH and electric field, an "inorganic-species-free" BGE (or ISF BGE) for CE-LIF of fluorescently labeled beta amyloid peptide Aβ 1-42 (a model analyte) offered a signal intensity and peak efficiency at least three-times higher than those obtained with a conventional BGE normally used for CE-LIF, while producing an electric current twice lower. Good peak performance (in terms of height and shape) was maintained when using ISF BGEs even with samples prepared in high-conductivity phosphate buffer saline matrix. The advantageous features of such BGEs used at high concentrations over conventional ones in terms of high separation resolution, improved signal intensities, tuning of EOF magnitudes and minimization of protein adsorption on an uncoated fused silica capillary are demonstrated using Alexa-488-labelled trypsin inhibitor. Such BGE selection approach was applied for investigation of separation performance for CE-LIF of ovalbumin labelled with different fluorophores.

Downregulation of Calpain 1 Causes Neurotoxicity and Apoptosis in Primary Neurons Induced by Aβ25-35

Amyloid-peptides (Aβ), which can aggregate oligomers or fibrils into neurons, play a critical role in Alzheimer's disease (AD). Calpain 1 (CAPN1) is one of the Ca2+ regulated proteases, involved in cell death, apoptosis, and motility. As an important signal transduction pathway, it has been reported to be closely related to muscle atrophy, myoblast fusion, diabetes mellitus, and neurode-generative diseases, including Alzheimer's disease. Our previous study investigated the effect of CAPN1 RNAi on neurotoxicity and apoptosis in primary neurons induced by Aβ25-35. The primary neurons were cultured and separated into different groups pretreated with Aβ25-35 (10 μM). Three groups were treated with CAPN1 shRNA, while one group was not. Along with CAPN1 shRNA, P25 (2 μg/mL) and rapamycin (20 ng/mL) were added to the culture. The results showed that CAPN1 RNAi enhanced the formation of autophagosomes in cells, as observed by confocal microscopy. Parallelly, CAPN1 RNAi enhanced the cell viability, as observed by Cell Counting Kit-8 (CCK8) assay, and decreased the apoptotic rate, as observed by flow cytometry. In addition, CAPN1 RNAi decreased the mRNA level of CAPN1 and downregulated the expression levels of CDK5, GSK3β, and p-tau in primary neurons induced by Aβ25-35. All these results indicated the effect of CAPN1 RNAi against Aβ-induced neurotoxicity. Our results suggested that CAPN1 RNAi exhibits a neuroprotective effect on the treatment of AD and provided a pharmacological basis for its clinical treatment.

The role of cholesterol trafficking in BACE‐1 and APP co‐localization

Beta amyloid (Aβ) peptides play a central role in the pathogenesis of Alzheimer's disease (AD). Aβ peptides are derived from the processing of amyloid precursor protein (APP). This protein undergoes extensive processing involving two different pathways that produces several fragments. The α‐secretase pathway produces normal peptides. The pathogenic form of Aβ is derived from a cleavage product generated by beta‐site APP Cleaving Enzyme 1 (BACE‐1) that is then cleaved by γ‐secretase. Although the interaction of APP and BACE‐1 is critical for understanding how AD occurs, it is not clear how or where this occurs. Cholesterol has been identified as a risk factor in AD, and in vitro studies suggest that increased cholesterol levels promote misprocessing of APP. Our lab found that phospholipase A2 inhibitors, which inhibit the formation of membrane tubules, caused the accumulation of cholesterol in the recycling endosome in HeLa cells grown in moderate levels of LDL. APP also co‐localized to this compartment, and immunoblotting showed that the processing of APP and the association of APP fragments with cholesterol‐rich domains was altered by treatment with ONO‐RS‐082, a PLA2 inhibitor. However, BACE‐1 did not co‐localize with APP under these conditions. Surprisingly, in SY‐SH5Y cells co‐localization with BACE‐1 and APP did occur when cells were grown in low levels of LDL, which promote the synthesis of cholesterol. Using immunofluorescence/confocal microscopy and immunoblotting, we are confirming these results and extending this research by investigating the effects of statins or increased LDL on the localization and processing of these proteins.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Mast Cells in Stress, Pain, Blood-Brain Barrier, Neuroinflammation and Alzheimer's Disease.

Mast cell activation plays an important role in stress-mediated disease pathogenesis. Chronic stress cause or exacerbate aging and age-dependent neurodegenerative diseases. The severity of inflammatory diseases is worsened by the stress. Mast cell activation-dependent inflammatory mediators augment stress associated pain and neuroinflammation. Stress is the second most common trigger of headache due to mast cell activation. Alzheimer’s disease (AD) is a progressive irreversible neurodegenerative disease that affects more women than men and woman’s increased susceptibility to chronic stress could increase the risk for AD. Modern life-related stress, social stress, isolation stress, restraint stress, early life stress are associated with an increased level of neurotoxic beta amyloid (Aβ) peptide. Stress increases cognitive dysfunction, generates amyloid precursor protein (APP), hyperphosphorylated tau, neurofibrillary tangles (NFTs), and amyloid plaques (APs) in the brain. Stress-induced Aβ persists for years and generates APs even several years after the stress exposure. Stress activates hypothalamic-pituitary adrenal (HPA) axis and releases corticotropin-releasing hormone (CRH) from hypothalamus and in peripheral system, which increases the formation of Aβ, tau hyperphosphorylation, and blood-brain barrier (BBB) disruption in the brain. Mast cells are implicated in nociception and pain. Mast cells are the source and target of CRH and other neuropeptides that mediate neuroinflammation. Microglia express receptor for CRH that mediate neurodegeneration in AD. However, the exact mechanisms of how stress-mediated mast cell activation contribute to the pathogenesis of AD remains elusive. This mini-review highlights the possible role of stress and mast cell activation in neuroinflammation, BBB, and tight junction disruption and AD pathogenesis.

Suppressive Effects of Beta Amyloid Peptides (1-42) and (25-35) on Kv1.1 Channel Activity

Beta amyloid (Aβ) peptides have long been implicated in Alzheimer's Disease (AD) pathology, linking them to disruption of: Ca2+ homeostasis, synaptic communication, and long-term potentiation (LTP). But the mechanism(s) underlying these effects are still unclear. Because Kv1.1 and related channels are activated during an action potential, regulate depolarization-produced Ca2+ influx, and inhibition of Kv1 channels can be neurotoxic, we speculate that Aβ-suppression of Kv1 channels may be an early event in AD pathogenesis. Using murine Kv1.1 channels expressed in Xenopus oocytes, we have observed the effects of Aβ(1-42) and the “core” peptide (25-35) on both macro- and micro-scopic currents. Both the bath application of Aβ(1-42) and Aβ(25-35) produced 40-50% suppression of macroscopic Kv1.1 current within 30 m. Suppression of Kv1.1 by Aβ(1-42) was partially dependent on intracellular Ca2+ and PP2B, showing only ∼25% reduction when cells were loaded with BAPTA-AM or exposed to the PP2B-inhibitor cyclosporine A (CsA). Patch-clamp results suggested that Aβ-suppression of Kv1.1 involved both PP2B-dephosphorylation and direct protein-protein interaction of Aβ with Kv1.1. Exposure of the intracellular face of Kv1.1 channels in ripped-off oocyte patches to either catalytically-active PP2B, or Aβ(1-42), produced gradual reductions in p(open), followed by the abrupt disappearance of Kv1.1 activity. Using “tip-dip” artificial membrane methods, Aβ(25-35) exposure eliminated Kv1.1 channel activity when applied to the channel intracellular face. Kv1.1 channels have also been incorporated into Black Lipid Membranes (BLMs), and we are currently assessing the effects of exposure of Aβ to both intra- and extra-cellular faces of Kv1.1. Suppression of presynaptic Kv1.1 (and related) channels could lead to enhanced action potentials, thus allowing greater influx of Ca2+ and subsequent increase in glutamate release. Postsynaptically, the increased glutamate release, through activation of AMPA and NMDA receptors, may contribute to excitotoxicity.

Indirect pharmacodynamic models for responses with circadian removal.

Rhythmicity in baseline responses over a 24-h period for an indirect pharmacological effect R(t) can arise from either a periodic time-dependent input rate [Formula: see text] or a periodic time-dependent loss constant [Formula: see text]. If either [Formula: see text] or [Formula: see text] follows some nonstationary biological rhythm (e.g., circadian), then the response R(t) also displays a periodic behavior. Indirect response models assuming time-dependent input rates [Formula: see text] have been utilized to capture drug effects on various physiological responses such as hormone suppression, immune cell trafficking, and gene expression in tissues. This paradigm was extended to consider responses with circadian-controlled loss [Formula: see text] mechanisms. Theoretical equations describing this model are presented and simulations were performed to examine expected response behaviors. The model was able to capture the chronobiology and pharmacodynamics of applicable drug responses, including the uricosuric effects of lesinurad in humans, suppression of the beta amyloid (Aβ) peptide by a gamma-secretase inhibitor in mouse brain, and the modulation of extracellular dopamine by a dopamine transporter inhibitor in rat brain. This type of model has a mechanistic basis and shows utility for capturing drug responses displaying nonstationary baselines controlled by removal mechanism(s).

γ-Secretase Studied by Atomistic Molecular Dynamics Simulations: Global Dynamics, Enzyme Activation, Water Distribution and Lipid Binding.

γ-secretase, an intramembrane-cleaving aspartyl protease is involved in the cleavage of a large number of intramembrane proteins. The most prominent substrate is the amyloid precursor protein, whose proteolytic processing leads to the production of different amyloid Aβ peptides. These peptides are known to form toxic aggregates and may play a key role in Alzheimer's disease (AD). Recently, the three-dimensional structure of γ-secretase has been determined via Cryo-EM, elucidating the spatial geometry of this enzyme complex in different functional states. We have used molecular dynamics (MD) simulations to study the global dynamics and conformational transitions of γ-secretase, as well as the water and lipid distributions in and around the transmembrane domains in atomic detail. Simulations were performed on the full enzyme complex and on the membrane embedded parts alone. The simulations revealed global motions compatible with the experimental enzyme structures and indicated little dependence of the dynamics of the transmembrane domains on the soluble extracellular subunits. During the simulation on the membrane spanning part a transition between an inactive conformation (with catalytic residues far apart) toward a putatively active form (with catalytic residues in close proximity) has been observed. This conformational change is associated with a distinct rearrangement of transmembrane helices, a global compaction of the catalytically active presenilin subunit a change in the water structure near the active site and a rigidification of the protein fold. The observed conformational rearrangement allows the interpretation of the effect of several mutations on the activity of γ-secretase. A number of long-lived lipid binding sites could be identified on the membrane spanning surface of γ-secretase which may coincide with association regions of hydrophobic membrane helices to form putative substrate binding exosites.

Membrane domain modulation of Aβ1-42 oligomer interactions with supported lipid bilayers: an atomic force microscopy investigation.

Alzheimer's disease is a devastating pathology affecting an increasing number of individuals following the general rise in life expectancy. Amyloid peptide Aβ1-42 has been identified as one of the main culprits of the disease. The peptide has been shown to have major effects on lipid membranes, including membrane fragmentation. The membrane composition has been identified as a factor that plays a pivotal role in regulating peptide/membrane interactions and several results suggest that lipid domains, or rafts, can promote peptide-induced membrane damage. In this work, we examined the effects of lipid segregation on the membrane-perturbing ability of Aβ1-42 and an oligomeric mutant (G37C), a peptide that shares common features with the suspected toxic intermediates involved in the neurodegeneration process. Atomic force microscopy (AFM) was used to determine the impact of these peptides on the supported lipid bilayers of various compositions. In 1,2-dioleoyl-sn-glycero-3-phosphocholine/1,2-dipalmitoyl-sn-glycero-3-phosphocholine/cholesterol (DOPC/DPPC/cholesterol) and DOPC/sphingomyelin/cholesterol ternary mixtures, two systems exhibiting liquid-liquid phase separations, it was shown that Aβ1-42 and G37C exclusively aggregated on liquid-disordered-phase domains, creating large deposits and even causing membrane fragmentation for the latter composition. Cholesterol and ganglioside GM1, the two most documented lipids in the context of Alzheimer's disease, are also considered to play a crucial role in promoting detrimental interactions with amyloid peptides. We show that, in model 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membranes, the presence of either cholesterol or GM1 in a proportion of 10 mol%, a content supposed to lead to domain formation, favoured the association of both Aβ1-42 and G37C, leading to a harmful membrane fragmentation. The AFM results established that the presence of domains favoured membrane perturbations induced by the amyloid peptides. It is proposed that lipid packing defects at the domain interface could act as adsorption and nucleation sites for the amyloid peptides. The more extensive bilayer perturbations induced by G37C compared to Aβ1-42 supported this hypothesis, indicating that oligomers that cannot mature to the fibril state can present considerable toxicity.

Regulation mechanism of nanobiointerfaces in amyloid peptide assembly and aggregation structures

In this review, we try to reflect the recent progress on assembly structures, aggregation behaviors and the cytotoxicity of beta amyloid (Aβ) peptides, which are closely related to the pathogenesis of Alzheimer’s disease (AD). Based on these studies, the progress on the regulation mechanism of various nanobiointerfaces in amyloid peptide assembly and aggregation structures is reviewed and discussed, especially the interaction patterns and mechanisms between Aβ peptides and nanomaterials on the molecule level. These progresses could help to deepen the insights of the complex interactions between amyloid peptides and modulators. To study Aβ peptide conformation, assembly mechanism and aggregation process, developing new efficient nanobiointerface modulators is of great importance for the therapeutic strategy evolution.

Magnetite Fe3O4 Has no Intrinsic Peroxidase Activity, and Is Probably not Involved in Alzheimer's Oxidative Stress

AbstractDespite stated in some highly cited articles, magnetite is devoided of peroxidase activity. In fact, this very stable mixed valence FeIIO⋅FeIII2O3 complex is not catalytically competent to oxidize standard peroxidase substrates, especially at the biologically relevant pH value of 7.4. In addition, magnetite whose deleterious redox activity has been suspected in Alzheimer's disease brain damages, does not significantly interact with amyloid peptide Aβ in vitro, and is not able to induce, either in the presence or absence of Aβ, the reductive activation of dioxygen, the first step of an oxidative stress. In fact, this highly insoluble mineral iron derivative is probably not involved in the oxidative damage of brain neurons of patients with AD.

Magnetite Fe3 O4 Has no Intrinsic Peroxidase Activity, and Is Probably not Involved in Alzheimer's Oxidative Stress.

Despite stated in some highly cited articles, magnetite is devoided of peroxidase activity. In fact, this very stable mixed valence FeII O⋅FeIII2 O3 complex is not catalytically competent to oxidize standard peroxidase substrates, especially at the biologically relevant pH value of 7.4. In addition, magnetite whose deleterious redox activity has been suspected in Alzheimer's disease brain damages, does not significantly interact with amyloid peptide Aβ in vitro, and is not able to induce, either in the presence or absence of Aβ, the reductive activation of dioxygen, the first step of an oxidative stress. In fact, this highly insoluble mineral iron derivative is probably not involved in the oxidative damage of brain neurons of patients with AD.

GM1 locates to mature amyloid structures implicating a prominent role for glycolipid-protein interactions in Alzheimer pathology

While the molecular mechanisms underlying Alzheimer's disease (AD) remain largely unknown, abnormal accumulation and deposition of beta amyloid (Aβ) peptides into plaques has been proposed as a critical pathological process driving disease progression. Over the last years, neuronal lipid species have been implicated in biological mechanisms underlying amyloid plaque pathology. While these processes comprise genetic features along with lipid signaling as well as direct chemical interaction of lipid species with Aβ mono- and oligomers, more efforts are needed to spatially delineate the exact lipid-Aβ plaque interactions in the brain. Chemical imaging using mass spectrometry (MS) allows to probe the spatial distribution of lipids and peptides in complex biological tissues comprehensively and at high molecular specificity. As different imaging mass spectrometry (IMS) modalities provide comprehensive molecular and spatial information, we here describe a multimodal ToF-SIMS- and MALDI-based IMS strategy for probing lipid and Aβ peptide changes in a transgenic mouse model of AD (tgAPPArcSwe). Both techniques identified a general AD-associated depletion of cortical sulfatides, while multimodal MALDI IMS revealed plaque specific lipid as well as Aβ peptide isoforms. In addition, MALDI IMS analysis revealed chemical features associated with morphological heterogeneity of individual Aβ deposits. Here, an altered GM1 to GM2/GM3 ganglioside metabolism was observed in the diffuse periphery of plaques but not in the core region. This was accompanied by an enrichment of Aβ1–40arc peptide at the core of these deposits. Finally, a localization of arachidonic acid (AA) conjugated phosphatidylinositols (PI) and their corresponding degradation product, lyso-phosphatidylinositols (LPI) to the periphery of Aβ plaques was observed, indicating site specific macrophage activation and ganglioside processing.

Inflammation in Alzheimer’s disease: A friend or foe?

Background: There is a dearth of precise information for molecular and cellular mechanisms responsible for the development of Alzheimer’s disease (AD). However, convincing data from clinical research and basic molecular biology have shown that inflammation of the brain is an integral part of AD. In this review, the role of inflammation in AD will be highlighted.
 Methods: Articles from credible scientific databases, such as ScienceDirect, Scopus, PubMed, Google Scholar and Mendeley, were searched and retrieved using keywords ‘inflammation’, ‘Alzheimer’s disease’, ‘tau’, and ‘beta amyloid’.
 Results: At present, there is no local inflammatory-inciting factor that is closely associated with AD, although it has been proposed that inflammation could be induced by pathologic hallmarks of AD, such as beta amyloid (Aβ) peptide plagues and neurofibrillary tangles (NFTs), or fragments of degenerated neurons. However, it is still unclear whether inflammation leads to the development of AD or if the pathological hallmarks of AD induce inflammation.
 Conclusion: Inflammation is, indeed, an integral part of AD. Further studies on inflammatory-targeted therapies for AD are highly recommended.

Alzheimer's disease: amyloid-based pathogenesis and potential therapies.

Alzheimer’s disease is one of the most severe neurodegenerative diseases among elderly people. Different pathogenic factors for Alzheimer’s disease have been posited and studied in recent decades, but no effective treatment has been found, necessitating further studies. In this Viewpoint article, we assess studies on the mechanisms underlying the accumulation of amyloid (Aβ) peptide and the formation of Aβ oligomers because their accumulation in amyloid plaques in brain tissue has become a well-studied hallmark of Alzheimer’s disease. We focus on the production of Aβ and its impact on the function of synapses and neural circuits, and also discuss the clinical prospects for amyloid-targeted therapies.

A discrete mathematical model for the aggregation of β-Amyloid.

Dementia associated with the Alzheimer's disease is thought to be correlated with the conversion of the β − Amyloid (Aβ) peptides from soluble monomers to aggregated oligomers and insoluble fibrils. We present a discrete-time mathematical model for the aggregation of Aβ monomers into oligomers using concepts from chemical kinetics and population dynamics. Conditions for the stability and instability of the equilibria of the model are established. A formula for the number of monomers that is required for producing oligomers is also given. This may provide compound designers a mechanism to inhibit the Aβ aggregation.