Alzheimer's Beta-amyloid Research Articles

The relationships between neuroinflammation, beta-amyloid and tau deposition in Alzheimer\u2019s disease: a longitudinal PET study

BackgroundThe aim of this longitudinal study was to assess with positron emission tomography (PET) the relationship between levels of inflammation and the loads of aggregated β-amyloid and tau at baseline and again after 2 years in prodromal Alzheimer's disease.MethodsForty-three subjects with mild cognitive impairment (MCI) had serial 11C-PK11195 PET over 2 years to measure inflammation changes, and 11C-PiB PET to determine β-amyloid fibril load; 22 also had serial 18F-Flortaucipir PET to determine tau tangle load. Cortical surface statistical mapping was used to localise areas showing significant changes in tracer binding over time and to interrogate correlations between tracer binding of the tracers at baseline and after 2 years.ResultsThose MCI subjects with high 11C-PiB uptake at baseline (classified as prodromal Alzheimer’s disease) had raised inflammation levels which significantly declined across cortical regions over 2 years although their β-amyloid levels continued to rise. Those MCI cases who had low/normal 11C-PiB uptake at baseline but their levels then rose over 2 years were classified as prodromal AD with low Thal phase 1-2 amyloid deposition at baseline. They showed levels of cortical inflammation which correlated with their rising β-amyloid load. Those MCI cases with baseline low 11C-PiB uptake that remained stable were classified as non-AD, and they showed no correlated inflammation levels. Finally, MCI cases which showed both high 11C-PiB and 18F-Flortaucipir uptake at baseline (MCI due to AD) showed a further rise in their tau tangle load over 2 years with a correlated rise in levels of inflammation.ConclusionsOur baseline and 2-year imaging findings are compatible with a biphasic trajectory of inflammation in Alzheimer’s disease: MCI cases with low baseline but subsequently rising β-amyloid load show correlated levels of microglial activation which then later decline when the β-amyloid load approaches AD levels. Later, as tau tangles form in β-amyloid positive MCI cases with prodromal AD, the rising tau load is associated with higher levels of inflammation.

Transgenic Overexpression of the Disordered Prion Protein N1 Fragment in Mice Does Not Protect Against Neurodegenerative Diseases Due to Impaired ER Translocation

The structurally disordered N-terminal half of the prion protein (PrPC) is constitutively released into the extracellular space by an endogenous proteolytic cleavage event. Once liberated, this N1 fragment acts neuroprotective in ischemic conditions and interferes with toxic peptides associated with neurodegenerative diseases, such as amyloid-beta (Aβ) in Alzheimer’s disease. Since analog protective effects of N1 in prion diseases, such as Creutzfeldt-Jakob disease, have not been studied, and given that the protease releasing N1 has not been identified to date, we have generated and characterized transgenic mice overexpressing N1 (TgN1). Upon intracerebral inoculation of TgN1 mice with prions, no protective effects were observed at the levels of survival, clinical course, neuropathological, or molecular assessment. Likewise, primary neurons of these mice did not show protection against Aβ toxicity. Our biochemical and morphological analyses revealed that this lack of protective effects is seemingly due to an impaired ER translocation of the disordered N1 resulting in its cytosolic retention with an uncleaved signal peptide. Thus, TgN1 mice represent the first animal model to prove the inefficient ER translocation of intrinsically disordered domains (IDD). In contrast to earlier studies, our data challenge roles of cytoplasmic N1 as a cell penetrating peptide or as a potent “anti-prion” agent. Lastly, our study highlights both the importance of structured domains in the nascent chain for proteins to be translocated and aspects to be considered when devising novel N1-based therapeutic approaches against neurodegenerative diseases.

Taurodeoxycholate, a master key locking both priming and activation signal necessary for inflammasomal activation of microglia by Amyloid beta in Alzheimer’s diseases

Abstract Alzheimer’s disease (AD) is an inflammatory neurodegenerative condition characterized by deposition of amyloid beta (Abeta) in the brain and origins dementia. Neuronal apoptosis following neuroinflammation by Abeta impairs cognition and memory. In this study we focused on Taurodeoxyxcholate (TDCA) is an active bile acid derivative with potent anti-inflammatory function. In 5× Familial Alzheimer’s disease (5xFAD) mice model, chronic administration of TDCA in 5xFAD mice improved learning and memory in different memory test compared with PBS group. TDCA treatment significantly decreased neuronal apoptosis, load of Abeta plaques, the number of activated GFAP+ astrocytes and Iba-1+ microglia in different brain region of 5xFAD mice. CD11bhiGr1intF4/80+ myeloid cells in brain and spleen increased significantly in TDCA-treated group compared to PBS-treated group when brain single cell were immune-stained. In vitro, TDCA increased phagocytosis of Abeta. TDCA suppressed NLRP3-ASC oligomerization and production of mature IL-1β/IL-18 in Microglia by Abeta. TDCA inhibited Ca++ influx incurred by ATP or BzATP (P2X7 agonists). Compared with wild type, Ca++ influx of macrophages from TGR5 KO mice was like that of P2X7 KO mice in response to BzATP, suggesting that TDCA might play role as an inverse agonist for TGR5 complexed with P2X7. TDCA activates adenylate cyclase and cAMP inhibit priming phase of inflammasomal activation and oligomerization of NLRP3-ASC complex, suggesting that TDCA suppresses both priming and activation phase of NLRP3 inflammasome. TDCA and its novel chemical derivatives could be better choice in ameliorating broad spectrum of neuroinflammation to improve cognition and memory in AD patients.

Exposure of ultrafine particulate matter causes glutathione redox imbalance in the hippocampus: A neurometabolic susceptibility to Alzheimer's pathology

Particulate matter (PM) exposure is related to an increased risk of sporadic Alzheimer's disease (AD), the pathogenesis of which is explained by chronic neurometabolic disturbance. Therefore, PM-induced alterations in neurometabolism might herald AD. We aimed to identify brain region-specific changes in metabolic pathways associated with ultrafine particle (UFP) exposure and to determine whether such metabolic alterations are linked to susceptibility to AD. We constructed UFP exposure chambers and generated UFP by the pyrolysis method, which produces no toxic oxidized by-products of combustion, such as NOx and CO. Twenty male C57BL6 mice (11–12 months old) were exposed either to UFP or room air in the chambers for 3 weeks. One week following completion of UFP exposure, regional brain tissues, including the olfactory bulb, cortex, hippocampus, and cerebellum, were obtained and analyzed by metabolomics based on GC–MS and LC-MS, western blot analysis, and immunohistochemistry. Our results demonstrated that the metabolomic phenotype was distinct within the 4 different anatomical regions following UFP exposure. The highest level of metabolic change was identified in the hippocampus, a vulnerable region involved in AD pathogenesis. In this region, one of the key changes was perturbed redox homeostasis via alterations in the methionine-glutathione pathway. UFP exposure also induced oxidative stress and neuroinflammation, and importantly, increased Alzheimer's beta-amyloid levels in the hippocampus. These results suggest that inhaled UFP-induced perturbation in hippocampal redox homeostasis has a role in the pathogenesis of AD. Therefore, chronic exposure to UFP should be regarded as a cumulative environmental risk factor for sporadic AD.

Cu2+ Effects on Beta-Amyloid Oligomerisation Monitored by the Fluorescence of Intrinsic Tyrosine.

A non-invasive intrinsic fluorescence sensing of the early stages of Alzheimer's beta amyloid peptide aggregation in the presence of copper ions is reported. By using time-resolved fluorescence techniques the formation of beta amyloid-copper complexes and the accelerated peptide aggregation are demonstrated. The shifts in the emission spectral peaks indicate that the peptides exhibit different aggregation pathways than in the absence of copper.

Pathological Influences on Clinical Heterogeneity in Lewy Body Diseases.

PD, PD with dementia, and dementia with Lewy bodies are clinical syndromes characterized by the neuropathological accumulation of alpha-synuclein in the CNS that represent a clinicopathological spectrum known as Lewy body disorders. These clinical entities have marked heterogeneity of motor and nonmotor symptoms with highly variable disease progression. The biological basis for this clinical heterogeneity remains poorly understood. Previous attempts to subtype patients within the spectrum of Lewy body disorders have centered on clinical features, but converging evidence from studies of neuropathology and ante mortem biomarkers, including CSF, neuroimaging, and genetic studies, suggest that Alzheimer's disease beta-amyloid and tau copathology strongly influence clinical heterogeneity and prognosis in Lewy body disorders. Here, we review previous clinical biomarker and autopsy studies of Lewy body disorders and propose that Alzheimer's disease copathology is one of several likely pathological contributors to clinical heterogeneity of Lewy body disorders, and that such pathology can be assessed in vivo. Future work integrating harmonized assessments and genetics in PD, PD with dementia, and dementia with Lewy bodies patients followed to autopsy will be critical to further refine the classification of Lewy body disorders into biologically distinct endophenotypes. This approach will help facilitate clinical trial design for both symptomatic and disease-modifying therapies to target more homogenous subsets of Lewy body disorders patients with similar prognosis and underlying biology. © 2019 International Parkinson and Movement Disorder Society.

Passive Immunotherapies Targeting Amyloid Beta and Tau Oligomers in Alzheimer's Disease.

Alzheimer's disease (AD) is historically difficult to treat, in part because of the inaccessible nature of brain pathology. Amyloid beta and tau proteins drive pathology by forming toxic oligomers that eventually deposit as insoluble amyloid plaques and neurofibrillary tangles. Recent clinical studies suggest that effective drugs must specifically target oligomers, not native monomers or insoluble fibrils. Passive immunotherapy is a promising pharmaceutical strategy used to specifically target these oligomers in situ. Using the specificity of antibodies coupled with the natural power of the body's immune response, this treatment provides an opportunity for safe clearance of pathogenic protein species from the brain. Passive immunotherapies against amyloid beta and tau oligomers have progressed to clinical trials, with many currently in progress. Biochemical studies of antibody-oligomer complexes have helped identify previously unknown toxic epitopes, thus providing knowledge to the AD field as a whole. This mini-review focuses on the efforts to develop passive immunotherapy treatments for AD and discusses the knowledge gained from recent failures and clinical trials in progress.

Correlation between oligomerizaton of amyloid beta in plasma and other Alzheimer's disease biomarkers

Correlation between oligomerizaton of amyloid beta in plasma and other Alzheimer's disease biomarkers

Identification of a BACE1 Binding Peptide Candidate for the Prevention of Amyloid Beta in Alzheimer’s Disease

Amyloid plaques, generated during the progression of Alzheimer's disease, cause major neurological deficits due to substantial cell toxicity and death. The underlying cause of plaque generation stems from cleavage of the amyloid precursor protein (APP) by β-secretase (BACE1). A resulting amyloid-β (Aβ) fragment forms aggregates to produce the main constituent of a plaque. Phage display and biopanning techniques were used to identify a 12-mer peptide that had a natural affinity for the BACE1 enzyme. The peptide was translated from phage DNA and synthetically produced. The peptide, at concentrations of 1nM, 10nM and 100nM, was used to confirm binding by direct assay. Non-specific binding to BACE2, renin and cathepsin D was tested by direct binding assay. A BACE1 activity assay was used to determine the peptide effect on cleavage of an APP substrate. Treatment of SY5Y cells with the peptide was used to determine toxicity and prevention of Aβ40 and Aβ42 production. After identification and synthetic production, the peptide exhibited a strong affinity for BACE1 at nanomolar concentrations in the direct assay. In case of non-specific binding to homologous BACE2, renin and cathepsin D, the peptide showed minor binding but was nullified when in solution with BACE1. The peptide addition to a BACE1 activity assay was able to significantly reduce the amount of substrate cleavage. SY5Y cells, when treated with the peptide, did not show any detrimental morphological changes while being able to reduce the production of natural Aβ40 and Aβ42. Even under stressed conditions (H2O2 treatment) where the Aβ production was higher, the peptide was still able to significantly reduce the effect of BACE1 while not effecting cell viability. The identified peptide exhibited strong binding to BACE1 in vitro and was able to reduce production of Aβ, suggesting a favourable BACE1 inhibitor for future refining and characterisation.

Importance of time-ordered non-uniform sampling of multi-dimensional NMR spectra of Aβ1-42 peptide under aggregating conditions.

Although the order of the time steps in which the non-uniform sampling (NUS) schedule is implemented when acquiring multi-dimensional NMR spectra is of limited importance when sample conditions remain unchanged over the course of the experiment, it is shown to have major impact when samples are unstable. In the latter case, time-ordering of the NUS data points by the normalized radial length yields a reduction of sampling artifacts, regardless of the spectral reconstruction algorithm. The disadvantage of time-ordered NUS sampling is that halting the experiment prior to its completion will result in lower spectral resolution, rather than a sparser data matrix. Alternatively, digitally correcting for sample decay prior to reconstruction of randomly ordered NUS data points can mitigate reconstruction artifacts, at the cost of somewhat lower sensitivity. Application of these sampling schemes to the Alzheimer's amyloid beta (Aβ1-42) peptide at an elevated concentration, low temperature, and 3 kbar of pressure, where approximately 75% of the peptide reverts to an NMR-invisible state during the collection of a 3D 15N-separated NOESY spectrum, highlights the improvement in artifact suppression and reveals weak medium-range NOE contacts in several regions, including the C-terminal region of the peptide.

What Is the "Relevant" Amyloid β42 Concentration?

Alzheimer's amyloid beta can perform a wide variety of actions that are highly concentration dependent. This viewpoint aims to provide a framework for basic considerations on what might be considered brain-relevant concentrations of the peptide. Some implications for the therapeutic implementation of the recently emerged oligomer-to-fibril strategy are discussed.

The Role of Structural Polymorphism in Driving the Mechanical Performance of the Alzheimer's Beta Amyloid Fibrils.

Alzheimer's Disease (AD) is related with the abnormal aggregation of amyloid β-peptides Aβ1−40 and Aβ1−42, the latter having a polymorphic character which gives rise to U- or S-shaped fibrils. Elucidating the role played by the nanoscale-material architecture on the amyloid fibril stability is a crucial breakthrough to better understand the pathological nature of amyloid structures and to support the rational design of bio-inspired materials. The computational study here presented highlights the superior mechanical behavior of the S-architecture, characterized by a Young's modulus markedly higher than the U-shaped architecture. The S-architecture showed a higher mechanical resistance to the enforced deformation along the fibril axis, consequence of a better interchain hydrogen bonds' distribution. In conclusion, this study, focusing the attention on the pivotal multiscale relationship between molecular phenomena and material properties, suggests the S-shaped Aβ1−42 species as a target of election in computational screen/design/optimization of effective aggregation modulators.

Cubeben induces autophagy via PI3K-AKT-mTOR pathway to protect primary neurons against amyloid beta in Alzheimer's disease.

Autophagy is a lysosomal degradative process by which it recycles cytosolic components and degrades protein aggregates inside cells. Here, we identified cubeben as an inducer of autophagy in primary neuronal cells. Autophagy induction was accompanied the upregulation of autophagic proteins like Beclin, ATG5, ATG12 and lipidation of LC3-II in primary neuronal cells. Cubeben induces autophagy by the inhibition of PI3K-AKT pathway in a dose dependent manner. Constitutive active P110α abrogates cubeben induced autophagic induction in primary neuronal cells. Furthermore, cubeben inhibits amyloid beta induced toxicity in primary neuronal cells. Thus our data suggests that cubeben as a potential anti-Alzheimer therapeutic lead.

Presence of UCP2 and Amylin in human Alzheimer's disease brains

Although the role of amyloid beta in Alzheimer's disease has been studied for decades, the link between amyloid beta and amylin is fairly new. Amylin is a protein that is co‐secreted from pancreatic beta cells alongside insulin and has been shown to cross the blood‐brain barrier and impact the formation of amyloid plaques. The normal function of amylin in the brain is directly correlated to metabolism because amylin is considered a satiety protein. The output involved in the metabolic process involves oxidative phosphorylation and includes a set of proteins known as uncoupling proteins (UCPs), which are proteins that directly impact oxidative phosphorylation. Traditionally, UCPs are known to impact the ATP levels that occur in oxidative phosphorylation. However, recently it has been postulated that UCPs may have an additional role that involves cell signaling. In fact, UCP2 has been shown to be present in pancreatic beta cells and to have diminished protein levels in Alzheimer's disease brains. The experiments conducted in this study analyzed the relationship between UCP2 and amylin. Specifically, immunohistochemistry experiments that examine both the presence of amylin and UCP2 in Alzheimer's disease brains were conducted. Western Blot analysis experiments were also conducted to compare the findings from the immunohistochemistry experiments. The initial studies suggest that the role of UCP2 may influence the role of amylin or the role of amylin may influence the role of UCP2.Support or Funding InformationNational Science Foundation Research Initiation Award #24430This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer\u2019s disease

In Alzheimer’s disease (AD), a single-nucleotide polymorphism in the gene encoding brain-derived neurotrophic factor (BDNFVal66Met) is associated with worse impact of primary AD pathology (beta-amyloid, Aβ) on neurodegeneration and cognitive decline, rendering BDNFVal66Met an important modulating factor of cognitive impairment in AD. However, the effect of BDNFVal66Met on functional networks that may underlie cognitive impairment in AD is poorly understood. Using a cross-validation approach, we first explored in subjects with autosomal dominant AD (ADAD) from the Dominantly Inherited Alzheimer Network (DIAN) the effect of BDNFVal66Met on resting-state fMRI assessed functional networks. In seed-based connectivity analysis of six major large-scale networks, we found a stronger decrease of hippocampus (seed) to medial-frontal connectivity in the BDNFVal66Met carriers compared to BDNFVal homozogytes. BDNFVal66Met was not associated with connectivity in any other networks. Next, we tested whether the finding of more pronounced decrease in hippocampal-medial-frontal connectivity in BDNFVal66Met could be also found in elderly subjects with sporadically occurring Aβ, including a group with subjective cognitive decline (N = 149, FACEHBI study) and a group ranging from preclinical to AD dementia (N = 114, DELCODE study). In both of these independently recruited groups, BDNFVal66Met was associated with a stronger effect of more abnormal Aβ-levels (assessed by biofluid-assay or amyloid-PET) on hippocampal-medial-frontal connectivity decreases, controlled for hippocampus volume and other confounds. Lower hippocampal-medial-frontal connectivity was associated with lower global cognitive performance in the DIAN and DELCODE studies. Together these results suggest that BDNFVal66Met is selectively associated with a higher vulnerability of hippocampus-frontal connectivity to primary AD pathology, resulting in greater AD-related cognitive impairment.

Protein-Encoding RNA-to-RNA Information Transfer in Mammalian Cells: Principles of RNA-Dependent mRNA Amplification

The transfer of protein-encoding genetic information from DNA to RNA to protein, a process formalized as the "Central Dogma of Molecular Biology", has undergone a significant evolution since its inception. It was amended to account for the information flow from RNA to DNA, the reverse transcription, and for the information transfer from RNA to RNA, the RNA-dependent RNA synthesis. These processes, both potentially leading to protein production, were initially described only in viral systems, and although RNA-dependent RNA polymerase activity was shown to be present, and RNA-dependent RNA synthesis found to occur, in mammalian cells, its function was presumed to be restricted to regulatory. However, recent results, obtained with multiple mRNA species in several mammalian systems, strongly indicate the occurrence of protein-encoding RNA to RNA information transfer in mammalian cells. It can result in the rapid production of the extraordinary quantities of specific proteins as was seen in cases of terminal cellular differentiation and during cellular deposition of extracellular matrix molecules. A malfunction of this process may be involved in pathologies associated either with the deficiency of a protein normally produced by this mechanism or with the abnormal abundance of a protein or of its C-terminal fragment. It seems to be responsible for some types of familial thalassemia and may underlie the overproduction of beta amyloid in sporadic Alzheimer's disease. The aim of the present article is to systematize the current knowledge and understanding of this pathway. The outlined framework introduces unexpected features of the mRNA amplification such as its ability to generate polypeptides non-contiguously encoded in the genome, its second Tier, a physiologically occurring intracellular polymerase chain reaction, iPCR, a "Two-Tier Paradox" and RNA "Dark Matter". RNA-dependent mRNA amplification represents a new mode of genomic protein-encoding information transfer in mammalian cells. Its potential physiological impact is substantial, it appears relevant to multiple pathologies and its understanding opens new venues of therapeutic interference, it suggests powerful novel bioengineering approaches and its further rigorous investigations are highly warranted.

Cerebrospinal fluid biomarkers in idiopathic normal pressure hydrocephalus

The diagnosis of idiopathic normal pressure hydrocephalus (iNPH) presents difficulties because of the same symptomatology in neurodegenerative diseases. The data of brain magnetic resonance imaging (MRI) and invasive techniques (tap test, external lumbar drainage, and infusion test) not always allow an accurate diagnosis of iNPH, especially when patients have comorbidity. This increases the role of cerebrospinal fluid (CSF) biomarkers in the differential diagnosis of iNPH and comorbidities at early stages. Objective : to analyze the data available in the literature on current ideas about CSF biomarkers and their role in the differential diagnosis of iNPH and neurodegenerative diseases in the brain. Material and methods . The literature data were sought in the internet resource PubMed by the keywords: normal pressure hydrocephalus, CSF biomarkers, neurodegeneration, Alzheimer's disease (AD), beta-amyloid protein, and tau protein. Fifty-three communications published in 1965 to 2018 were reviewed. Results and discussion . In accordance with the data available in the literature, the most informative CSF biomarkers for the differential diagnosis of iNPH are beta-amyloid (Aβ) proteins β42, Aβ-40, Aβ -38, sAPPβ, sAPPβ, and t-tau and p-tau. The study of CSF biomarkers opens up prospects not only for the detection of iNPH, but also for its differential diagnosis with neurodegenerative diseases, primarily with AD. The detection of biomarkers can be used in addition to brain MRI and invasive techniques to improve the accuracy of diagnosis, as well as to predict the efficiency of bypass surgery, but provided that they are comprehensively assessed. Conclusion . The analysis of the levels of specific CSF proteins holds promise for the differential diagnosis of iNPH.

Aquaporin-4 Water Channel in the Brain and Its Implication for Health and Disease.

Aquaporin-4 (AQP4) is a water channel expressed on astrocytic endfeet in the brain. The role of AQP4 has been studied in health and in a range of pathological conditions. Interest in AQP4 has increased since it was discovered to be the target antigen in the inflammatory autoimmune disease neuromyelitis optica spectrum disorder (NMOSD). Emerging data suggest that AQP4 may also be implicated in the glymphatic system and may be involved in the clearance of beta-amyloid in Alzheimer’s disease (AD). In this review, we will describe the role of AQP4 in the adult and developing brain as well as its implication for disease.

Clusterin accumulates in synapses in Alzheimer's disease and is increased in apolipoprotein E4 carriers.

One of the major challenges in developing effective therapeutic strategies for Alzheimer's disease is understanding how genetic risk factors contribute to neurodegeneration. The apolipoprotein epsilon 4 isoform (APOE4) and variants in the Clusterin (CLU) gene (also known as apolipoprotein J) are associated with increased risk of developing Alzheimer's. Our previous work demonstrated that APOE4 exacerbates synapse degeneration and synaptic accumulation of toxic oligomeric amyloid beta in human Alzheimer's and mouse models of disease. Here, we observe clusterin in synapses in human Alzheimer's disease brain. The percentage of synapses containing clusterin is higher in APOE4 carriers than APOE3 carriers. Furthermore, we observe oligomeric amyloid beta accumulation within synapses containing clusterin which is also higher in APOE4 carriers. These data link two genetic risk factors with synapse degeneration in Alzheimer's and support a potential role for clusterin working with APOE in causing synaptic damage.

Molecular docking, molecular dynamics simulations and QSAR studies on some of 2-arylethenylquinoline derivatives for inhibition of Alzheimer's amyloid-beta aggregation: Insight into mechanism of interactions and parameters for design of new inhibitors

Alzheimer's disease is characterized using amyloid-beta (Aβ) aggregation. The present work was carried out to extend and design a novel quantitative structure–activity relationship (QSAR) model on inhibition efficiency of some of new 2-arylethenylquinoline derivatives against the Aβ1-42 peptide aggregation. The QSAR study, molecular docking and molecular dynamics (MD) simulations were performed to explore the influence of the structural features and investigate the molecular mechanism of ligands interactions with the Aβ1-42 peptide. Using molecular docking was understood that electron donating groups with small size help to create interactions between the ligands and peptide residues to stabilize the conformation of ligands at the binding pocket. QSAR model was developed using the most stable conformations and parameters that obtained from the molecular docking. It is shown that, a combination of docking parameters and structural descriptors of inhibitor compounds can describe the inhibition efficiency on Aβ1-42 peptide. The model exhibited statistically significant results so that the coefficient of determination R2train, Q2LOO, R2ext and GH (goodness of hit) are 0.912, 0.915, 0.836 and 0.804, respectively. The stability and binding modes of the compounds 1 and 13 with the most inhibition efficiency and compounds 12 and 36 with the lowest inhibition efficiency were determined by molecular dynamics simulations in GROMACS package. It is showed that interactions of compounds 1 and 13 are stable after 25ns of trajectories. Based on obtained results, 10 new drug compounds have been designed that provide better inhibition efficiency with the Aβ1-42 peptide than the reference compounds.