The Drosophila adult neuromuscular junction as a model for unravelling amyloid peptide influence on synapse dynamics

Amyloid peptide(Aβ)oligomers are considered one of the primary causal factors for the synaptic loss characteristic of Alzheimer’s disease(AD)(Karran and De Strooper,2016).However,Aβis generated in normal brains and accumulates at synaptic sites,which raises the question whether Aβplays a physiological role in synapses.This unresolved issue is especially relevant in view

Computational Analyses of Docosahexaenoic Acid (DHA, C22:6, n-3) with Alzheimer’s Disease-Causing Amyloid Peptide Aβ1-42 Reassures Its Therapeutic Utility

The accumulation of amyloid β peptide1-42 (Aβ1-42) masses in the brains of Alzheimer’s Disease (AD) patients is associated with neuronal loss and memory deficits. We have previously reported that oral administration of docosahexaenoic acid (DHA, C22:6, n-3) significantly decreases Aβ burden in the brains of AD model rats and that direct in vitro incubation of DHA with Aβ1-42 curbs the progression of amyloid fibrillation. In the present in silico study, we investigated whether DHA computationally binds with amyloid peptides. The NMR solution structures of Aβ1-42 were downloaded from the Protein Data Bank (PDB IDs: 1Z0Q and 2BEG). The binding of DHA to Aβ peptides was assessed by molecular docking using both a flexible and rigid docking system. Thioflavin T (ThT) was used as positive control. The chemical structures of ThT and DHA were modeled and converted to the PDB format using PRODRUG. Drug-like properties of DHA were evaluated by ADME (Absorption, Distribution, Metabolism, and Excretion). DHA was found to successfully dock with Aβ1-42. Computational analyses of the binding of DHA to Aβ1-42, as evaluated by docking studies, further corroborated the inhibitory effect of DHA on in vitro Aβ1-42 fibrillogenesis and might explain the in vivo reduction of amyloid burden observed in the brains of DHA-administered AD model rats demonstrated in our previous study. These computational data suggest the potential utility of DHA as a preventive medication in Aβ-induced neurodegenerative diseases, including AD.

Cannabidiol-Mediated Sequestration of Alzheimer’s Amyloid-β Peptides in ADDL Oligomers

Cannabidiol (CBD), one of the most studied phytocannabinoids, is non-psychotropic and can induce protective effects on the central nervous system against acute and chronic brain injury. Interestingly, CBD inhibits processes relating to amyloid beta (Aβ)-induced neurotoxicity in mouse models of Alzheimer’s disease, though the detailed molecular mechanism underlying the CBD neurotoxicity modulation is not fully understood. In this study, using atomic force microscopy, we find that CBD promotes the aggregation of Aβ peptides, enhancing the formation of Aβ oligomers, also known as Aβ-derived diffusible ligands (ADDLs). The CBD-mediated sequestration of Aβ monomers in soluble ADDLs could reduce neurotoxicity. This study highlights a possible role of CBD in modulating the formation of ADDL aggregates and provides insight into potentially neuroprotective properties of CBD in Alzheimer’s disease.

Amyloid beta peptides, tau protein acetylation and therapeutic strategies for treating Alzheimer’s disease: a review

Alzheimer’s disease(AD)is the most common progressive neurodegenerative disorder.It is often lethal and currently lacks a satisfactory therapy.The disease has a specific neuro-pathological profile:accumulation of proteinaceous deposits in the brain–amyloid plaques(containingβ-amyloid peptides)and neurofibrillary tangles which are accumulation of a profusion of long stringy tangles of proteins called tau.Between the two highly recognized AD hypotheses,amyloid beta(Aβ)peptide aggregation and accumulation play a significant role and are considered as an important mechanism of AD pathology.Aβis a proteolytic product of amyloid precursor protein and genetic studies supported the relevance of Aβin AD pathogenesis.A large number of small molecules were studied for their ability to inhibit Aβ-aggregation in oligomer form or after fibrillization.However,the protein-misfolding process has certain setbacks which are inevitable due to the different morphology of protein.In recent years,it has been demonstrated that tau also plays a central role in pathogenesis of this disease.Moreover,abnormal post-translational modifications of tau,in particular,increases in acetylation at specific sites likely contribute to the toxicity of tau.Although it is evident that tau with these aberrant post-translational modifications likely facilitates neurodegeneration,the precise cellular mechanisms by which tau compromises neuronal function remain unknown.In addition,much remains to be learned about new interventions that might be developed to prevent or reduce the negative impact of tau posttranslational modifications-related damage.This review article addresses the key roles of amyloid beta and tau protein in AD as well as the possible therapeutic agents that can reduce the toxic levels of both the proteins,and thus providing beneficial effect for the AD patients.

Amyloid cross-seeding between Ab and hIAPP in relation to the pathogenesis of Alzheimer and type 2 diabetes

Amyloid cross-seeding of different amyloid proteins is considered as a highly possible mechanism for exacerbating the transmissible pathogenesis of protein misfolding disease(PMDs)and for explaining a molecular link between different PMDs,including Alzheimer disease(AD)and type 2 diabetes(T2D),AD and Parkinson disease(PD),and AD and prion disease.Among them,AD and T2D are the most prevalent PMDs,affecting millions of people globally,while Ab and hIAPP are the causative peptides responsible for AD and T2D,respectively.Increasing clinical and epidemiological evidences lead to a hypothesis that the cross-seeding of Ab and hIAPP is more biologically responsible for a pathological link between AD and T2D.In this review,we particularly focus on(i)the most recent and important findings of amyloid cross-seeding between Ab and hIAPP from in vitro,in vivo,and in silico studies,(ii)a mechanistic role of structural compatibility and sequence similarity of amyloid proteins(beyond Ab and hIAPP)in amyloid cross-seeding,and(iii)several current challenges and future research directions in this lessstudied field.Review of amyloid cross-seeding hopefully provides some mechanistic understanding of amyloidogenesis and inspires more efforts for the better design of next-generation drugs/strategies to treat different PMDs simultaneously.

Contradictory effect of gold nanoparticle-decorated molybdenum sulfide nanocomposites on amyloid-β-40 aggregation

The effect of gold nanoparticle-decorated molybdenum sulfide(AuNP-MoS2)nanocomposites on amyloid-β-40(Aβ40)aggregation was investigated.The interesting discovery was that the effect of AuNPMoS2 nanocomposites on Aβ40 aggregation was contradictory.Low concentration of AuNP-MoS2 nanocomposites could enhance the nucleus formation of Aβ40 peptides and accelerate Aβ40 fibrils aggregation.However,although high concentration of AuNP-MoS2 nanocomposites could enhance the nucleus formation of Aβ40 peptides,it eventually inhibited Aβ40 aggregation process.It might be attributed to the interaction between AuNP-MoS2 nanocomposites and Aβ40 peptides.For low concentration of AuNP-MoS2 nanocomposites,it was acted as nuclei,resulting in the acceleration of the nucleation process.However,the structural flexibility of Aβ40 peptides was limited as the concentration of AuNP-MoS2 nanocomposites was increased,resulting in the inhibition of Aβ40aggregation.These findings suggested that AuNP-MoS2 nanocomposites might have a great potential to design new multifunctional material for future treatment of amyloid-related diseases.

Effect of a Short Peptide with Alternating L-and D-Amino Acid on the Aggregation and Membrane Damage of hIAPP

Alpha-sheet is believed to be a significant structural compo-nent,formed in the fibrillation process of the amyloid pep-tide.However,the knowledge about the role of a-sheet played in the amyloidosis and toxicity is lack.In this work,we modi-fied a short peptide derived from the core region of human islet amyloid polypetide(hIAPP,hIAPP18-27)with an alternating D-amino acid replacement and investigated the effects of the L/D alternating peptide on the fibrillar aggregation and the membrane damage of hIAPP using NMR,ThT fluorescence assay,circular dichroism(CD),transmission electron microscopy(TEM)and leakage assay,and com-pared the results with those of hIAPP_(18-27) without D-amino acid re-placement.We show that the short peptide with alternating L-and D-amino acids forms an a-sheet structure and is more potent in pro-moting the fibrillation of hIAPP and reducing the ability of hIAPP to disrupt the membrane composed of POPG and POPC[1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1′-rac-glycerol)and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine]1:4 lipids than the short pep-tide with all L-amino acids in a random coil structure.The higher po-tency of the D/L alternating peptide in these activities is attributed to its ability to induce the a-sheet-like structure in the core region of hIAPP and block the interaction of hIAPP with the membrane more effectively.

Associations of cerebrospinal fluid amyloidogenic nanoplaques with cytokines in Alzheimer’s disease

Background:The aggregation of amyloidβ(Aβ)is central in the pathogenesis of Alzheimer’s disease(AD).Recently it has been shown that specifically,larger,Thioflavin T-binding Aβaggregates are associated with increased neuroinflammation and cytokine release.This study was aimed to quantify fibrillary amyloid aggregates,so-called nanoplaques,and investigate their relationship with cytokines in the cerebrospinal fluid(CSF).Methods:CSF was collected from 111 patients assessed for cognitive complaints at the Oslo University Hospital Memory Clinic.The patients were grouped based on their amyloid status.The CSF nanoplaque concentration was quantified with the Thioflavin T-fluorescence correlation spectroscopy(ThT-FCS)assay.The levels of nine cytokines(eotaxin-1,granulocyte stimulating factor,interleukin[IL]-6,IL-7,IL-8,monocyte chemoattractant protein-1,gammainduced protein 10,macrophage inflammatory protein[MIP]-1α,and MIP-1β)were quantified with a magnetic bead-based multiplex assay and read on a Luminex IS 200 instrument.Results:There were 49 amyloid-negative and 62 amyloid-positive patients in the cohort;none of the cytokines differed significantly between the amyloid groups.The increased nanoplaque levels were associated with levels of MIP-1βbelow the lower limit of quantification,and with decreased levels of MIP-1αand IL-8.The associations remained significant when adjusted for age,sex,cognitive function,apolipoproteinε4 status and CSF core biomarker levels.Conclusion:The cytokine levels were not associated with amyloid status in this cohort.The nanoplaque levels were negatively associated with MIP-1β,MIP-1αand IL-8,which is in line with recent findings suggesting that the upregulation of some cytokine markers has a protective role and is negatively associated with AD progression.

Transplantation of bone marrow mesenchymal stem cells improves cognitive deficits and alleviates neuropathology in animal models of Alzheimer’s disease: a meta-analytic review on potential mechanisms

Background Alzheimer’s disease is a neurodegenerative disorder.Therapeutically,a transplantation of bone marrow mesenchymal stem cells(BMMSCs)can play a beneficial role in animal models of Alzheimer’s disease.However,the relevant mechanism remains to be fully elucidated.Main body Subsequent to the transplantation of BMMSCs,memory loss and cognitive impairment were significantly improved in animal models with Alzheimer’s disease(AD).Potential mechanisms involved neurogenesis,apoptosis,angiogenesis,inflammation,immunomodulation,etc.The above mechanisms might play different roles at certain stages.It was revealed that the transplantation of BMMSCs could alter some gene levels.Moreover,the differential expression of representative genes was responsible for neuropathological phenotypes in Alzheimer’s disease,which could be used to construct gene-specific patterns.Conclusions Multiple signal pathways involve therapeutic mechanisms by which the transplantation of BMMSCs improves cognitive and behavioral deficits in AD models.Gene expression profile can be utilized to establish statistical regression model for the evaluation of therapeutic effect.The transplantation of autologous BMMSCs maybe a prospective therapy for patients with Alzheimer’s disease.

Advances in the development of new biomarkers for Alzheimer’s disease

Alzheimer’s disease(AD)is a complex,heterogeneous,progressive disease and is the most common type of neurodegenerative dementia.The prevalence of AD is expected to increase as the population ages,placing an additional burden on national healthcare systems.There is a large need for new diagnostic tests that can detect AD at an early stage with high specificity at relatively low cost.The development of modern analytical diagnostic tools has made it possible to determine several biomarkers of AD with high specificity,including pathogenic proteins,markers of synaptic dysfunction,and markers of inflammation in the blood.There is a considerable potential in using microRNA(miRNA)as markers of AD,and diagnostic studies based on miRNA panels suggest that AD could potentially be determined with high accuracy for individual patients.Studies of the retina with improved methods of visualization of the fundus are also showing promising results for the potential diagnosis of the disease.This review focuses on the recent developments of blood,plasma,and ocular biomarkers for the diagnosis of AD.

Impairment of the autophagy-lysosomal pathway in Alzheimer’s diseases: Pathogenic mechanisms and therapeutic potential

Alzheimer’s disease(AD),the most common neurodegenerative disorder,is characterized by memory loss and cognitive dysfunction.The accumulation of misfolded protein aggregates including amyloid beta(Aβ)peptides and microtubule associated protein tau(MAPT/tau)in neuronal cells are hallmarks of AD.So far,the exact underlying mechanisms for the aetiologies of AD have not been fully understood and the effective treatment for AD is limited.Autophagy is an evolutionarily conserved cellular catabolic process by which damaged cellular organelles and protein aggregates are degraded via lysosomes.Recently,there is accumulating evidence linking the impairment of the autophagy-lysosomal pathway with AD pathogenesis.Interestingly,the enhancement of autophagy to remove protein aggregates has been proposed as a promising therapeutic strategy for AD.Here,we first summarize the recent genetic,pathological and experimental studies regarding the impairment of the autophagy-lysosomal pathway in AD.We then describe the interplay between the autophagy-lysosomal pathway and two pathological proteins,Aβand MAPT/tau,in AD.Finally,we discuss potential therapeutic strategies and small molecules that target the autophagy-lysosomal pathway for AD treatment both in animal models and in clinical trials.Overall,this article highlights the pivotal functions of the autophagy-lysosomal pathway in AD pathogenesis and potential druggable targets in the autophagy-lysosomal pathway for AD treatment.

Progress in mechanisms of acetylcholinesterase inhibitors and memantine for the treatment of Alzheimer’s disease

Alzheimer’s disease(AD)is the most common causes of dementia in the elderly.Currently,only two classes of drugs,acetylcholinesterase inhibitors(AChEIs)and memantine are approved.AChEIs ameliorate cognitive and psychiatric symptoms in AD patients through activation of acetylcholine(ACh)receptors by increased synaptic ACh levels and also have protective effects against glutamate neurotoxicity and inflammation,whereas memantine appears to mainly protect against excitotoxicity and neurodegeneration.Herein,we review the pharmacologic properties of the available AChEIs and memantine,and focus on recent progress in the mechanisms of AD in relation to acetylcholinergic and glutamatergic involvement.