• lung cancer
• mTOR
• molecular dynamics simulation
• tetrahydroquinolines

• IPNU/2024-26/144 Nirma University, Ahmedabad

• L-asparaginase
• PEGylation
• bio-better.
• immunogenicity
• molecular docking
• molecular dynamic simulation
• pharmacokinetics

• Asparaginase/pharmacokinetics
• Asparaginase/chemistry
• Asparaginase/blood
• Polyethylene Glycols/chemistry
• Pseudomonas aeruginosa/enzymology
• Molecular Dynamics Simulation
• Recombinant Proteins/chemistry
• Recombinant Proteins/pharmacokinetics
• Recombinant Proteins/blood
• Animals
• Molecular Weight
• Half-Life
• Enzyme Stability
• Male
• Rats

• Alzheimer's disease
• Anti-amyloid
• Anti-tau
• Clinical trials
• Neuroprotection
• Precision medicine.
• Tautopathy

• Alzheimer Disease/drug therapy
• Alzheimer Disease/diagnosis
• Alzheimer Disease/metabolism
• Humans
• Precision Medicine
• Cholinesterase Inhibitors/therapeutic use
• Cholinesterase Inhibitors/pharmacology
• Cholinesterase Inhibitors/chemistry
• Amyloid beta-Peptides/antagonists & inhibitors
• Amyloid beta-Peptides/metabolism

• amyloid-β
• cholesterol
• lipid bilayer
• molecular dynamics

• Přírodovědecká Fakulta, Univerzita Karlova

• Alzheimer’s disease
• Amyloid aggregates
• Aβ peptides
• Cellular death
• Cellular organelles

• Animals
• Cell Membrane/chemistry
• Cell Membrane/metabolism
• Humans
• Lipid Bilayers/chemistry
• Lipid Bilayers/metabolism
• Membrane Lipids/chemistry
• Membrane Lipids/metabolism
• Membrane Proteins/chemistry
• Membrane Proteins/metabolism
• Molecular Dynamics Simulation
• Protein Conformation

• R01 GM123455 NIGMS NIH HHS
• U54 GM087519 NIGMS NIH HHS
• F31 HL136155 NHLBI NIH HHS
• P41 GM104601 NIGMS NIH HHS
• R01 GM101048 NIGMS NIH HHS

The amyloid β (Aβ) peptide and its shorter variants, including a highly cytotoxic Aβ_25–35 peptide, exert their neurotoxic effect during Alzheimer’s disease by various mechanisms, including cellular membrane permeabilization. The intrinsic polymorphism of Aβ has prevented the identification of the molecular basis of Aβ pore formation by direct structural methods, and computational studies have led to highly divergent pore models. Here, we have employed a set of biophysical techniques to directly monitor Ca²⁺-transporting Aβ_25–35 pores in lipid membranes, to quantitatively characterize pore formation, and to identify the key structural features of the pore. Moreover, the effect of membrane cholesterol on pore formation and the structure of Aβ_25–35 has been elucidated. The data suggest that the membrane-embedded peptide forms 6- or 8-stranded β-barrel like structures. The 8-stranded barrels may conduct Ca²⁺ ions through an inner cavity, whereas the tightly packed 6-stranded barrels need to assemble into supramolecular structures to form a central pore. Cholesterol affects Aβ_25–35 pore formation by a dual mechanism, i.e., by direct interaction with the peptide and by affecting membrane structure. Collectively, our data illuminate the molecular basis of Aβ membrane pore formation, which should advance both basic and clinical research on Alzheimer’s disease and membrane-associated pathologies in general.

An overview of recent advances in computational investigation of peptide–lipid interactions in neurodegeneration – Alzheimer's, Parkinson's and Huntington's disease.

• Aggregation
• Lipid bilayer
• Membrane adsorption
• PrP106–126
• Prion diseases

• Alzheimer's disease
• Aβ
• amyloid-β
• ion channel
• membrane
• oligomer
• pore
• toxicity

This data article supports the research article entitled “Maximally Asymmetric Transbilayer Distribution of Anionic Lipids Alters the Structure and interaction with Lipids of an Amyloidogenic Protein Dimer Bound to the Membrane Surface” [1]. We describe supporting data on the binding kinetics, time evolution of secondary structure, and residue-contact maps of a surface-absorbed beta-amyloid dimer protein on different membrane surfaces. We further demonstrate the sorting of annular and non-annular regions of the protein/lipid bilayer simulation systems, and the correlation of lipid-number mismatch and surface area per lipid mismatch of asymmetric lipid membranes.

• Asymmetric lipid membranes
• Beta-Amyloid
• Protein aggregation
• Protein structure on surfaces
• Protein–lipid interactions

• RC1 GM090897 NIGMS NIH HHS

• Asymmetric lipid membrane
• Beta-amyloid
• Molecular dynamics simulations
• Protein aggregation
• Protein structures on surfaces
• Protein–lipid interactions

After the synthesis of transmembrane peptides/proteins (TMPs), their insertion into a lipid bilayer is a fundamental biophysical process.

Alzheimer’s disease (AD), the most common neurodegenerative disorder associated with dementia, is typified by the pathological accumulation of amyloid Aβ peptides and neurofibrillary tangles (NFT) within the brain. Considerable evidence indicates that many events contribute to AD progression, including oxidative stress, inflammation, and altered cholesterol metabolism. The brain’s high lipid content makes it particularly vulnerable to oxidative species, with the consequent enhancement of lipid peroxidation and cholesterol oxidation, and the subsequent formation of end products, mainly 4-hydroxynonenal and oxysterols, respectively from the two processes. The chronic inflammatory events observed in the AD brain include activation of microglia and astrocytes, together with enhancement of inflammatory molecule and free radical release. Along with glial cells, neurons themselves have been found to contribute to neuroinflammation in the AD brain, by serving as sources of inflammatory mediators. Oxidative stress is intimately associated with neuroinflammation, and a vicious circle has been found to connect oxidative stress and inflammation in AD. Alongside oxidative stress and inflammation, altered cholesterol metabolism and hypercholesterolemia also significantly contribute to neuronal damage and to progression of AD. Increasing evidence is now consolidating the hypothesis that oxidized cholesterol is the driving force behind the development of AD, and that oxysterols are the link connecting the disease to altered cholesterol metabolism in the brain and hypercholesterolemia; this is because of the ability of oxysterols, unlike cholesterol, to cross the blood brain barrier (BBB). The key role of oxysterols in AD pathogenesis has been strongly supported by research pointing to their involvement in modulating neuroinflammation, Aβ accumulation, and cell death. This review highlights the key role played by cholesterol and oxysterols in the brain in AD pathogenesis.

• Alzheimer’s disease
• inflammation
• oxidative stress
• oxidized cholesterol
• oxysterols

• amyloid precursor protein
• amyloid-β peptide
• cerebral endothelium
• membrane fluidity
• membrane molecular order

• R01 AG044404 NIA NIH HHS
• SC2 NS082475 NINDS NIH HHS

• Amyloid peptide
• Cholesterol
• Lipid–protein interaction
• MD simulation
• Membrane protein

• Annular lipid
• Cholesterol
• Lipid domain
• Lipid/protein interaction
• Voro++

Neurodegenerative pathology can be seeded by introduction of misfolded proteins and peptides into the nervous system. Models of Alzheimer’s disease (AD) and Parkinson’s disease (PD) have both demonstrated susceptibility to this seeding mechanism, emphasizing the role of misfolded conformations of disease-specific proteins and peptides in disease progression. Thinking of the amyloidogenic amyloid-beta peptide (Aβ) and alpha-synuclein (α-syn), of AD and PD, respectively, as prionoids requires a comparison of these molecules and the mechanisms underlying the progression of disease. Aβ and α-syn, despite their size differences, are both natively unstructured and misfold into β-structured conformers. Additionally, several studies implicate the significant role of membrane interactions, such as those with lipid rafts in the plasma membrane, in mediating protein aggregation and transfer of Aβ and α-syn between cells that may be common to both AD and PD. Examination of inter-neuronal transfer of proteins/peptides provides evidence into the core mechanism of neuropathological propagation. Specifically, uptake of aggregates likely occurs by the endocytic pathway, possibly in response to their formation of membrane pores via a mechanism shared with pore-forming toxins. Failure of cellular clearance machinery to degrade misfolded proteins favours their release into the extracellular space, where they can be taken up by directly connected, nearby neurons. Although similarities between AD and PD are frequent and include mechanistically similar transfer processes, what differentiates these diseases, in terms of temporal and spatial patterns of propagation, may be in part due to the differing kinetics of protein misfolding. Several examples of animal models demonstrating seeding and propagation by exogenous treatment with Aβ and α-syn highlight the importance of both the environment in which these seeds are formed as well as the environment into which the seeds are propagated. Although these studies suggest potent seeding effects by both Aβ and α-syn, they emphasize the need for future studies to thoroughly characterize “seeds” as well as analyze changes in the nervous system in response to exogenous insults.

• Alzheimer’s disease
• Parkinson’s disease
• Prionoid
• Seeding
• Propagation
• Protein misfolding

• Amino Acid Sequence
• Amyloid beta-Peptides/chemistry
• Diffusion
• Lipid Bilayers/chemistry
• Molecular Dynamics Simulation
• Molecular Sequence Data
• Protein Structure, Secondary

• RC1 GM090897 NIGMS NIH HHS
• GM090897-02 NIGMS NIH HHS

• Amyloid beta-Peptides/chemistry
• Cholesterol/chemistry
• Humans
• Lipid Bilayers/chemistry
• Membrane Microdomains/chemistry
• Membrane Microdomains/ultrastructure
• Microscopy, Atomic Force
• Peptide Fragments/chemistry
• Phospholipids/chemistry
• Sphingomyelins/chemistry

• Coarse-grained simulations
• Lipid raft
• Membrane domain
• Membrane protein
• Molecular dynamics simulations
• Peptide
• Receptor

• Cholesterol/chemistry
• Cholesterol/metabolism
• Glycolipids/chemistry
• Glycolipids/metabolism
• Humans
• Lipid Bilayers/chemistry
• Membrane Microdomains/chemistry
• Membrane Microdomains/metabolism
• Peptides/chemistry
• Peptides/metabolism
• Phosphatidylcholines/chemistry
• Proteins/chemistry
• Proteins/metabolism
• Sphingolipids/chemistry
• Sphingolipids/metabolism
• Sphingomyelins/chemistry
• Sphingomyelins/metabolism

• Alzheimer Disease/drug therapy
• Alzheimer Disease/etiology
• Alzheimer Disease/genetics
• Dementia/drug therapy
• Dementia/genetics
• Drug Discovery
• Genetic Association Studies
• Humans
• Neurodegenerative Diseases/drug therapy
• Neurodegenerative Diseases/genetics
• Pharmacogenetics
• Precision Medicine

Alzheimer’s disease (AD) is a major problem of health and disability, with a relevant economic impact on society (e.g., €177 billion in Europe). Despite important advances in pathogenesis, diagnosis, and treatment, The primary causes of AD remain elusive, accurate biomarkers are not well characterized, and available pharmacological treatments are not cost-effective. As a complex disorder, AD is polygenic and multifactorial: hundreds of defective genes distributed across the human genome may contribute to its pathogenesis (with the participation of diverse environmental factors, cerebrovascular dysfunction, and epigenetic phenomena) and lead to amyloid deposition, neurofibrillary tangle formation, and premature neuronal death. Future perspectives for the global management of AD predict that structural and functional genomics and proteomics may help in the search for reliable biomarkers, and that pharmacogenomics may be an option in optimizing drug development and therapeutics.

Alzheimer pathogenesis involves mitochondrial dysfunction, which is closely related to amyloid-β (Aβ) generation, abnormal tau phosphorylation, oxidative stress, and apoptosis. Alterations in membranal components, including cholesterol and fatty acids, their characteristics, disposition, and distribution along the membranes, have been studied as evidence of cell membrane alterations in AD brain. The majority of these studies have been focused on the cytoplasmic membrane; meanwhile the mitochondrial membranes have been less explored. In this work, we studied lipids and mitochondrial membranes in vivo, following intracerebral injection of fibrillar amyloid-β (Aβ). The purpose was to determine how Aβ may be responsible for beginning of a vicious cycle where oxidative stress and alterations in cholesterol, lipids and fatty acids, feed back on each other to cause mitochondrial dysfunction. We observed changes in mitochondrial membrane lipids, and fatty acids, following intracerebral injection of fibrillar Aβ in aged Wistar rats. Melatonin, a well-known antioxidant and neuroimmunomodulator indoleamine, reversed some of these alterations and protected mitochondrial membranes from obvious damage. Additionally, melatonin increased the levels of linolenic and n-3 eicosapentaenoic acid, in the same site where amyloid β was injected, favoring an endogenous anti-inflammatory pathway.