Time-Evolved SERS Signatures of DEP-Trapped Aβ and Zn2+Aβ Peptides Revealed by a Sub-10 nm Electrode Nanogap

2021 ◽  
Author(s):  
Katrin H. P. Vu ◽  
Ming-Che Lee ◽  
Gerhard H. Blankenburg ◽  
Yu-Jen Chang ◽  
Ming-Lee Chu ◽  
...  
Keyword(s):  
Aβ Peptides

The Role of Lipids and Membranes in the Pathogenesis of Alzheimer's Disease: A Comprehensive View

2018 ◽  
Vol 15 (13) ◽  
pp. 1191-1212 ◽  
Author(s):  
Botond Penke ◽  
Gábor Paragi ◽  
János Gera ◽  
Róbert Berkecz ◽  
Zsolt Kovács ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathways ◽  
Membrane Lipids ◽  
Specific Protein ◽  
Dietary Factors ◽  
Lipid Signaling ◽  
Special Role ◽  
Aβ Peptides

Lipids participate in Amyloid Precursor Protein (APP) trafficking and processing - important factors in the initiation of Alzheimer’s disease (AD) pathogenesis and influence the formation of neurotoxic β-amyloid (Aβ) peptides. An important risk factor, the presence of ApoE4 protein in AD brain cells binds the lipids to AD. In addition, lipid signaling pathways have a crucial role in the cellular homeostasis and depend on specific protein-lipid interactions. The current review focuses on pathological alterations of membrane lipids (cholesterol, glycerophospholipids, sphingolipids) and lipid metabolism in AD and provides insight in the current understanding of biological membranes, their lipid structures and functions, as well as their role as potential therapeutic targets. Novel methods for studying the membrane structure and lipid composition will be reviewed in a broad sense whereas the use of lipid biomarkers for early diagnosis of AD will be shortly summarized. Interactions of Aβ peptides with the cell membrane and different subcellular organelles are reviewed. Next, the details of the most important lipid signaling pathways, including the role of the plasma membrane as stress sensor and its therapeutic applications are given. 4-hydroxy-2-nonenal may play a special role in the initiation of the pathogenesis of AD and thus the “calpain-cathepsin hypothesis” of AD is highlighted. Finally, the most important lipid dietary factors and their possible use and efficacy in the prevention of AD are discussed.

scholarly journals Electrical characteristics of amyloid beta peptides in vertical junctions

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Sohyeon Seo ◽  
Jinju Lee ◽  
Jungsue Choi ◽  
G. Hwan Park ◽  
Yeseul Hong ◽  
...  
Keyword(s):  
Electron Transfer ◽  
Electron Transport ◽  
Amyloid Beta ◽  
Field Effect Transistors ◽  
Brain Diseases ◽  
Electrical Characteristics ◽  
Transport Pathway ◽  
Sequence Dependence ◽  
Aβ Oligomers ◽  
Aβ Peptides

AbstractAssembled amyloid beta (Aβ) peptides have been considered pathological assemblies involved in human brain diseases, and the electron transfer or electron transport characteristics of Aβ are important for the formation of structured assemblies. Here, we report the electrical characteristics of surface-assembled Aβ peptides similar to those observed in Alzheimer’s patients. These characteristics correlate to their electron transfer characteristics. Electrical current–voltage plots of Aβ vertical junction devices show the Aβ sequence dependence of the current densities at both Aβ monomers (mono-Aβs) and Aβ oligomers (oli-Aβs), while Aβ sequence dependence is not clearly observed in the electrical characteristics of Aβ planar field effect transistors (FETs). In particular, surface oligomerization of Aβ peptides drastically decreases the activity of electron transfer, which presents a change in the electron transport pathway in the Aβ vertical junctions. Electron transport at oli-Aβ junctions is symmetric (tunneling/tunneling) due to the weak and voltage-independent coupling of the less redox-reactive oli-Aβ to the contacts, while that at mono-Aβ junctions is asymmetric (hopping/tunneling) due to redox levels of mono-Aβ voltage-dependently coupled with contact electrodes. Consequently, through vertical junctions, the sequence- and conformation-dependent electrical characteristics of Aβs can reveal their electron transfer activities.

scholarly journals Extracellular fluid, cerebrospinal fluid and plasma biomarkers of axonal and neuronal injury following intracerebral hemorrhage

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lovisa Tobieson ◽  
Henrik Zetterberg ◽  
Kaj Blennow ◽  
Niklas Marklund
Keyword(s):  
Cerebrospinal Fluid ◽  
Intracerebral Hemorrhage ◽  
Brain Tissue ◽  
Single Molecule ◽  
Tissue Injury ◽  
Extracellular Fluid ◽  
Neurofilament Light ◽  
Aβ Peptides ◽  
Post Surgery ◽  
Fluid Compartments

AbstractSpontaneous intracerebral hemorrhage (ICH) is the most devastating form of stroke. To refine treatments, improved understanding of the secondary injury processes is needed. We compared energy metabolic, amyloid and neuroaxonal injury biomarkers in extracellular fluid (ECF) from the perihemorrhagic zone (PHZ) and non-injured (NCX) brain tissue, cerebrospinal fluid (CSF) and plasma. Patients (n = 11; age 61 ± 10 years) undergoing ICH surgery received two microdialysis (MD) catheters, one in PHZ, and one in NCX. ECF was analysed at three time intervals within the first 60 h post- surgery, as were CSF and plasma samples. Amyloid-beta (Aβ) 40 and 42, microtubule associated protein tau (tau), and neurofilament-light (NF-L) were analysed using Single molecule array (Simoa) technology. Median biomarker concentrations were lowest in plasma, higher in ECF and highest in CSF. Biomarker levels varied over time, with different dynamics in the three fluid compartments. In the PHZ, ECF levels of Aβ40 were lower, and tau higher when compared to the NCX. Altered levels of Aβ peptides, NF-L and tau may reflect brain tissue injury following ICH surgery. However, the dynamics of biomarker levels in the different fluid compartments should be considered in the study of pathophysiology or biomarkers in ICH patients.

scholarly journals A glutaminyl cyclase-catalyzed α-synuclein modification identified in human synucleinopathies

2021 ◽  
Author(s):  
Maike Hartlage-Rübsamen ◽  
Alexandra Bluhm ◽  
Sandra Moceri ◽  
Lisa Machner ◽  
Janett Köppen ◽  
...  
Keyword(s):  
Cell Viability ◽  
Neurodegenerative Disorder ◽  
Lewy Bodies ◽  
Size Exclusion ◽  
Lewy Neurites ◽  
Enzymatic Assays ◽  
Aβ Peptides ◽  
Glutaminyl Cyclase ◽  
Affect Cell Viability ◽  
Exclusion Chromatography

AbstractParkinson’s disease (PD) is a progressive neurodegenerative disorder that is neuropathologically characterized by degeneration of dopaminergic neurons of the substantia nigra (SN) and formation of Lewy bodies and Lewy neurites composed of aggregated α-synuclein. Proteolysis of α-synuclein by matrix metalloproteinases was shown to facilitate its aggregation and to affect cell viability. One of the proteolysed fragments, Gln79-α-synuclein, possesses a glutamine residue at its N-terminus. We argue that glutaminyl cyclase (QC) may catalyze the pyroglutamate (pGlu)79-α-synuclein formation and, thereby, contribute to enhanced aggregation and compromised degradation of α-synuclein in human synucleinopathies. Here, the kinetic characteristics of Gln79-α-synuclein conversion into the pGlu-form by QC are shown using enzymatic assays and mass spectrometry. Thioflavin T assays and electron microscopy demonstrated a decreased potential of pGlu79-α-synuclein to form fibrils. However, size exclusion chromatography and cell viability assays revealed an increased propensity of pGlu79-α-synuclein to form oligomeric aggregates with high neurotoxicity. In brains of wild-type mice, QC and α-synuclein were co-expressed by dopaminergic SN neurons. Using a specific antibody against the pGlu-modified neo-epitope of α-synuclein, pGlu79-α-synuclein aggregates were detected in association with QC in brains of two transgenic mouse lines with human α-synuclein overexpression. In human brain samples of PD and dementia with Lewy body subjects, pGlu79-α-synuclein was shown to be present in SN neurons, in a number of Lewy bodies and in dystrophic neurites. Importantly, there was a spatial co-occurrence of pGlu79-α-synuclein with the enzyme QC in the human SN complex and a defined association of QC with neuropathological structures. We conclude that QC catalyzes the formation of oligomer-prone pGlu79-α-synuclein in human synucleinopathies, which may—in analogy to pGlu-Aβ peptides in Alzheimer’s disease—act as a seed for pathogenic protein aggregation.

scholarly journals Impact of Gut Microbiome Manipulation in 5xFAD Mice on Alzheimer’s Disease-Like Pathology

2021 ◽  
Vol 9 (4) ◽  
pp. 815
Author(s):  
Malena dos Santos Guilherme ◽  
Vu Thu Thuy Nguyen ◽  
Christoph Reinhardt ◽  
Kristina Endres
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gut Microbiome ◽  
Microbial Composition ◽  
Aβ Peptides ◽  
Plaque Deposition ◽  
Glycation End Products ◽  
Plaque Load ◽  
5Xfad Mice ◽  
Building Capability

The gut brain axis seems to modulate various psychiatric and neurological disorders such as Alzheimer’s disease (AD). Growing evidence has led to the assumption that the gut microbiome might contribute to or even present the nucleus of origin for these diseases. In this regard, modifiers of the microbial composition might provide attractive new therapeutics. Aim of our study was to elucidate the effect of a rigorously changed gut microbiome on pathological hallmarks of AD. 5xFAD model mice were treated by antibiotics or probiotics (L. acidophilus and L. rhamnosus) for 14 weeks. Pathogenesis was measured by nest building capability and plaque deposition. The gut microbiome was affected as expected: antibiotics significantly reduced viable commensals, while probiotics transiently increased Lactobacillaceae. Nesting score, however, was only improved in antibiotics-treated mice. These animals additionally displayed reduced plaque load in the hippocampus. While various physiological parameters were not affected, blood sugar was reduced and serum glucagon level significantly elevated in the antibiotics-treated animals together with a reduction in the receptor for advanced glycation end products RAGE—the inward transporter of Aβ peptides of the brain. Assumedly, the beneficial effect of the antibiotics was based on their anti-diabetic potential.

scholarly journals Curcumin Inhibits the Primary Nucleation of Amyloid-Beta Peptide: A Molecular Dynamics Study

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1323
Author(s):  
Irini Doytchinova ◽  
Mariyana Atanasova ◽  
Evdokiya Salamanova ◽  
Stefan Ivanov ◽  
Ivan Dimitrov
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bonds ◽  
Amyloid Beta ◽  
Amyloid Plaques ◽  
Amyloid Beta Peptide ◽  
Aβ Peptides ◽  
Amyloid Peptides ◽  
Primary Nucleation ◽  
Beta Peptide ◽  
Good Agreement

The amyloid plaques are a key hallmark of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Amyloidogenesis is a complex long-lasting multiphase process starting with the formation of nuclei of amyloid peptides: a process assigned as a primary nucleation. Curcumin (CU) is a well-known inhibitor of the aggregation of amyloid-beta (Aβ) peptides. Even more, CU is able to disintegrate preformed Aβ firbils and amyloid plaques. Here, we simulate by molecular dynamics the primary nucleation process of 12 Aβ peptides and investigate the effects of CU on the process. We found that CU molecules intercalate among the Aβ chains and bind tightly to them by hydrogen bonds, hydrophobic, π–π, and cation–π interactions. In the presence of CU, the Aβ peptides form a primary nucleus of a bigger size. The peptide chains in the nucleus become less flexible and more disordered, and the number of non-native contacts and hydrogen bonds between them decreases. For comparison, the effects of the weaker Aβ inhibitor ferulic acid (FA) on the primary nucleation are also examined. Our study is in good agreement with the observation that taken regularly, CU is able to prevent or at least delay the onset of neurodegenerative disorders.

A theoretical study on the molecular determinants of the affibody protein ZAβ3bound to an amyloid β peptide

2015 ◽  
Vol 17 (26) ◽  
pp. 16886-16893 ◽  
Author(s):  
Xu Wang ◽  
Xianqiang Sun ◽  
Guanglin Kuang ◽  
Hans Ågren ◽  
Yaoquan Tu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Theoretical Study ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Aβ Peptides ◽  
Molecular Determinants

The investigation of the (ZAβ3)2:Aβ complex highlights the energetic contribution of affibody residues to the binding with alzheimer's disease associated Aβ peptides.

scholarly journals Aβ peptides go mad

2012 ◽  
Vol 8 (7) ◽  
pp. 602-602
Author(s):  
Angeliki Chalkiadaki
Keyword(s):  
Aβ Peptides
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