Combinational therapy, concomitantly targeting post‐translational modified Aβ peptides and CD33, leads to an add‐on effect in passive immunotherapy

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.

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Electrical characteristics of amyloid beta peptides in vertical junctions

NPG Asia Materials ◽

10.1038/s41427-021-00321-z ◽

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.

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Smart Nanoparticles for Chemo-Based Combinational Therapy

Pharmaceutics ◽

10.3390/pharmaceutics13060853 ◽

2021 ◽

Vol 13 (6) ◽

pp. 853

Author(s):

Binita Shrestha ◽

Lijun Wang ◽

Eric M. Brey ◽

Gabriela Romero Uribe ◽

Liang Tang

Keyword(s):

Cancer Treatment ◽

Cancer Biology ◽

Complex Disease ◽

Rapid Development ◽

Acquired Resistance ◽

Therapeutic Index ◽

Chemotherapeutic Agents ◽

Combinational Therapy ◽

Precision Therapy ◽

External Stimuli

Cancer is a heterogeneous and complex disease. Traditional cancer therapy is associated with low therapeutic index, acquired resistance, and various adverse effects. With the increasing understanding of cancer biology and technology advancements, more strategies have been exploited to optimize the therapeutic outcomes. The rapid development and application of nanomedicine have motivated this progress. Combinational regimen, for instance, has become an indispensable approach for effective cancer treatment, including the combination of chemotherapeutic agents, chemo-energy, chemo-gene, chemo-small molecules, and chemo-immunology. Additionally, smart nanoplatforms that respond to external stimuli (such as light, temperature, ultrasound, and magnetic field), and/or to internal stimuli (such as changes in pH, enzymes, hypoxia, and redox) have been extensively investigated to improve precision therapy. Smart nanoplatforms for combinational therapy have demonstrated the potential to be the next generation cancer treatment regimen. This review aims to highlight the recent advances in smart combinational therapy.

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Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides

Journal of Biological Chemistry ◽

10.1016/j.jbc.2021.100393 ◽

2021 ◽

pp. 100393

Author(s):

Lei Liu ◽

Bianca M. Lauro ◽

Michael S. Wolfe ◽

Dennis J. Selkoe

Keyword(s):

Presenilin 1 ◽

Aβ Peptides ◽

Hydrophilic Loop

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

Scientific Reports ◽

10.1038/s41598-021-96364-x ◽

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.

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Tau antibody isotype induces differential effects following passive immunisation of tau transgenic mice

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01147-0 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Rinie Bajracharya ◽

David Brici ◽

Liviu-Gabriel Bodea ◽

Phillip W. Janowicz ◽

Jürgen Götz ◽

...

Keyword(s):

Receptor Binding ◽

Microglial Activation ◽

Fc Receptor ◽

Passive Immunisation ◽

Antibody Isotype ◽

Passive Immunotherapy ◽

Microglial Phagocytosis ◽

Promising Strategy ◽

Murine Igg1

AbstractOne of the main pathological hallmarks of Alzheimer’s disease (AD) is the intraneuronal accumulation of hyperphosphorylated tau. Passive immunotherapy is a promising strategy for the treatment of AD and there are currently a number of tau-specific monoclonal antibodies in clinical trials. A proposed mechanism of action is to engage and clear extracellular, pathogenic forms of tau. This process has been shown in vitro to be facilitated by microglial phagocytosis through interactions between the antibody-tau complex and microglial Fc-receptors. As this interaction is mediated by the conformation of the antibody's Fc domain, this suggests that the antibody isotype may affect the microglial phagocytosis and clearance of tau, and hence, the overall efficacy of tau antibodies. We therefore aimed to directly compare the efficacy of the tau-specific antibody, RN2N, cloned into a murine IgG1/κ framework, which has low affinity Fc-receptor binding, to that cloned into a murine IgG2a/κ framework, which has high affinity Fc-receptor binding. Our results demonstrate, for RN2N, that although enhanced microglial activation via the IgG2a/κ isotype increased extracellular tau phagocytosis in vitro, the IgG1/κ isoform demonstrated enhanced ability to reduce tau pathology and microgliosis following passive immunisation of the P301L tau transgenic pR5 mouse model.

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

Acta Neuropathologica ◽

10.1007/s00401-021-02349-5 ◽

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.

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Hybrid-cell membrane-coated nanocomplex-loaded chikusetsusaponin IVa methyl ester for a combinational therapy against breast cancer assisted by Ce6

Biomaterials Science ◽

10.1039/d0bm02211j ◽

2021 ◽

Vol 9 (8) ◽

pp. 2991-3004

Author(s):

Qian Xie ◽

Yang Liu ◽

Ying Long ◽

Zhou Wang ◽

Sai Jiang ◽

...

Keyword(s):

Breast Cancer ◽

Methyl Ester ◽

Cell Membrane ◽

Hybrid Cell ◽

Combinational Therapy ◽

Membrane Coating

Hybrid-cell membrane coating nanocomplexes loading chikusetsusaponin IVa methyl ester for combinational therapy against breast cancer assisted with Ce6.

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Oxygen-producing proenzyme hydrogels for photodynamic mediated metastasis-inhibited combinational therapy

Journal of Materials Chemistry B ◽

10.1039/d1tb01009c ◽

2021 ◽

Author(s):

Jiansheng Liu ◽

Xueqin Qing ◽

Qin Zhang ◽

Ningyue Yu ◽

Mengbin Ding ◽

...

Keyword(s):

Photodynamic Therapy ◽

Tumor Microenvironment ◽

Solid Tumors ◽

Therapeutic Efficacy ◽

Tumor Metastasis ◽

Combinational Therapy ◽

Hypoxic Tumor

Photodynamic therapy (PDT) has provided a promising approach for treatment of solid tumors, while the therapeutic efficacy is often limited due to hypoxic tumor microenvironment, resulting in tumor metastasis. We...

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