A shorter linker in the bispecific antibody RmAb158-scFv8D3 improves TfR-mediated blood-brain barrier transcytosis in vitro.

Transferrin Receptor (TfR)-mediated transcytosis across the blood-brain barrier (BBB) enables the uptake of bispecific therapeutic antibodies into the brain. At therapeutically relevant concentrations, bivalent binding to TfR appears to reduce the transcytosis efficiency by receptor crosslinking. In this study, we aimed to improve BBB transcytosis of symmetric antibodies through minimizing their ability to cause TfR crosslinking.

Early Astrocytic Dysfunction Is Associated with Mistuned Synapses as well as Anxiety and Depressive-Like Behavior in the AppNL-F Mouse Model of Alzheimer's Disease.

Background: Alzheimer's disease (AD) is the most common neurodegenerative disease. Unfortunately, efficient and affordable treatments are still lacking for this neurodegenerative disorder, it is therefore urgent to identify new pharmacological targets. Astrocytes are playing a crucial role in the tuning of synaptic transmission and several studies have pointed out severe astrocyte reactivity in AD.

Long-term effects of immunotherapy with a brain penetrating Aβ antibody in a mouse model of Alzheimer's disease.

Background: Brain-directed immunotherapy is a promising strategy to target amyloid-β (Aβ) deposits in Alzheimer's disease (AD). In the present study, we compared the therapeutic efficacy of the Aβ protofibril targeting antibody RmAb158 with its bispecific variant RmAb158-scFv8D3, which enters the brain by transferrin receptor-mediated transcytosis.

Methods: App knock-in mice received RmAb158, RmAb158-scFv8D3, or PBS in three treatment regimens.

Standardized Preclinical Blood-Brain Barrier Mouse Assay Validates Endocytosis-Dependent Antibody Transcytosis Using Transferrin-Receptor-Mediated Pathways.

The presence of the blood-brain barrier (BBB) creates a nigh-on impenetrable obstacle for large macromolecular therapeutics that need to be delivered to the brain milieu to treat neurological disorders. To overcome this, one of the strategies used is to bypass the barrier with what is referred to as a "Trojan Horse" strategy, where therapeutics are designed to use endogenous receptor-mediated pathways to piggyback their way through the BBB. Even though methodologies are commonly used to test the efficacy of BBB-penetrating biologics, comparable BBB models are in high demand, as they benefit from being an isolated cellular system devoid of physiological factors that can on occasion mask the processes behind BBB transport via transcytosis.

A single-chain fragment constant design enables easy production of a monovalent blood-brain barrier transporter and provides an improved brain uptake at elevated doses.

The interest for developing antibody-driven therapeutic interventions has exponentially grown over the last few decades. Even though there have been promising leaps in the development of efficacious antibody therapies, problems revolving around production and site-directed delivery of these large macromolecules persist. This is especially pertinent when it comes to designing and producing antibodies to penetrate the blood-brain barrier (BBB) to tackle neurodegenerative diseases.

Introducing or removing heparan sulfate binding sites does not alter brain uptake of the blood-brain barrier shuttle scFv8D3.

The blood-brain barrier (BBB) greatly limits the delivery of protein-based drugs into the brain and is a major obstacle for the treatment of brain disorders. Targeting the transferrin receptor (TfR) is a strategy for transporting protein-based drugs into the brain, which can be utilized by using TfR-binding BBB transporters, such as the TfR-binding antibody 8D3. In this current study, we investigated if binding to heparan sulfate (HS) contributes to the brain uptake of a single chain fragment variable of 8D3 (scFv8D3).

Blood-brain barrier penetrating neprilysin degrades monomeric amyloid-beta in a mouse model of Alzheimer's disease.

Background: Aggregation of the amyloid-β (Aβ) peptide in the brain is one of the key pathological events in Alzheimer's disease (AD). Reducing Aβ levels in the brain by enhancing its degradation is one possible strategy to develop new therapies for AD. Neprilysin (NEP) is a membrane-bound metallopeptidase and one of the major Aβ-degrading enzymes.

A Brain-Targeting Bispecific-Multivalent Antibody Clears Soluble Amyloid-Beta Aggregates in Alzheimer's Disease Mice.

Amyloid-β (Aβ) oligomers and protofibrils are suggested to be the most neurotoxic Aβ species in Alzheimer's disease (AD). Hence, antibodies with strong and selective binding to these soluble Aβ aggregates are of therapeutic potential. We have recently introduced HexaRmAb158, a multivalent antibody with additional Aβ-binding sites in the form of single-chain fragment variables (scFv) on the N-terminal ends of Aβ protofibril selective antibody (RmAb158).

Destination and Specific Impact of Different Bile Acids in the Intestinal Pathogen .

The anaerobic bacterium represents one of the most problematic pathogens, especially in hospitals. Dysbiosis has been proven to largely reduce colonization resistance against this intestinal pathogen. The beneficial effect of the microbiota is closely associated with the metabolic activity of intestinal microbes such as the ability to transform primary bile acids into secondary ones.

Wide-Ranging Effects on the Brain Proteome in a Transgenic Mouse Model of Alzheimer's Disease Following Treatment with a Brain-Targeting Somatostatin Peptide.

Alzheimer's disease is the most common neurodegenerative disorder characterized by the pathological aggregation of amyloid-β (Aβ) peptide. A potential therapeutic intervention in Alzheimer's disease is to enhance Aβ degradation by increasing the activity of Aβ-degrading enzymes, including neprilysin. The somatostatin (SST) peptide has been identified as an activator of neprilysin.

Enhanced neprilysin-mediated degradation of hippocampal Aβ42 with a somatostatin peptide that enters the brain.

Aggregation of the amyloid-beta (Aβ) peptide is one of the main neuropathological events in Alzheimer's disease (AD). Neprilysin is the major enzyme degrading Aβ, with its activity enhanced by the neuropeptide somatostatin (SST). SST levels are decreased in the brains of AD patients.

Differential View on the Bile Acid Stress Response of .

is an intestinal human pathogen that uses the opportunity of a depleted microbiota to cause an infection. It is known, that the composition of the intestinal bile acid cocktail has a great impact on the susceptibility toward a infection. However, the specific response of growing cells to diverse bile acids on the molecular level has not been described yet.

Gender disparity in health-related quality of life and fatigue after living renal donation.

Background: The clinical outcome and health-related quality of life (HRQoL) of living kidney donors is mostly not detrimental, but some donors experience impairment after donation. Gender-specific effects of living kidney donors was evaluated.

Methods: Clinical outcome was assessed in living kidney donors and HRQoL was obtained by self-reporting validated test systems as the Multidimensional Fatigue Inventory (MFI-20), the Short Form 36 (SF-36), and the Patient Health Questionnaire (PHQ-9).

Organization of ribosomes and nucleoids in Escherichia coli cells during growth and in quiescence.

We have examined the distribution of ribosomes and nucleoids in live Escherichia coli cells under conditions of growth, division, and in quiescence. In exponentially growing cells translating ribosomes are interspersed among and around the nucleoid lobes, appearing as alternative bands under a fluorescence microscope. In contrast, inactive ribosomes either in stationary phase or after treatment with translation inhibitors such as chloramphenicol, tetracycline, and streptomycin gather predominantly at the cell poles and boundaries with concomitant compaction of the nucleoid.