Ultrasound-mediated delivery of novel tau-specific monoclonal antibody enhances brain uptake but not therapeutic efficacy

Tau-specific immunotherapy is an attractive therapeutic strategy for the treatment of Alzheimer's disease and other tauopathies. However, targeting tau effectively remains a considerable challenge due to the restrictive nature of the blood-brain barrier (BBB), which excludes 99.9% of peripherally administered antibodies. We have previously shown that the delivery of tau-specific monoclonal antibody (mAb) with low-intensity scanning ultrasound in combination with intravenously injected microbubbles (SUS+MB) increases the passage of IgG antibodies into the brain. SUS+MB transiently opens tight junctions to allow paracellular transport, but also facilitates transcellular transport, particularly for larger cargoes. However, therapeutic efficacy after enhanced brain delivery has not been explored. To assess whether ultrasound-mediated delivery of tau-specific mAbs leads to an enhanced therapeutic response, K369I tau transgenic K3 mice were passively immunised once weekly for 12 weeks with a novel mAb, RNF5, in combination with SUS+MB. While none of the treatment arms improved behaviour or motor functions in these mice, we found that both RNF5 and SUS+MB treatments on their own reduced tau pathology, but, surprisingly, the combination of both (RNF5+SUS+MB) did not achieve an additive reduction in tau pathology. This was despite observing increased antibody penetration in the brain. Interestingly, a significant fraction of the antibody in the combination treatment was visualized in brain endothelial cells, suggesting that paracellular transport may not be the preferred uptake mechanism for RNF5. Taken altogether, more research is warranted to develop SUS+MB as a delivery modality for anti-tau antibodies.

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Acquisition of a brief behavioural experience in the rat is inhibited by the brain-specific monoclonal antibody, F3-87-8

Neuroscience Letters ◽

10.1016/0304-3940(87)90457-5 ◽

1987 ◽

Vol 79 (3) ◽

pp. 346-350 ◽

Cited By ~ 12

Author(s):

Patrick M. Nolan ◽

Robert Bell ◽

Ciaran M. Regan

Keyword(s):

Monoclonal Antibody ◽

Specific Monoclonal Antibody ◽

The Brain

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Levosimendan prevents tau pathology by inhibiting disulfide-linked tau oligomerization posing as a promising anti-tau therapeutics

10.21203/rs.3.rs-128169/v1 ◽

2020 ◽

Author(s):

Yun Kyung Kim ◽

Sungsu Lim ◽

Seulgi Shin ◽

Ha Eun Lee ◽

Ji Yeon Song ◽

...

Keyword(s):

Therapeutic Strategy ◽

Isotope Labeling ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Tau Pathology ◽

Tau Oligomers ◽

Disease Modifying Therapy ◽

Cellular Context ◽

Targeted Drug Discovery ◽

The Brain

Abstract Tau oligomers play critical roles in tau pathology, responsible for neuronal cell death and transmitting the disease in the brain. Accordingly, preventing tau oligomerization becomes an important therapeutic strategy to treat tauopathies including Alzheimer’s disease, however progress has been slow due to difficulties of detecting tau oligomers in cellular context. Toward tau-targeted drug discovery, our group have developed a tau-BiFC platform to monitor and quantify tau oligomerization. By using the tau-BiFC platform, we screened 1,018 compounds in FDA-approved & Passed Phase I drug library, and identified levosimendan as a potent anti-tau agent inhibiting tau oligomerization. 14C-isotope labeling of levosimendan identified that levosimendan covalently bound to tau cysteines, directly inhibiting disulfide-linked tau oligomerization. In addition, levosimendan was able to disassemble tau oligomers into monomers, and rescuing neurons from aggregation states. In comparison, the well-known anti-tau agents, methylene blue (MB) and LMTM, failed to protect neurons from tau-mediated toxicity, generating high-molecular weight tau oligomers. The administration of levosimendan also suppressed tau pathology in the brain, preventing cognitive declines in TauP301L-BiFC transgenic mice. Although careful validation is required, here we present the potential of levosimendan as a disease modifying therapy for tauopathies targeting tau oligomerization.

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Delta-secretase cleavage of Tau mediates its pathology and propagation in Alzheimer’s disease

Experimental & Molecular Medicine ◽

10.1038/s12276-020-00494-7 ◽

2020 ◽

Vol 52 (8) ◽

pp. 1275-1287

Author(s):

Seong Su Kang ◽

Eun Hee Ahn ◽

Keqiang Ye

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Strategy ◽

Senile Plaques ◽

Tau Pathology ◽

Disease Modifying ◽

Tau Aggregation ◽

The Brain ◽

Insight Into

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disease with age as a major risk factor. AD is the most common dementia with abnormal structures, including extracellular senile plaques and intraneuronal neurofibrillary tangles, as key neuropathologic hallmarks. The early feature of AD pathology is degeneration of the locus coeruleus (LC), which is the main source of norepinephrine (NE) supplying various cortical and subcortical areas that are affected in AD. The spread of Tau deposits is first initiated in the LC and is transported in a stepwise manner from the entorhinal cortex to the hippocampus and then to associative regions of the neocortex as the disease progresses. Most recently, we reported that the NE metabolite DOPEGAL activates delta-secretase (AEP, asparagine endopeptidase) and triggers pathological Tau aggregation in the LC, providing molecular insight into why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in the disease and how δ-secretase mediates the spread of Tau pathology to the rest of the brain. This review summarizes our current understanding of the crucial role of δ-secretase in driving and spreading AD pathologies by cleaving multiple critical players, including APP and Tau, supporting that blockade of δ-secretase may provide an innovative disease-modifying therapeutic strategy for treating AD.

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The Role of BAR Proteins and the Glycocalyx in Brain Endothelium Transcytosis

Cells ◽

10.3390/cells9122685 ◽

2020 ◽

Vol 9 (12) ◽

pp. 2685

Author(s):

Diana M. Leite ◽

Diana Matias ◽

Giuseppe Battaglia

Keyword(s):

Endothelial Cells ◽

Small Molecules ◽

The Other ◽

Brain Endothelial Cells ◽

Brain Endothelium ◽

Transcellular Transport ◽

Molecular Transporters ◽

Membrane Bound ◽

The Brain

Within the brain, endothelial cells lining the blood vessels meticulously coordinate the transport of nutrients, energy metabolites and other macromolecules essential in maintaining an appropriate activity of the brain. While small molecules are pumped across specialised molecular transporters, large macromolecular cargos are shuttled from one side to the other through membrane-bound carriers formed by endocytosis on one side, trafficked to the other side and released by exocytosis. Such a process is collectively known as transcytosis. The brain endothelium is recognised to possess an intricate vesicular endosomal network that mediates the transcellular transport of cargos from blood-to-brain and brain-to-blood. However, mounting evidence suggests that brain endothelial cells (BECs) employ a more direct route via tubular carriers for a fast and efficient transport from the blood to the brain. Here, we compile the mechanism of transcytosis in BECs, in which we highlight intracellular trafficking mediated by tubulation, and emphasise the possible role in transcytosis of the Bin/Amphiphysin/Rvs (BAR) proteins and glycocalyx (GC)—a layer of sugars covering BECs, in transcytosis. Both BAR proteins and the GC are intrinsically associated with cell membranes and involved in the modulation and shaping of these membranes. Hence, we aim to summarise the machinery involved in transcytosis in BECs and highlight an uncovered role of BAR proteins and the GC at the brain endothelium.

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Neutralization of Relaxin within the Brain Affects the Timing of Birth in Rats*

Endocrinology ◽

10.1210/endo.139.2.5741 ◽

1998 ◽

Vol 139 (2) ◽

pp. 479-484 ◽

Cited By ~ 14

Author(s):

A. J. S. Summerlee ◽

D. G. Ramsey ◽

R. S. Poterski

Keyword(s):

Monoclonal Antibody ◽

Birth Rate ◽

Physiological Role ◽

Live Birth Rate ◽

Premature Delivery ◽

Specific Monoclonal Antibody ◽

Pregnant Rats ◽

Plasma Progesterone ◽

The Brain ◽

Length Of Gestation

Abstract Experiments were performed to determine whether neutralization of relaxin in the brain, by injecting monoclonal antibodies to rat relaxin into the ventricular system of the brain, affected either the timing or the processes of birth in rats. Pregnant rats were injected daily through a chronically implanted intracerebroventricular cannula either with a specific monoclonal antibody raised against rat relaxin from days 12–22 of gestation or with an antibody raised against fluorescein as a control. The rats were watched closely from the afternoon of day 20 of pregnancy, and the process of birth was observed. No sign of dystocia was observed in any of the rats in the experiment. Neutralization of endogenous relaxin caused a significant decrease in the length of gestation (505.4 ± 3.1 h) compared with that in rats treated with PBS (524.6 ± 0.5 h) or that in rats treated with a nonspecific antibody (525.9 ± 0.7 h). The time to the onset of delivery was also shorter in the relaxin-neutralized group (507.8 ± 1.1 h) compared with that in either PBS-treated (526.5 ± 0.6 h) or fluorescein antibody-treated (525.3 ± 0.7 h) animals. In contrast, there was no significant effect of the relaxin antibody on length of straining, duration of parturition, delivery interval, live birth rate, or body weight of the neonates. Premature delivery in the relaxin-neutralized group was accompanied by a 24-h advance in the fall in plasma progesterone. These data support the hypothesis that there may be a central relaxin system that is independent of the peripheral relaxin system. Central relaxin may have a significant physiological role on the timing of pregnancy in the rat, but does not affect the course of labor once it has started.

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