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Pathological hyperphosphorylation and aggregation of microtubule‐associated Tau protein contribute to Alzheimer's Disease (AD) and other related tauopathies. Currently, no cure exists for Alzheimer's Disease. Aptamers offer significant potential as next‐generation therapeutics in biotechnology and the treatment of neurological disorders. Traditional aptamer selection methods for Tau protein focus on binding affinity rather than interference with pathological Tau. In this study, we developed a new selection strategy to enrich DNA aptamers that bind to surviving monomeric Tau protein under conditions that would typically promote Tau aggregation. Employing this approach, we identified a set of aptamer candidates. Notably, BW1c demonstrates a high binding affinity (Kd=6.6 nM) to Tau protein and effectively inhibits arachidonic acid (AA)‐induced Tau protein oligomerization and aggregation. Additionally, it inhibits GSK3β‐mediated Tau hyperphosphorylation in cell‐free systems and okadaic acid‐mediated Tau hyperphosphorylation in cellular milieu. Lastly, retro‐orbital injection of BW1c tau aptamer shows the ability to cross the blood brain barrier and gain access to neuronal cell body. Through further refinement and development, these Tau aptamers may pave the way for a first‐in‐class neurotherapeutic to mitigate tauopathy‐associated neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Children of parents with traumatic brain injury (TBI) are more likely to develop psychiatric disorders. This association is usually attributed to TBI-induced changes in parents' personality and families' social environment. We tested the hypothesis that offspring of young adult male rats with TBI develop neurodevelopmental abnormalities in the absence of direct social contact with sires. Male Sprague-Dawley rats (F0 generation) in the TBI group underwent moderate TBI via a midline fluid percussion injury that involved craniectomy under sevoflurane (SEVO) anesthesia for 40 min on post-natal Day 60 (P60), while F0 rats in the control group were placed in a new cage, one per cage, for the equivalent time duration. A subset of F0 rats was sacrificed on P66 to assess acute changes in hypothalamic-pituitary-adrenal (HPA) axis and inflammation markers. The remaining F0 males were mated with naive females on P90 to generate offspring (F1 generation). The F0 males and F1 males and females were sequentially evaluated in the elevated plus maze, for pre-pulse inhibition of acoustic startle, in the Morris water maze, and for resting and stress levels of serum corticosterone starting on ∼P105 (F0) and ∼P60 (F1), followed by tissue collection for further analyses. Acutely, the F0 TBI males had messenger RNA (mRNA) transcripts altered to support an increased hypothalamic and hippocampal Na+-K+-Cl- (Slc12a2) Cl- importer / K+-2Cl- (Slc12a5) Cl- exporter ratio and decreased hippocampal glucocorticoid receptors (Nr3c1), as well as increased serum levels of corticosterone, interleukin-1β (IL-1β), and biomarkers of activated hippocampal microglia and astrocytes. Long-term, F0 TBI rats exhibited increased corticosterone concentrations at rest and under stress, anxiety-like behavior, impaired sensory-motor gating, and impaired spatial memory. These abnormalities were underpinned by reduced mRNA levels of hypothalamic and hippocampal mineralocorticoid receptors (Nr3c2), hippocampal Nr3c1, and hypothalamic brain-derived neurotrophic factor (Bdnf), as well as elevated serum levels of IL-1β, and biomarkers of activated hippocampal microglia and astrocytes. F1 male offspring of TBI sires exhibited abnormalities in all behavioral tests, while their F1 female counterparts had abnormal pre-pulse inhibition responses only. F1 male offspring of TBI sires also had reduced mRNA levels of hippocampal Nr3c1 and Nr3c2, as well as hypothalamic and hippocampal Bdnf, whereas increases in inflammatory markers were more profound in F1 females. These findings suggest that offspring of sires with a history of a moderate TBI that involved craniectomy under SEVO anesthesia for 40 min, develop sex-dependent neurobehavioral abnormalities in the absence of direct social interaction between the sire and the offspring. [ABSTRACT FROM AUTHOR]

Pathological hyperphosphorylation and aggregation of microtubule-associated Tau protein contribute to Alzheimer's Disease (AD) and other related tauopathies. Currently, no cure exists for Alzheimer's Disease. Aptamers offer significant potential as next-generation therapeutics in biotechnology and the treatment of neurological disorders. Traditional aptamer selection methods for Tau protein focus on binding affinity rather than interference with pathological Tau. In this study, we developed a new selection strategy to enrich DNA aptamers that bind to surviving monomeric Tau protein under conditions that would typically promote Tau aggregation. Employing this approach, we identified a set of aptamer candidates. Notably, BW1c demonstrates a high binding affinity (K d =6.6 nM) to Tau protein and effectively inhibits arachidonic acid (AA)-induced Tau protein oligomerization and aggregation. Additionally, it inhibits GSK3β-mediated Tau hyperphosphorylation in cell-free systems and okadaic acid-mediated Tau hyperphosphorylation in cellular milieu. Lastly, retro-orbital injection of BW1c tau aptamer shows the ability to cross the blood brain barrier and gain access to neuronal cell body. Through further refinement and development, these Tau aptamers may pave the way for a first-in-class neurotherapeutic to mitigate tauopathy-associated neurodegenerative disorders., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Introduction: Decompression sickness (DCS) results from a decrease in ambient pressure leading to supersaturation of tissues with inert gas and bubble formation. Perfluorocarbons (PFCs) are able to dissolve vast amounts of non-polar gases. Intravenous (IV) PFC emulsions reduce both morbidity and mortality associated with DCS, but the mechanism of this protective effect has not yet been demonstrated., Methods: Juvenile Dorper-cross sheep (n = 31) were anaesthetised and instrumented for physiological monitoring, IV fluid administration and blood sampling. Animals were compressed in air in a hyperbaric chamber to 608 kPa for 30 minutes and then rapidly decompressed. Upon decompression, animals were randomly assigned to receive 6 mmol per L of PFC or saline over 10 minutes beginning immediately after chamber exit. Arterial and mixed venous bloods were drawn at 5, 10, 15, 30, 60 and 90 minutes to examine pH, partial pressures of oxygen and carbon dioxide, oxygen saturation and electrolytes., Results: Compared to saline, PFC administration increased arterial oxygen content (16.33 ± 0.28 vs. 14.68 ± 0.26 ml per dL, P < 0.0001), mixed venous oxygen content (12.56 ± 0.28 vs. 11.62 ± 0.26 ml per dL, P = 0.0167), oxygen delivery (14.83 ± 0.28 vs. 13.39 ± 0.26 mmol per L kg, P = 0.0003) and tissue oxygen consumption (3.30 ± 0.15 vs. 2.78 ± 0.13 mmol per L kg, P = 0.0149) but did not increase extraction ratio (0.22 ± 0.012 vs. 0.21 ± 0.011, P = 0.5343)., Conclusions: It is likely that the improved oxygenation explains, at least in part, the previously-observed therapeutic effects of PFCs in DCS.

Formation of bubbles in tissue and vasculature from a sudden reduction in ambient pressure is likely an underlying cause of the clinical symptoms of decompression sickness (DCS). Thus, tools detecting bubbles in the vasculature may be important for evaluating DCS. Sheep were air-compressed to 6.0 ATA (30 minutes bottom time) then rapidly decompressed to the surface. A fundus camera was quickly positioned for continuous observation of the retinal vasculature. Bubbles were observed in the retinal vasculature of 25.8% (n = 31) of the sheep. Bubble onset time ranged from 5-22 minutes post-chamber and lodge time ranged from 0-70+ minutes. Bubbles were visualized mostly in the arteries of the retinal circulation. Severe vasoconstriction was captured using red-free angiography in two sheep. In two other sheep, fluorescein angiography demonstrated occluded blood flow caused by arterial gas emboli. This study demonstrates that retinal angiography is a practical tool for real-time, noninvasive detection of bubbles in the retinal circulation, a visible window to the cerebral circulation. Thus retinal angiography may prove invaluable in the early detection of arterial gas emboli in the cerebral circulation, the resolution of which is imperative to favorable neurological outcomes. This study also presents for the first time images of bubbles in the retinal circulation associated with DCS captured by a fundus camera.