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Tau pathology is instrumental in the gradual loss of neuronal functions and cognitive decline in tauopathies, including Alzheimer's disease (AD). Earlier reports showed that adenosine metabolism is abnormal in the brain of AD patients while consequences remained ill-defined. Herein, we aimed at investigating whether manipulation of adenosine tone would impact Tau pathology, associated molecular alterations and subsequent neurodegeneration. We demonstrated that treatment with an inhibitor (J4) of equilibrative nucleoside transporter 1 (ENT1) exerted beneficial effects in a mouse model of Tauopathy. Treatment with J4 not only reduced Tau hyperphosphorylation but also rescued memory deficits, mitochondrial dysfunction, synaptic loss, and abnormal expression of immune-related gene signatures. These beneficial effects were particularly ascribed to the ability of J4 to suppress the overactivation of AMPK (an energy reduction sensor), suggesting that normalization of energy dysfunction mitigates neuronal dysfunctions in Tauopathy. Collectively, these data highlight that targeting adenosine metabolism is a novel strategy for tauopathies.

This study investigated the factorial invariance of the Taiwan Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V) across age and gender. A higher order five-factor model was tested on a nationally representative sample of 1,034 children aged 6-16 years. The results demonstrated full factorial invariance for Taiwan children of different ages and gender. The WISC-V subtests demonstrated the same underlying theoretical latent constructs, strength of relations among factors and subtests, validity of each first-order factor, and communalities, regardless of age and gender, which supported the same interpretive approach of the WISC-V. These results accord with findings in the United States, indicating a full factorial invariance of the WISC-V five-factor structure across ages and gender.

Virtual reality (VR) exercise has been used as a strategy to promote physical health in older adults. Studies have revealed that the effects of exercise interventions vary across age groups. This study aimed to investigate the effects of a 12-week semi-immersion VR-based multicomponent exercise program on the functional fitness of young-old (65–73 years) and middle-old (74–85 years) adults. This study recruited two age groups (young-old adults, n = 49; middle-old adults, n = 37) and randomly assigned them to the experimental (EG) and control (CG) groups. EG participants performed a 75–90-min semi-immersion VR exercise routine twice weekly for 12 weeks, whereas CG participants maintained their original lifestyles without any alterations. The Senior Fitness Test was used to measure functional fitness by assessing upper- and lower-limb flexibility and muscle strength, cardiorespiratory fitness, and balance. EG participants exhibited greater improvements than their CG counterparts in certain functional fitness tests, specifically the Back Scratch, Arm Curl, 2-Minute Step, and 8-Foot Up-and-Go Tests. On comparing the age groups, a difference was exclusively noted in the effects of the Chair Sit-and-Reach Test. In the EG, the intervention significantly improved lower-body flexibility in young-old adults but elicited no such improvement in middle-old adults. Semi-immersion VR exercise improved the functional fitness of young-old and middle-old adults in the EG, with superior results in the former. Elucidating the impact of age-specific exercise interventions on functional capacity will help practitioners design age-specific exercise training content that enhances functional fitness in older adults of different ages. [ABSTRACT FROM AUTHOR]

Proteolytic processing of amyloid precursor protein (APP) C-terminal fragments (CTFs) by γ-secretase underlies the pathogenesis of Alzheimer's disease (AD). An RNA interference screen using APP-CTF [99-residue CTF (C99)]- and Notch-specific γ-secretase interaction assays identified a unique ErbB2-centered signaling network that was predicted to preferentially govern the proteostasis of APP-C99. Consistently, significantly elevated levels of ErbB2 were confirmed in the hippocampus of human AD brains. We then found that ErbB2 effectively suppressed autophagic flux by physically dissociating Beclin-1 from the Vps34-Vps15 complex independent of its kinase activity. Down-regulation of ErbB2 by CL-387,785 decreased the levels of C99 and secreted amyloid-β in cellular, zebrafish, and mouse models of AD, through the activation of autophagy. Oral administration of an ErbB2-targeted CL-387,785 for 3 wk significantly improves the cognitive functions of APP/presenilin-1 (PS1) transgenic mice. This work unveils a noncanonical function of ErbB2 in modulating autophagy and establishes ErbB2 as a therapeutic target for AD.

Thrombosis, characterized by blood clot formation within vessels, poses a significant medical challenge. Despite extensive research, the development of effective thrombosis therapies is hindered by substantial costs, lengthy development times, and high failure rates in medication commercialization. Conventional pre-clinical models often oversimplify cardiovascular disease, leading to a disparity between experimental results and human physiological responses. In response, we have engineered a photothrombosis-on-a-chip system. This microfluidic model integrates human endothelium, human whole blood, and blood flow dynamics and employs the photothrombotic method. It enables precise, site-specific thrombus induction through controlled laser irradiation, effectively mimicking both normal and thrombotic physiological conditions on a single chip. Additionally, the system allows for the fine-tuning of thrombus occlusion levels via laser parameter adjustments, offering a flexible thrombus model with varying degrees of obstruction. Additionally, the formation and progression of thrombosis noted on the chip closely resemble the thrombotic conditions observed in mice in previous studies. In the experiments, we perfused recalcified whole blood with Rose Bengal into an endothelialized microchannel and initiated photothrombosis using green laser irradiation. Various imaging methods verified the model's ability to precisely control thrombus formation and occlusion levels. The effectiveness of clinical drugs, including heparin and rt-PA, was assessed, confirming the chip's potential in drug screening applications. In summary, the photothrombosis-on-a-chip system significantly advances human thrombosis modeling. Its precise control over thrombus formation, flexibility in the thrombus severity levels, and capability to simulate dual physiological states on a single platform make it an invaluable tool for targeted drug testing, furthering the development of organ-on-a-chip drug screening techniques. [ABSTRACT FROM AUTHOR]