Yeung, L. | Search bioRxiv

bioRxiv2026

Tau-induced mitochondrial reverse electron transport drives neurodegeneration

Hyperphosphorylation and aggregation of the microtubule-associated protein tau are recognized as pathological hallmarks of tauopathies; however, the biological activity of tau that drives its pathophysiological effects remains poorly understood1-6. Mitochondrial dysfunction is a common feature of tauopathies7,8. Despite this, the mechanistic link between tau abnormalities and mitochondrial dysfunction, as well as its relationship to taus physiological function, remains unclear. Here, we demonstrate that tau regulates mitochondrial reverse electron transport (RET), which produces excess ROS, reduces the NAD+/NADH ratio, and is activated by aging or stress. In flies, mice, and human induced pluripotent stem cells (hiPSC)-derived neurons, tau depletion eliminates stress-induced RET and confers significant stress resistance. Mechanistically, tau enters mitochondria and directly interacts with the mitochondrial complex I (C-I) subunit NDUFS3, enhancing RET activation in a phosphorylation-dependent manner that correlates with tau pathogenicity. Elevated RET further drives tau hyperphosphorylation, establishing a self-perpetuating pathological loop. Blocking tau entry into mitochondria or disrupting tau/NDUFS3 interaction reduces tau-induced RET. Genetic or pharmacological inhibition of RET protects against tau-induced neurodegeneration across species. RET regulation represents a previously unrecognized normal function of tau that becomes pathological in disease, providing a therapeutic target for conditions characterized by tau abnormalities and mitochondrial dysfunction.

neuroscience↗

bioRxiv2026

Reduced Pupil-Linked Arousal Marks Implicit Memory for Complex Auditory Sequences

Observers rapidly form long-lasting implicit memories for recurring sensory patterns, supporting adaptive behaviour through learning of environmental contingencies. Here we tested how such memories interact with neuromodulatory systems that regulate arousal--whether implicit familiarity increases arousal through retrieval-related processes or instead decreases arousal via more efficient sensory processing. We examined these competing accounts using complex auditory tone-pip sequences in which a subset of patterns recurred approximately every three minutes. One group of participants (N=30) actively detected transitions from random to regular structure, whereas a second group (N=40) heard the same sequences while performing a decoy task. Consistent with prior work, recurring regular sequences elicited faster reaction times in the active group, confirming the formation of implicit memory. Subsequently, both groups listened to previously encountered regular patterns (REGr) and matched novel regular patterns (REGn) while pupil diameter was recorded. Across groups, REGr sequences evoked significantly smaller pupil dilations than REGn sequences, indicating attenuated arousal for familiar patterns. This reduction was sustained until sequence offset in the active group but was transient in the exposure group, suggesting that task demands during exposure shape the stability of pupil-linked memory expression. Importantly, the REGr-REGn pupil difference did not correlate with explicit post-session recognition, demonstrating that the effect was not driven by conscious awareness. Together, these findings identify pupil dynamics as a robust physiological marker of learned auditory structure and show that implicit auditory sequence memory attenuates arousal. The results support predictive processing accounts in which familiarity reduces uncertainty and, consequently, neuromodulatory drive. Significance StatementHumans rapidly acquire implicit memories for recurring sounds, yet how such memories influence arousal during subsequent exposure remains poorly understood. Using pupillometry, we show that implicitly remembered auditory sequences evoke reduced pupil-linked arousal relative to matched novel sequences, even when listeners are unaware that the patterns have been previously experienced. This effect dissociates from explicit recognition, which typically yields the opposite "old/new" pattern of larger pupil responses to familiar items. Together, these findings establish pupil dynamics as a sensitive, non-invasive marker of implicit auditory memory and support predictive processing accounts in which familiarity reduces uncertainty and, consequently, neuromodulatory drive.

neuroscience↗

bioRxiv2020

Segmentation boosting with compensation methods in optical coherence tomography angiography images

Optical coherence tomography angiography is a noninvasive imaging modality to establish the diagnosis of retinal vascular diseases. However, angiography images are significantly interfered if patients jitter or blink. In this study, a novel retinal image analysis method to accurately detect blood vessels and compensate the effect of interference was proposed. We call this the patch U-Net compensation (PUC) system, which is based on the famous U-Net. Several techniques, including a better training mechanism, direction criteria, area criteria, gap criteria, and probability map criteria, have been proposed to improve its accuracy. Simulations show that the proposed PUC achieves much better performance than state-of-art methods.

bioengineering↗