Biology subjects

Otsuka, T.

Publications and source records attributed to Otsuka, T..

3 recordsLinked to original sources

bioRxiv2024

Extracellular disposal of nuclear waste by APP: a protective mechanism impaired in Alzheimer's disease

Although the amyloid beta (A{beta}) hypothesis1 has long been central to Alzheimers disease (AD) research, effective therapeutic strategies remain elusive2,3. Here we re-evaluate the functions of amyloid precursor protein (APP) and reveal its critical function in protecting against nuclear impairment-induced cell death and inflammation4,5. Overexpression of APP mitigated etoposide or lamin A knockdown-induced nuclear damage, while APP removal or mutations exacerbated these effects. Interestingly, neurons differentiated from induced pluripotent stem cells (iPSCs) exhibited similar patterns, and notably, familial AD-associated mutant APP failed to confer protection against nuclear impairment. We identify APPs interaction with a cytoplasmic structure of nuclear origin, termed "nuclear waste", and propose its role in extracellular waste disposal. Intriguingly, cells lacking APP showed impaired nuclear waste clearance, leading to abnormal cytoplasmic accumulation of the nuclear waste. Similarly, neuron-specific APP overexpression using adeno-associated virus (AAV) in mice reduced neuronal death and inflammation caused by nuclear damage. Conversely, shRNA-mediated APP exacerbated these effects, and mutant APP associated with familial AD lacked protective effects. Moreover, postmortem analysis of AD brains revealed accumulation of abnormal nuclear waste in the neurocytoplasm, irregular nuclear morphology, and reduced APP levels per neuron. Our data underscore APPs crucial role in disposing of nuclear waste, maintaining cellular homeostasis, and suggest its dysregulation as a potential contributor to AD pathogenesis. Restoring APP waste clearance in AD could be a promising target for disease-modifying therapies.

neuroscience↗

bioRxiv2023

Near-optimal integration of the magnitude Information of time and numerosity

Magnitude information is often correlated in the external world, providing complementary information about the environment. As if to reflect this relationship, the perceptions of different magnitudes (e.g., time and numerosity) are known to influence one another. Recent studies suggest that such magnitude interaction is similar to cue integration, such as multisensory integration. Here, we tested whether human observers could integrate the magnitudes of two quantities with distinct physical units (i.e., time and numerosity) as abstract magnitude information. The participants compared the magnitudes of two visual stimuli based on time, numerosity, or both. Consistent with the predictions of the maximum likelihood estimation (MLE) model, the participants integrated time and numerosity in a near-optimal manner; the weights for numerosity increased as the reliability of the numerosity information increased, and the integrated estimate was more reliable than either the time or numerosity estimate. Furthermore, the integration approached a statistical optimum as the temporal discrepancy of the acquisition of each piece of information became smaller. These results suggest that magnitude interaction arises through a similar computational mechanism to cue integration. They are also consistent with the idea that different magnitudes are processed by a generalized magnitude system.

neuroscience↗

bioRxiv2022

Castration alters the circadian clock and Ucp1 expression in subcutaneous white adipose tissue of mice

Castration increases the risk of metabolic syndromes in mammals. In addition, recent studies have demonstrated that castration increases the expression of Ucp1 in subcutaneous white adipose tissue (scWAT). However, how castration leads to thermogenic aberration remains poorly understood. Here, we found that castrated mice showed elevated Ucp1 expression in scWAT in response to cold exposure with an increase in body temperature in the light phase and a reduction in body weight gain with fat reduction despite showing no alterations in food intake, locomotor activity in a novel environment, and gastrocnemius muscle weight. We also analyzed the circadian behavioral rhythm and the expression rhythm of clock genes in the suprachiasmatic nucleus (SCN) and scWAT. We found that castrated mice showed fluctuations in circadian locomotor activity and a decrease in the expression rhythm of clock genes in the SCN (clock) and scWAT (Bmal1 and Per2). Moreover, the expression of Ucp1 in scWAT was rhythmic, and it was increased in castrated mice, while the expression of clock genes was decreased. These results indicate that castration may impact browning in scWAT through variations in the circadian clock and Ucp1 expression.

physiology↗