With Japan’s aging population, the number of individuals diagnosed with dementia has been steadily rising, creating significant social and economic challenges. Dementia is caused by various underlying conditions that lead to acquired brain injury. It is characterized by a progressive decline in cognitive function, which can impair activities of daily living (ADLs) and social interactions. However, current medical interventions for neurodegenerative dementias remain insufficient to achieve a complete cure.

Over the years, research has accumulated a vast amount of knowledge about the pathogenesis of dementia, including Alzheimer’s disease (AD). However, fundamental treatments for AD have not yet been established. In this article, we discuss an Aβ receptor, paired immunoglobulin like receptor B (PirB) and its endogenous regulator lateral olfactory tract usher substance (LOTUS), which are completely different novel drug target from existing drugs, and the possibility of endogenous inhibitors of PirB. PirB expressed in neurons is a negative regulator of neuronal plasticity, as loss or inhibition of PirB increases neuronal plasticity, leading to increased spine density and improved cognitive function. Furthermore, PirB is known to function as a receptor for Aβ, leading to reduced neuronal plasticity and cell death. These findingss suggest that PirB can be positioned as a novel drug target for the treatment of AD. The neuronal circuit-forming factor LOTUS, which binds to PirB and functions as an endogenous antagonist, has been shown to inhibit the neurotoxic effects of Aβ mediated by PirB. Namely, LOTUS is an endogenous molecule that inhibits Aβ receptor function of PirB and may have medicinal effects against Aβ pathology.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia. Its pathological features include abnormal aggregation of amyloid-β (Aβ) and tau proteins, neuronal loss, and brain atrophy. The “amyloid hypothesis” suggests that Aβ accumulation triggers disease progression, leading to the development of anti-Aβ antibody therapies. However, their effectiveness is limited once dementia has developed, highlighting the need for early intervention in the preclinical stage. This review focuses on type 2 diabetes (T2D) and insulin resistance as acquired risk factors for AD, summarizing epidemiological and experimental evidence on their impact on AD neuropathology. While early postmortem studies produced inconsistent results regarding the association between T2D, insulin resistance, and Aβ deposition, recent amyloid PET imaging studies have clarified this relationship in the human brain. Additionally, animal studies suggest that diet-induced insulin resistance promotes Aβ accumulation. Conversely, genetic disruption of insulin signaling molecules significantly suppresses Aβ pathology. These seemingly contradictory findings suggest that while reduced brain insulin signaling may inhibit Aβ pathology, peripheral metabolic disturbances associated with worsening insulin resistance may accelerate Aβ deposition. Understanding the multifaceted roles of insulin signaling and the molecular basis of these complex interactions is crucial for identifying new preventive and disease-modifying therapeutic targets. Advancing this knowledge is essential for developing innovative AD treatments.

More than half of chronic methamphetamine (METH) users exhibit multi-domain cognitive deficits, including impaired attention, executive function, and memory. MRI studies consistently demonstrate hippocampal atrophy and frontotemporal cortical thinning; these structural changes spatially overlap with glial activation, indicating the coexistence of morphological damage and ongoing neuroinflammation. To clarify causality, we developed a mouse model in which low-dose METH is micro-infused into the nucleus accumbens. The mice displayed cognitive dysfunction and hippocampal long-term potentiation deficits together with microglial activation and mRNA up-regulation of IL-1β and the complement component C1q. Suppressing microglial activation with minocycline normalized these soluble factors and restored cognitive function. Complement proteins drive microglia-mediated synaptic pruning, and their over-activation has been implicated in Alzheimer’s disease and schizophrenia. Taken together, our findings suggest that METH-induced cognitive impairment is mediated by abnormal microglial pruning via complement signaling. This review summarizes the clinical phenotype of METH-related cognitive dysfunction, integrates preclinical findings, and proposes novel therapeutic avenues that target microglial activation.

In recent years, the “translational gap” has become problematic in drug development, wherein promising results from animal experiments and in vitro tests fail to demonstrate the expected efficacy and safety in clinical trials. This translational gap has also impacted on the development of therapeutic agents for brain diseases, including Alzheimer’s disease (AD). While microglia, which are immune cells in the brain, have gained attention as therapeutic targets of AD, the inter-species difference in microglia between humans and experimental model animals may cause this gap. To reveal the pathogenic mechanisms of AD and develop a therapeutic strategy, experimental models that appropriately reproduce pathological conditions using human-derived materials are required. Pluripotent stem cells can differentiate into various cells such as neurons and microglia. Therefore, it is expected that the creation of neural organoids from human pluripotent stem cells will enable the construction of a human-based analysis system that can reproduce three-dimensional brain structures and intercellular interactions, thereby overcoming the translational gap. Furthermore, combining patient-derived induced pluripotent stem cells and gene editing technology with neural organoid technology is leading to cutting-edge research. In this review, we introduce global research trends aimed at developing neural organoids containing microglia derived from human pluripotent stem cells and applying them to elucidate the pathogenesis and to develop therapeutic drugs for AD.

Age-related alterations in brain function are considered a physiological phenomenon that everyone may experience as a decline in memory and cognitive abilities. However, the rate of progression varies among individuals, and the underlying mechanisms remain largely unclear. Microglia, the resident immune cells of the brain, play a crucial role in maintaining central nervous system homeostasis through diverse functions such as phagocytosis of cellular debris, synaptic pruning, and regulation of neuroinflammatory responses. Previous studies have demonstrated that the cellular morphology of microglia undergoes significant changes with age. Furthermore, recent advances in RNA sequencing analysis techniques have revealed that microglia are not a homogeneous cell population but rather consist of diverse subpopulations. Notably, white matter-associated microglia (WAM) and interferon-response microglia (IRM) are reported to increase in proportion with aging. Thus, aging induces complex changes in the morphology, function, and subpopulation composition of microglia, which may impair the homeostatic maintenance of brain and contribute to age-related alterations in brain function, such as cognitive decline. This review focuses on the impact of aging on microglia and their association with changes in brain function, presenting the latest findings in this field.

Glaucoma is the leading cause of blindness worldwide. Vision loss in glaucoma is caused by damage to retinal ganglion cells (RGCs), which are responsible for transmitting visual information from the retina to the brain. Glaucoma is a multifactorial disease with multiple risk factors, among which elevated intraocular pressure (IOP) is the most well-established. Currently, lowering IOP is the mainstay of glaucoma treatment. However, disease progression is frequently observed even in patients whose IOP is well controlled. Notably, the majority of Japanese glaucoma patients are diagnosed with normal-tension glaucoma (NTG). These observations highlight the urgent need to elucidate IOP-independent mechanisms contributing to glaucoma pathogenesis. In this context, increasing attention has been directed toward the potential role of glial cells in the development and progression of glaucoma. Glial cells are known to play critical roles in various neurodegenerative diseases. In glaucoma, glial activation and dysfunction have been documented in the ocular tissue of human patients, as well as in primate and rodent models. Importantly, glial activation is observed at early stages of glaucoma, even before detectable RGC loss occurs. This raises the possibility that glial dysfunction is not merely a secondary response to neuronal injury but may serve as a primary driver of disease onset. For example, deletion of glial cell-specific genes has been shown to induce NTG-like phenotypes. This article provides an overview of recent advances in our understanding of the role of glial cells in glaucoma pathogenesis, with a focus on insights gained from our own research.

Various behavior analysis methods have been developed using different animal species to elucidate the pathophysiology of behavioral abnormalities in humans and develop therapeutic agents. The development of behavior analysis methods using zebrafish has also been progressing, and a substantial body of knowledge has been accumulated. In this paper, we introduce the Novel tank test for assessing anxiety, the Mirror biting test for assessing aggression, and the Social interaction test for assessing sociality. These methods are relatively easy to implement in ordinary laboratories. We also discuss the problems associated with behavioral analyses using zebrafish. For example, zebrafish strains frequently used in behavioral analyses are not inbred, such as C57BL/6 in mice and F344 in rats. There are differences among the zebrafish strains in terms of cortisol levels, neural marker expression, and behavior characteristics. The housing and husbandry of zebrafish also vary among laboratories. Standardizing these factors is important to increase the reproducibility and replicability of zebrafish neurobehavioral research. Understanding the characteristics of each method and selecting the appropriate behavior analysis method according to the purpose will facilitate the understanding of the pathophysiology of human diseases and the development of new treatments.

This study evaluated the utility of an integrated drug discovery strategy that combines three emerging data-driven approaches: real-world data analysis, in silico screening, and network pharmacology. First, transcriptomic data from public gene expression databases and adverse event reports were analyzed to address myocarditis induced by immune checkpoint inhibitors. The findings suggested a preventive effect of non-steroidal anti-inflammatory drugs, particularly those targeting the arachidonic acid metabolism pathway. Second, to identify therapeutic options for trastuzumab-resistant HER2-positive breast cancer, a cheminformatics approach was applied. A machine learning classification model and structure-based docking simulations enabled efficient in silico screening of approved drugs, identifying novel YES1 kinase inhibitors. Third, network-based analysis evaluated the topological distance between disease-associated gene modules and statin-induced gene modules in drug-induced peripheral neuropathy. This analysis indicated that certain statins may protect against drug-induced peripheral neuropathy through modulation of shared targets and neurodegenerative pathways. These findings demonstrate that integrating heterogeneous data modalities—from transcriptomics and chemical structure to protein–protein interaction networks and real-world clinical observations—can enable the discovery of repositioning candidates and risk-mitigating therapies. The study highlights the potential of multi-layered, data-driven strategies in constructing translational drug discovery frameworks aimed at both efficacy and safety.

Hereditary angioedema (HAE) is a rare life-threatening disease with recurrent edema. We outline the pharmacological characteristics and study results of a new drug, garadacimab (human anti-activated factor XII [FXIIa] monoclonal antibody), which has novel mechanism of action and suppresses acute HAE attacks. In HAE, excessive bradykinin production, an inflammatory mediator increasing vascular permeability, causes edema, and activation of factor XII initiates bradykinin production. Garadacimab suppresses bradykinin production by inhibiting FXIIa. HAE attacks include fatal laryngeal edema, and overall severity varies substantially among patients. There is an unmet medical need for treatment to reduce its frequency and severity. For prophylactic treatment, a convenient drug with long-administration interval is desired to reduce patients’ burden. Based on results of Phase I study in healthy subjects and Phase II study of multiple doses in patients, efficacy and safety of monthly administration of 200 mg garadacimab were compared in 64 patients (ITT: 39 in garadacimab and 25 in placebo) in Phase III study. The primary endpoint, monthly attack frequency was significantly lower in garadacimab than placebo (0.27 vs. 2.01; P < 0.001), with relative reduction rate 87%. Monthly subcutaneous administration of 200 mg garadacimab showed favorable safety profile. The proportion of patients who remained attack-free during the 6-month was 62% in garadacimab and 0% in placebo, and effect after the first dose was maintained throughout the study period. Since this drug is administered subcutaneously once a month with autoinjector, reduction of patients’ burden is also expected.