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Brain capillary endothelial cells form the blood-brain barrier (BBB), which is covered with basement membranes and is also surrounded by pericytes and astrocyte end-feet in the neurovascular unit. The BBB tightly regulates the molecular exchange between the blood flow and brain parenchyma, thereby regulating the homeostasis of the central nervous system (CNS). Thus, dysfunction of the BBB is likely involved in the pathogenesis of several neurological diseases, including Alzheimer’s disease (AD). While amyloid-β (Aβ) deposition and neurofibrillary tangle formation in the brain are central pathological hallmarks in AD, cerebrovascular lesions and BBB alteration have also been shown to frequently coexist. Although further clinical studies should clarify whether BBB disruption is a specific feature of AD pathogenesis, increasing evidence indicates that each component of the neurovascular unit is significantly affected in the presence of AD-related pathologies in animal models and human patients. Conversely, since some portions of Aβ are eliminated along the neurovascular unit and across the BBB, disturbing the pathways may result in exacerbated Aβ accumulation in the brain. Thus, current evidence suggests that BBB dysfunction may causatively and consequently contribute to AD pathogenesis, forming a vicious cycle between brain Aβ accumulation and neurovascular unit impairments during disease progression.

Polymorphism in the apolipoprotein E (APOE) gene is a major genetic risk determinant of late-onset Alzheimer disease (AD), with the APOE*ε4 allele conferring an increased risk and the APOE*ε2 allele conferring a decreased risk relative to the common APOE*ε3 allele. Strong evidence from clinical and basic research suggests that a major pathway by which APOE4 increases the risk of AD is by driving earlier and more abundant amyloid pathology in the brains of APOE*ε4 carriers. The number of amyloid-β (Aβ)-dependent and Aβ-independent pathways that are known to be differentially modulated by APOE isoforms is increasing. For example, evidence is accumulating that APOE influences tau pathology, tau-mediated neurodegeneration and microglial responses to AD-related pathologies. In addition, APOE4 is either pathogenic or shows reduced efficiency in multiple brain homeostatic pathways, including lipid transport, synaptic integrity and plasticity, glucose metabolism and cerebrovascular function. Here, we review the recent progress in clinical and basic research into the role of APOE in AD pathogenesis. We also discuss how APOE can be targeted for AD therapy using a precision medicine approach.

APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer’s disease (AD). To address the underlying mechanism, we develop cerebral organoid models using induced pluripotent stem cells (iPSCs) with APOE ε3/ε3 or ε4/ε4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying APOE ε4/ε4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of Aβ and phosphorylated tau compared to healthy subject-derived cerebral organoids, APOE4 exacerbates tau pathology in both healthy subject-derived and AD patient-derived organoids. Transcriptomics analysis by RNA-sequencing reveals that cerebral organoids from AD patients are associated with an enhancement of stress granules and disrupted RNA metabolism. Importantly, isogenic conversion of APOE4 to APOE3 attenuates the APOE4 -related phenotypes in cerebral organoids from AD patients. Together, our study using human iPSC-organoids recapitulates APOE4 -related phenotypes and suggests APOE4 -related degenerative pathways contributing to AD pathogenesis. APOE4 is a strong genetic risk factor for late-onset Alzheimer’s disease. Here, the authors show that APOE4 is associated with AD features in hiPSCs-derived cerebral organoids. Isogenic conversion of APOE4 to APOE3 attenuates the AD-associated phenotype.

The ε4 allele of the apolipoprotein E (APOE) gene, a genetic risk factor for Alzheimer’s disease, is abundantly expressed in both the brain and periphery. Here, we present evidence that peripheral apoE isoforms, separated from those in the brain by the blood–brain barrier, differentially impact Alzheimer’s disease pathogenesis and cognition. To evaluate the function of peripheral apoE, we developed conditional mouse models expressing human APOE3 or APOE4 in the liver with no detectable apoE in the brain. Liver-expressed apoE4 compromised synaptic plasticity and cognition by impairing cerebrovascular functions. Plasma proteome profiling revealed apoE isoform-dependent functional pathways highlighting cell adhesion, lipoprotein metabolism and complement activation. ApoE3 plasma from young mice improved cognition and reduced vessel-associated gliosis when transfused into aged mice, whereas apoE4 compromised the beneficial effects of young plasma. A human induced pluripotent stem cell-derived endothelial cell model recapitulated the plasma apoE isoform-specific effect on endothelial integrity, further supporting a vascular-related mechanism. Upon breeding with amyloid model mice, liver-expressed apoE4 exacerbated brain amyloid pathology, whereas apoE3 reduced it. Our findings demonstrate pathogenic effects of peripheral apoE4, providing a strong rationale for targeting peripheral apoE to treat Alzheimer’s disease.Mouse models expressing liver apoE in the absence of brain apoE reveal detrimental effects of peripheral apoE4 associated with Alzheimer’s risk on cognition and amyloid pathology through compromising vascular integrity and function.

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that causes progressive cognitive decline. The majority of AD cases are sporadic and late-onset (>65 years old) making it the leading cause of dementia in the elderly. While both genetic and environmental factors contribute to the development of late-onset AD (LOAD), APOE polymorphism is a major genetic risk determinant for LOAD. In humans, the APOE gene has three major allelic variants: ε2, ε3, and ε4, of which APOE ε4 is the strongest genetic risk factor for LOAD, whereas APOE ε2 is protective. Mounting evidence suggests that APOE ε4 contributes to AD pathogenesis through multiple pathways including facilitated amyloid-β deposition, increased tangle formation, synaptic dysfunction, exacerbated neuroinflammation, and cerebrovascular defects. Since APOE modulates multiple biological processes through its corresponding protein apolipoprotein E (apoE), APOE gene and apoE properties have been a promising target for therapy and drug development against AD. In this review, we summarize the current evidence regarding how the APOE ε4 allele contributes to the pathogenesis of AD and how relevant therapeutic approaches can be developed to target apoE-mediated pathways in AD.

Accumulation of TMEM106B fibrils composed of cleaved C-terminal fragments (CTF) of transmembrane protein 106B (TMEM106B) has recently been observed in the brains of elderly subjects and individuals with neurodegenerative diseases. To date, one antibody recognizing the residues 239-250 has been found to display immunoreactivity to the TMEM106B CTF, thereby defining TMEM106B C-terminal immunoreactive (TMEM-ir) material. Immunohistochemical characterization of the CTF using antibodies targeting different immunogens could further shed light on the attributes of TMEM-ir material and the biological relevance of TMEM106B fibril accumulation in vivo . Therefore, we generated and validated five polyclonal antibodies against distinct CTF immunogens, namely the residues 140-163, 164-187, 188-211, 239-250, and 253-274. The antibody recognizing the residues 239-250 (antibody no. 5: 239-250) was employed to identify cases positive for TMEM-ir material. Among the remaining four antibodies, antibody no. 3: 188-211 exhibited significant immunoreactivity in TMEM-ir material-positive cases. Comparative analyzes indicated that antibody no. 3: 188-211 and antibody no. 5: 239-250 likely recognized the same TMEM-ir material. The TMEM-ir material detected by antibody no. 3: 188-211 was observed across multiple brain cell types without co-localization with other pathogenic proteins. In conclusion, our findings suggest that the antibody recognizing the residues 188-211 displays immunohistochemical reactivity to TMEM-ir material. Therefore, in addition to the established antibody recognizing the residues 239-250, the antibody recognizing the residues 188-211 can potentially be used in immunohistochemical studies to further elucidate the significance of CTF accumulation in the brain.

Carrying premature termination codons in 1 allele of the ABCA7 gene is associated with an increased risk for Alzheimer’s disease (AD). While the primary function of ABCA7 is to regulate the transport of phospholipids and cholesterol, ABCA7 is also involved in maintaining homeostasis of the immune system. Since inflammatory pathways causatively or consequently participate in AD pathogenesis, we studied the effects of Abca7 haplodeficiency in mice on brain immune responses under acute and chronic conditions. When acute inflammation was induced through peripheral lipopolysaccharide injection in control or heterozygous Abca7 knockout mice, partial ABCA7 deficiency diminished proinflammatory responses by impairing CD14 expression in the brain. On breeding to AppNL-G-F knockin mice, we observed increased amyloid-β (Aβ) accumulation and abnormal endosomal morphology in microglia. Taken together, our results demonstrate that ABCA7 loss of function may contribute to AD pathogenesis by altering proper microglial responses to acute inflammatory challenges and during the development of amyloid pathology, providing insight into disease mechanisms and possible treatment strategies.

Weight loss, a key indicator of malnutrition in amyotrophic lateral sclerosis (ALS) patients, negatively impacts patient prognosis. However, effective nutritional interventions have not been adequately established. Research in ALS model mice has shown that L-arginine can prolong survival; however, no human intervention studies have been conducted. We conducted a single-center, single-arm, prospective, open-label, and comparative trial to assess the safety and tolerability of L-arginine hydrochloride in ALS patients. ALS patients were administered 15 g/day L-arginine hydrochloride for 90 days. The primary outcome of safety was evaluated on days 45 and 90. The secondary outcome of efficacy was evaluated by measuring nutritional status, ALS Functional Rating Scale (ALSFRS) scores, and the occurrence of events such as the initiation of tracheostomy positive pressure ventilation (TPPV) and death. The study included 20 patients (40% female; mean age, 62.0 ± 6.9 years; median disease duration, 1.9 years). Six participants (30%) experienced treatment-emergent adverse events (TEAEs), including elevated creatine kinase levels, liver function test abnormalities, glucose tolerance issues, hyperammonemia, anorexia, dysgeusia, and vasculitis. No serious TEAEs were associated with L-arginine hydrochloride. Over the course of three months, the average changes in body weight, body mass index, and the ALSFRS score were − 0.37 kg, -1.1 kg/m 2 , and − 1.7 points, respectively. There were no events requiring TPPV initiation or deaths. This study demonstrated that the oral administration of L-arginine hydrochloride over three months was well tolerated by ALS patients, with no serious TEAEs or deaths attributed to the study drug. Trial Registration number : Japan Registry of Clinical Trials (jRCTs061230001), first registered 11/04/2023.

Increasing evidence suggests that periodontitis may contribute to central nervous system disorders through chronic inflammation, but its role in multiple sclerosis (MS) remains unclear. This exploratory, cross-sectional study investigated the associations between the relative abundance of periodontal pathogens in the oral cavity and the clinical characteristics of MS. We enrolled 98 patients with MS, neuromyelitis optica spectrum disorder, or myelin oligodendrocyte glycoprotein antibody-associated disease. Tongue coating samples were analyzed using quantitative polymerase chain reaction targeting four periodontal species. High relative abundance was defined as an abundance exceeding the third quartile in proportion to the total abundance of bacteria. Associations between clinical and MRI features were assessed. Among the 56 patients with MS, only a high relative abundance of Fusobacterium nucleatum was associated with disease severity, as measured by the Expanded Disability Status Scale (EDSS) ( p  = 0.009). No associations were observed for the other three pathogens or in the non-MS groups. In a multivariate analysis, a high relative abundance of Fusobacterium nucleatum remained independently associated with the EDSS score. These findings suggest a potential association between the relative abundance of Fusobacterium nucleatum in the oral cavity and disease severity in MS.

This study aimed to evaluate the impact of the number of psychotropic medications on short-term neonatal outcomes in pregnancies complicated by maternal psychiatric disorders, focusing on the effect of non-opioid psychotropic polypharmacy and co-exposure. A retrospective study was conducted on pregnancies complicated by maternal mental disorders that resulted in full-term singleton deliveries at a tertiary perinatal hospital between 2019 and 2023. Among 4,367 deliveries during the study period, 358 were identified. Pregnant women prescribed three or more psychotropic medications had significantly higher rates of adverse neonatal outcomes. Significantly, most infants exhibiting neonatal abstinence syndrome (NAS)-related symptoms were exposed in utero to selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines (BZs). Furthermore, neonates exposed to CYP2D6-inhibiting psychotropic drugs had significantly lower Apgar scores and higher rates of neonatal intensive care unit admission, respiratory ventilator use, and NAS compared to those not exposed to such drugs. Full-term neonates born to women with mental illness taking three or more psychotropic drugs were significantly more likely to experience adverse short-term outcomes. Particular attention should be given to neonatal adaptation in infants exposed in utero to CYP2D6-inhibiting psychotropic drugs, as well as SSRIs and BZs, especially in cases of multiple psychotropic medications.