Yuta Yoshino

Background: Neuroinflammation plays an important role in the pathogenesis of Alzheimer's disease, but systemic immune alterations preceding clinical onset remain insufficiently characterized. Peripheral immune and vascular inflammatory processes may influence the central nervous system through endothelial dysfunction and blood–brain barrier vulnerability. Serum proteomics offers a minimally invasive approach to identify such early systemic changes. Objective: In this population-based longitudinal cohort study, we analyzed baseline serum proteomic profiles from cognitively normal older adults who were prospectively followed for up to five years for incident Alzheimer's disease. Methods: Serum samples obtained during the preclinical phase were analyzed using a high-throughput affinity-based proteomic platform. Differential protein abundance, pathway enrichment analyses, and regularized machine learning models were applied to identify coordinated biological alterations associated with future disease onset. Results: Although no individual proteins reached false discovery rate–corrected significance, pathway-level analyses revealed biologically coherent patterns. Proteins involved in immune resolution, Fc receptor–mediated phagocytosis, endosomal trafficking, and vascular repair signaling were downregulated, whereas pathways related to neutrophil activation and neutrophil extracellular trap formation were upregulated. Machine learning models using sparse feature selection demonstrated that a small subset of serum proteins could discriminate individuals who later developed Alzheimer's disease, although confidence intervals indicated limited model stability. Conclusions: Systemic immune dysregulation and vascular inflammation are detectable years before the clinical onset of Alzheimer's disease and may contribute to neuroinflammatory vulnerability. Serum proteomics may provide insights into early peripheral processes associated with future disease risk.

Alzheimer’s disease (AD) is a major neurodegenerative disorder with amyloid beta deposition in senile plaques and phosphorylated tau in neurofibrillary tangles pathologically. Triggering receptor expressed on myeloid cells 1 (TREM1) is one of the microglial proteins, and recently, rs2234246, located in the 3’-untranslated region (UTR) of TREM1 , was reported to be associated with amyloid beta deposition in AD patients and TREM1 expression. In this study, rs2234246 in TREM1 , microRNA (miR)-138-5p that binds TREM1 seed sequence, and the hippocampal atrophy of AD patients were investigated. Three studies, including SNP functional analysis (92 controls), TREM1 protein, mRNA, and miR-138-5p expression study (40 control and 40 AD patients), and brain MRI analysis (181 control and 50 AD patients), were performed. The genotyping of rs2234246 and measurement of TREM1 mRNA and miR-138-5p expressions were conducted by qPCR methods. A dual luciferase reporter assay was used to investigate the difference in miR-138-5p binding to the seed sequence in each allele of rs2234246. Atrophy of the hippocampi was assessed on magnetic resonance imaging (MRI). The expression of the membrane form ( mbTREM1 ), but not the soluble form ( TREM1sv ) of TREMI was significantly regulated by rs2234246. The dual luciferase reporter assay showed that miR-138-5p binds on the seed sequence when the rs2234246 genotype is A. Moreover, rs2234246 ^A was associated with progression of right hippocampal atrophy in AD patients. In conclusion, TREM1 and miR-138-5p may be the key factors in the inflammatory process involved in the pathogenesis of AD.

Background: Abnormal immunity in the periphery has been reported in the pathogenesis of Alzheimer's disease (AD). Objective: In this study, blood transcriptome analyses of patients with AD, those with mild cognitive impairment (MCI) due to AD, and heathy controls were performed to elucidate immune-related pathophysiology. Methods: The sample included 63 participants from a complete enumeration study of elderly people in Nakayama town (the Nakayama Study), who were over 65 years of age, diagnosed as (1) healthy controls (N = 21, mean age: 83.8 years), (2) having MCI due to AD (N = 20, mean age: 82.6 years), or (3) having AD (N = 21, mean age: 84.2 years). Every participant underwent blood tests, magnetic resonance imaging, and questionnaires about lifestyle and cognitive function. With transcriptome analysis, differential gene expressions in the blood of the three groups were evaluated by gene ontology, pathway enrichment, and ingenuity pathway analyses, and quantitative real-time PCR was performed. Results: Neutrophil extracellular trap signaling was increased, and lipid metabolism (FXR/RXR activation, triacylglycerol degradation) was decreased in AD, whereas MCI showed protective responses via decreased neutrophil extracellular trap signaling and mitochondrial functions such as upregulation of the sirtuin pathway and downregulation of oxidative stress. Conclusions: Based on these findings and consistent with other published studies, immune cells appear to have important roles in the pathogenesis of AD, and the transcriptome in blood may be useful as a biomarker for diagnosis via monitoring immunity in MCI and AD.

Introduction: Although ATP-binding cassette sub-family A member 7 gene (ABCA7) is known to be associated with Alzheimer’s disease, the relationship between ABCA7 and schizophrenia has been unknown. Methods: Schizophrenia patients (n = 50; 24 males, 62.1 ± 0.50 years old) and age- and sex-matched healthy controls (n = 50) were recruited for the mRNA analysis. Additionally, a case-control study for the rs3764650 genotypes was performed with 1308 samples (control subjects; n = 527, schizophrenia patients; n = 781). All participants were Japanese, unrelated to each other, and living in the same area. Results: The distributions of the rs3764650 genotypes in schizophrenia patients were not different from that of controls. However, the ABCA7 mRNA expression levels in schizophrenia patients were significantly higher than those in controls by a logistic regression analysis. Additionally, the ABCA7 mRNA expression levels in schizophrenia patients were correlated with the rs3764650 genotypes in a dose-dependent manner. Discussion: The ABCA7 mRNA expression levels in peripheral blood with the rs3764650 genotypes may be related to pathological mechanisms in schizophrenia and may be a biological marker for schizophrenia.

Shinichiro Ochi, Saori Inoue, Yuta Yoshino, Hideaki Shimizu, Jun-ichi Iga, Shu-ichi Ueno. Clin Psychopharmacol Neurosci 2019;17:559-63. https://doi.org/10.9758/cpn.2019.17.4.559

Yuta Yoshino, Takaaki Mori, Taku Yoshida, Yasutaka Toyota, Hideaki Shimizu, Jun-ichi Iga, Shusaku Nishitani, and Shu-ichi Ueno. Clin Psychopharmacol Neurosci 2017;15:243-7. https://doi.org/10.9758/cpn.2017.15.3.243