Award type：Award from Japanese society, conference, symposium, etc.  Country：Japan

Language：English   Publishing type：Research paper (scientific journal)  

Alzheimer's disease (AD) is the most common form of dementia and is characterized by the accumulation of amyloid β (Aβ) and phosphorylated tau. Neuroinflammation, mainly mediated by glial activation, plays an important role in AD progression. Although there is growing evidence for the anti-neuroinflammatory and neuroprotective effects of the cannabinoid system modulation, the detailed mechanism remains unclear. To address these issues, we analyzed the expression levels of cannabinoid receptor type II (Cnr2/Cb2) in AppNL-G-F/NL-G-F mice and human AD precuneus, which is vulnerable to amyloid deposition in AD, and the effects of JWH 133, a selective CB2 agonist, on neuroinflammation in primary glial cells and neuroinflammation and cognitive impairment in AppNL-G-F/NL-G-F mice. The levels of Cnr2/Cb2 were upregulated in microglia isolated from the cerebral cortex of AppNL-G-F/NL-G-F mice. CNR2 expression was also increased in RNAs derived from human precuneus with advanced AD pathology. Chronic oral administration of JWH 133 significantly ameliorated the cognitive impairment of AppNL-G-F/NL-G-F mice without neuropsychiatric side effects. Microglia and astrocyte mRNAs were directly isolated from the mouse cerebral cortex by magnetic-activated cell sorting, and the gene expression was determined by quantitative PCR. JWH 133 administration significantly decreased reactive astrocyte markers and microglial C1q, an inducer for the reactive astrocytes in AppNL-G-F/NL-G-F mice. In addition, JWH133 administration inhibited the expression of p-STAT3 (signal transducer and activator of transcription 3) in astrocytes in AppNL-G-F/NL-G-F mice. Furthermore, JWH 133 administration suppressed dystrophic presynaptic terminals surrounding amyloid plaques. In conclusion, stimulation of microglial CB2 ameliorates cognitive dysfunction in AppNL-G-F/NL-G-F mice by controlling astrocyte activation and inducing beneficial neuroinflammation, and our study has implications that CB2 may represent an attractive therapeutic target for the treatment of AD and perhaps other neurodegenerative diseases involving neuroinflammation.

DOI： 10.1038/s41419-024-07249-6

Open Access

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Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Vitamin C (VitC) is maintained at high concentrations in the brain and is an essential micronutrient for brain function. VitC deficiency leads to neuropsychiatric scurvy, which is characterized by depression and cognitive impairment. However, the molecular mechanism by which mild VitC deficiency impairs brain function is currently unknown. In the present study, we conducted RNA sequencing analysis and found that a short-term VitC deficiency altered the brain transcriptome in ODS rats, which cannot synthesize VitC. Bioinformatic analysis indicated that VitC deficiency affected the expression of genes controlled by the glucocorticoid receptor in the brain. We confirmed an increased secretion of glucocorticoids from the adrenal gland during VitC deficiency. We found that non-neuronal cells, including microglia, which are resident immune cells in the brain, changed their transcriptional patterns in response to VitC deficiency. Immunohistochemical analysis revealed that the quiescent ramified microglia transform into the activated amoeboid microglia during three weeks of VitC deficiency. The morphological activation of microglia was accompanied by increased expression of proinflammatory cytokines such as interleukin-6 in the hippocampus. Furthermore, VitC deficiency decreased the number of newly born neurons in the dentate gyrus of the hippocampus, suggesting that VitC was required for adult neurogenesis that plays a crucial role in learning and memory. Our findings may provide insights into the molecular mechanisms underlying the maintenance of normal brain function by adequate levels of VitC.

DOI： 10.1016/j.jnutbio.2024.109608

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Recent single-cell analyses have revealed the complexity of microglial heterogeneity in brain development, aging, and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Disease-associated microglia (DAMs) have been identified in ALS mice model, but their role in ALS pathology remains unclear. The effect of genetic background variations on microglial heterogeneity and functions remains unknown. Herein, we established and analyzed two mice models of ALS with distinct genetic backgrounds of C57BL/6 and BALB/c. We observed that the change in genetic background from C57BL/6 to BALB/c affected microglial heterogeneity and ALS pathology and its progression, likely due to the defective induction of neurotrophic factor-secreting DAMs and impaired microglial survival. Single-cell analyses of ALS mice revealed new markers for each microglial subtype and a possible association between microglial heterogeneity and systemic immune environments. Thus, we highlighted the role of microglia in ALS pathology and importance of genetic background variations in modulating microglial functions.

DOI： 10.1016/j.isci.2024.108872

Open Access

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Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Alzheimer's disease (AD) is the most common cause of dementia. A genome-wide association study has shown that several AD risk genes are involved in lipid metabolism. Additionally, epidemiological studies have indicated that the levels of several lipid species are altered in the AD brain. Therefore, lipid metabolism is likely changed in the AD brain, and these alterations might be associated with an exacerbation of AD pathology. Oligodendrocytes are glial cells that produce the myelin sheath, which is a lipid-rich insulator. Dysfunctions of the myelin sheath have been linked to white matter abnormalities observed in the AD brain. Here, we review the lipid composition and metabolism in the brain and myelin and the association between lipidic alterations and AD pathology. We also present the abnormalities in oligodendrocyte lineage cells and white matter observed in AD. Additionally, we discuss metabolic disorders, including obesity, as AD risk factors and the effects of obesity and dietary intake of lipids on the brain.

DOI： 10.1002/2211-5463.13661

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Organelle contact sites are multifunctional platforms for maintaining cellular homeostasis. Alternations of the mitochondria-associated membranes (MAM), one of the organelle contact sites where the endoplasmic reticulum (ER) is tethered to the mitochondria, have been involved in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the detailed mechanisms through which MAM integrity is disrupted in ALS have not been fully elucidated. Here, we examined whether AAA ATPase domain-containing protein 3A (ATAD3A), a mitochondrial membrane AAA ATPase accumulating at the MAM, is involved in ALS. We found that sigma-1 receptor (σ1R), an ER-resident MAM protein causative for inherited juvenile ALS, required ATAD3A to maintain the MAM. In addition, σ1R retained ATAD3A as a monomer, which is associated with an inhibition of mitochondrial fragmentation. ATAD3A dimerization and mitochondrial fragmentation were significantly induced in σ1R-deficient or SOD1-linked ALS mouse spinal cords. Overall, these observations indicate that MAM induction by σ1R depends on ATAD3A and that σ1R maintains ATAD3A as a monomer to inhibit mitochondrial fragmentation. Our findings suggest that targeting σ1R-ATAD3A axis would be promising for a novel therapeutic strategy to treat mitochondrial dysfunction in neurological disorders, including ALS.

DOI： 10.1016/j.nbd.2023.106031

Open Access

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PubMed

Responsible for pages：768-773   Language：Japanese

Event date： 2025.7

Language：English   Presentation type：Poster presentation  

Event date： 2025.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：名古屋  

Event date： 2024.11

Language：Japanese   Presentation type：Poster presentation  

Venue：郡山  

Event date： 2024.7

Language：English   Presentation type：Poster presentation  

Event date： 2024.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡  

アルツハイマー病モデルマウスの脳での免疫組織化学染色

マウス脳からのグリア細胞の初代培養法

アルツハイマー病モデルマウスの脳での免疫組織化学染色