Dec. 2016
Society Encouragement Award (Basic Research Category)
Elucidation of the regulatory and activation mechanisms of KLK7, an astrocyte derived Aβ degrading enzyme

Oct. 2015
Best poster award
IDENTIFICATION OF KLK7 AS A NOVEL AMYLOID-beta PEPTIDE-DEGRADING PROTEASE SECRETED FROM ASTROCYTES

Sep. 2015
Biological Pharmaceutical Sciences Division, Pharmaceutical Society of Japan, 14th Young Researchers Pharma and Bio Forum for the Next Generation, Outstanding Presentation Award
Elucidation of the pathological function of KLK7, a novel amyloid-beta-degrading protease derived from astrocytes

Jan. 2015
Grant-in-Aid for Scientific Research on Innovative Areas: “Brain Environmental Science.”, Research Encouragement Award
Identification of kallikrein-related peptidase 7 as a novel amyloid-beta peptide-degrading protease secreted from astrocytic cells

GPR120 Signaling Controls Amyloid-β Degrading Activity of Matrix Metalloproteinases.
Kazunori Kikuchi; Takuya Tatebe; Yuki Sudo; Miyabishara Yokoyama; Kiwami Kidana; Yung Wen Chiu; Sho Takatori; Makoto Arita; Yukiko Hori; Taisuke Tomita
The Journal of neuroscience : the official journal of the Society for Neuroscience, 14 Jul. 2021
Alzheimer's disease (AD) is characterized by the extensive deposition of amyloid-β peptide (Aβ) in the brain. Brain Aβ level is regulated by a balance between Aβ production and clearance. The clearance rate of Aβ is decreased in the brains of sporadic AD patients, indicating that the dysregulation of Aβ clearance mechanisms affects the pathologic process of AD. Astrocytes are among the most abundant cells in the brain and are implicated in the clearance of brain Aβ via their regulation of the blood-brain barrier, glymphatic system, and proteolytic degradation. The cellular morphology and activity of astrocytes are modulated by several molecules, including ω3 polyunsaturated fatty acids, such as docosahexaenoic acid, which is one of the most abundant lipids in the brain, via the G protein-coupled receptor GPR120/FFAR4. In this study, we analyzed the role of GPR120 signaling in the Aβ-degrading activity of astrocytes. Treatment with the selective antagonist upregulated the matrix metalloproteinase (MMP) inhibitor-sensitive Aβ-degrading activity in primary astrocytes. Moreover, the inhibition of GPR120 signaling increased the levels of Mmp2 and Mmp14 mRNAs, and decreased the expression levels of tissue inhibitor of metalloproteinases 3 (Timp3) and Timp4, suggesting that GPR120 negatively regulates the astrocyte-derived MMP network. Finally, the intracerebral injection of GPR120-specific antagonist substantially decreased the levels of TBS-soluble Aβ in male AD model mice, and this effect was canceled by the coinjection of an MMP inhibitor. These data indicate that astrocytic GPR120 signaling negatively regulates the Aβ-degrading activity of MMPs.SIGNIFICANCE STATEMENT The level of amyloid β (Aβ) in the brain is a crucial determinant of the development of Alzheimer's disease. Here we found that astrocytes, which are the most abundant cell type in the CNS, harbor degrading activity against Aβ, which is regulated by GPR120 signaling. GPR120 is involved in the inflammatory response and obesity in peripheral organs. However, the pathophysiological role of GPR120 in Alzheimer's disease remains unknown. We found that selective inhibition of GPR120 signaling in astrocytes increased the Aβ-degrading activity of matrix metalloproteases. Our results suggest that GPR120 in astrocytes is a novel therapeutic target for the development of anti-Aβ therapeutics.

Loss of kallikrein-related peptidase 7 exacerbates amyloid pathology in Alzheimer's disease model mice.
Kiwami Kidana; Takuya Tatebe; Kaori Ito; Norikazu Hara; Akiyoshi Kakita; Takashi Saito; Sho Takatori; Yasuyoshi Ouchi; Takeshi Ikeuchi; Mitsuhiro Makino; Takaomi C Saido; Masahiro Akishita; Takeshi Iwatsubo; Yukiko Hori; Taisuke Tomita
EMBO molecular medicine, Mar. 2018
Deposition of amyloid-β (Aβ) as senile plaques is one of the pathological hallmarks in the brains of Alzheimer's disease (AD) patients. In addition, glial activation has been found in AD brains, although the precise pathological role of astrocytes remains unclear. Here, we identified kallikrein-related peptidase 7 (KLK7) as an astrocyte-derived Aβ degrading enzyme. Expression of KLK7 mRNA was significantly decreased in the brains of AD patients. Ablation of Klk7 exacerbated the thioflavin S-positive Aβ pathology in AD model mice. The expression of Klk7 was upregulated by Aβ treatment in the primary astrocyte, suggesting that Klk7 is homeostatically modulated by Aβ-induced responses. Finally, we found that the Food and Drug Administration-approved anti-dementia drug memantine can increase the expression of Klk7 and Aβ degradation activity specifically in the astrocytes. These data suggest that KLK7 is an important enzyme in the degradation and clearance of deposited Aβ species by astrocytes involved in the pathogenesis of AD.

Dysregulated Metabolism of the Amyloid-β Protein and Therapeutic Approaches in Alzheimer Disease.
Kazunori Kikuchi; Kiwami Kidana; Takuya Tatebe; Taisuke Tomita
Journal of cellular biochemistry, Dec. 2017
Amyloid-β protein (Aβ) is the main component of senile plaques in the brains of Alzheimer disease (AD) patients. Aβ is proteolytically derived from amyloid-β precursor protein by β- and γ-secretases. Secreted Aβ is then eliminated from the central nervous system by multiple clearance mechanisms, including phagocytosis, immune responses, and proteolytic degradation. These dynamic metabolic processes, which are referred to as Aβ economy, regulate steady-state brain Aβ levels. Familial AD-linked genetic mutations augment the production and aggregation of Aβ. In contrast, rare genetic variants that reduce Aβ production were protective against AD. Moreover, decreased Aβ clearance has been demonstrated in sporadic AD patients, suggesting that dysregulation of Aβ economy contributes to the development of AD. Thus, several approaches to inhibit the production as well as to enhance the clearance of Aβ have been investigated as potential therapeutics against AD. In this manuscript, we introduce the molecules and cellular mechanisms involved in the regulation of Aβ economy and discuss the current understanding of these processes in the development of therapeutics against AD. J. Cell. Biochem. 118: 4183-4190, 2017. © 2017 Wiley Periodicals, Inc.

Memantine reduces the production of amyloid-β peptides through modulation of amyloid precursor protein trafficking.
Kaori Ito; Takuya Tatebe; Kunimichi Suzuki; Takashi Hirayama; Maki Hayakawa; Hideo Kubo; Taisuke Tomita; Mitsuhiro Makino
European journal of pharmacology, 05 Mar. 2017
Memantine, an uncompetitive glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonist, is widely used as medication for the treatment of Alzheimer's disease (AD). It has been reported that memantine reduces amyloid-β peptide (Aβ) levels in both neuronal cultures and in brains of animal models of AD. However, the underlying mechanism of these effects is unclear. Here we examined the effect of memantine on Aβ production. Memantine was administered to 9-month-old Tg2576 mice, a transgenic mouse model of AD, at 10 or 20mg/kg/day in drinking water for 1 month. Memantine significantly reduced the amounts of both CHAPS-soluble and CHAPS-insoluble Aβ in the brains of Tg2576 mice. Memantine at 10mg/kg/day for 1 month also reduced the levels of insoluble Aβ42 in the brains of aged F344 rats. Moreover, memantine reduced Aβ and sAPPβ levels in conditioned media from rat primary cortical cultures without affecting the enzymatic activities of α-secretase, β-secretase, or γ-secretase. Notably, in a cell-surface biotinylation assay, memantine increased the amount of amyloid precursor protein (APP) at the cell surface without changing the total amount of APP. Collectively, our results indicate that chronic treatment with memantine reduces the levels of Aβ both in AD models and in aged animals, and that memantine affects the endocytosis pathway of APP, which is required for β-secretase-mediated cleavage. This leads to a reduction in Aβ production. These results suggest that memantine reduces Aβ production and plaque deposition through the regulation of intracellular trafficking of APP.

Implementation of Virtual Reality in Pharmacology Education: A Pilot Approach to Practical Training Involving Animal Experiments　　　　　　　　　　　　　　　
Takahiro Toda; Takuya Tatebe; Kotaro Takasaki; Takashi Yoshida; Takayuki Yoshida; Mami Kikuchi; Miwako Kamei
Mar. 2025

Synthesis of 2-phenylbenzofuran BF168 with low toxicity and potent amyloid-β aggregation inhibitory activity and structure determination of unexpected product A
長谷川真子; 建部卓也; 中込広大; 鈴木英治
日本薬学会年会要旨集(Web), 2025

Induction of anti-tumor immunity by cancer cells expressing BCG antigen with IL-2
建部卓也; 石田功
日本薬学会年会要旨集(Web), Mar. 2021

BCG抗原発現がん細胞による抗腫瘍免疫誘導
2020

アストロサイト由来Aβ分解酵素Kallikrein-related peptidase 7の発現制御機構の解析
Sep. 2018

脳疾患におけるグリア病態の新展開 アストロサイト由来アミロイドβ分解酵素KLK7の発現制御機構の解明　　　　　　　　　　　　　　　
Dec. 2017

脂質メディエーターによるアミロイドβ分解活性の制御機構解明
Mar. 2017

アストロサイト由来Aβ分解酵素KLK7の発現制御・活性化機構の解明
Oct. 2016

アストロサイト由来新規アミロイドβ分解酵素KLK7の病的意義解明
Sep. 2016

アストロサイト由来新規Aβ分解酵素KLK7の病的機能解明
Mar. 2016

Aβ除去メカニズムUpdate Degradation/Clearance System of Pathogenic Molecules-Update アストロサイト由来新規Aβ分解酵素KLK7の同定と解析　　　　　　　　　　　　　　　
Sep. 2015

アストロサイト由来新規Aβ分解酵素KLK7の同定と解析
2015

グリア系培養細胞上清中に含まれるセリンプロテアーゼ様Aβ分解活性の解析
Mar. 2014

免疫誘導可能な外来抗原を発現させたがん細胞の有効活用　　　　　　　　　　　　　　　
Aug. 2025

新型コロナウイルス感染症と感染対策について　　　　　　　　　　　　　　　
2025

認知症について考えよう　　　　　　　　　　　　　　　
2024

新型コロナウイルスの基礎からワクチン開発状況について　　　　　　　　　　　　　　　
2021

Development of killer T cell-mediated cancer therapeutic vaccine by microbial-derived antigen-expressing cancer cell transplantation
Grant-in-Aid for Early-Career Scientists
Teikyo Heisei University
01 Apr. 2022 - 31 Mar. 2025

新型コロナウイルス細胞性免疫誘導型ワクチン開発とHLA発現マウスモデルでの評価
01 Apr. 2022 - 31 Mar. 2025

Development of cancer treatment vaccine that can cover the majority of Japanese
Grant-in-Aid for Early-Career Scientists
Teikyo Heisei University
01 Apr. 2019 - 31 Mar. 2022