作者: Hatakawa, Yusuke ; Konishi, Motomi ; Furubayashi, Tomoyuki ; Sakane, Toshiyasu ; Tanaka, Akiko ; Akizawa, Toshifumi ; Nakamura, Rina ; Katsumi, Hidemasa

JAL-TA9 (YKGSGFRMI), is a 9-residue catalytic peptide that cleaves amyloid β (Aβ) 42. Nasal administration was chosen to bypass the blood-brain barrier for efficient brain delivery of JAL-TA9 to treat Alzheimer's disease (AD). Plasma clearance of JAL-TA9 after intravenous bolus injection in rats was very rapid, with a half-life of <1 min. The stability of JAL-TA9 in cerebrospinal fluid (CSF) was much better than that in plasma and whole blood in vitro, suggesting the advantage of direct nasal delivery to avoid rapid elimination from the blood. JAL-TA9 in CSF was 0.115 μg/mL 10 min after nasal administration to rats, but below the detection limit after intravenous injection, indicating a significant direct delivery of JAL-TA9 to the brain. In mice brain, JAL-TA9 concentration was higher after nasal administration than that after intraperitoneal administration. Additionally, peak concentration in the olfactory bulb (OB) after nasal application was at 5 min, whereas in the frontal and occipital brains peaked at 30 and 60 min, respectively, suggesting sequential backward translocation of JAL-TA9 within the brain after direct transport from the nasal cavity to the OB. Therefore, nasal administration allows the efficient delivery of JAL-TA9 to the brain and may be a potential in AD treatment.

2024-11-01·Folia Pharmacologica Japonica

Effects of JAL-TA9 on cognitive deficits in Alzheimer’s disease model mouse

Article

作者: Zou, Suo

Many studies have been conducted to find an effective drug for Alzheimer's disease (AD) treatment. However, no effective drug applicable for clinical use has been developed. Recently, the FDA approved Lecanemab, an antibody drug that acts as an aggregation inhibitor against Amyloid-beta (Aβ), for AD treatment. However, there are still no fundamental drugs for AD. In this study, we present a strategy for AD treatment that removes Aβ by cleavage reaction using one of the Catalytides, JAL-TA9 (YKGSGFRMI). A single dose of JAL-TA9 administered into the CA1 region of the hippocampus and the intraventricular space improved the deficits in short-term memory of APP-knock-in mice. It also improved the memory of Aβ25-35-induced model mice, as evaluated by the Y-maze and objective recognition tests. These data strongly suggest that JAL-TA9 could be effective in treating AD. However, these administration methods are difficult to apply clinically due to their high invasiveness. Thus, we tested the improvement effects of dementia by administering JAL-TA9 nasally. It is very interesting and exciting that the dementia of Aβ25-35 induced AD model mice was improved by four applications once every three days. These results strongly suggest that JAL-TA9 is the best candidate for AD treatment because it is effective even in the late stage of AD.

2024-11-01·Folia Pharmacologica Japonica

The discovery of JAL-TA9 which cleaves amyloid-β with proteolytic activity

Article

作者: Nakamura, Rina

Amyloid-β (Aβ) 42, one of the causes of Alzheimer's disease (AD), is produced by the cleavage of amyloid precursor protein (APP) by β- or γ-secretases. Since Aβ42 oligomers exhibit strong neurotoxicity, Aβ42 is predicted to be a potentially efficient target for drug therapies. Recently, we screened peptides that activate MMP7 using our peptide library and found that the synthetic peptide JAL-TA9 (YKGSGFRMI), which is derived from the BoxA region of Tob1 protein, showed proteolytic activity. It is generally accepted that an enzyme should be a large molecular protein consisting of more than thousands of amino acids. Thus, this is the first finding that a small synthetic peptide has protease activity, and we termed Catalytide as the general name of peptides with protease activity. In this study, we demonstrate the cleavage activity of JAL-TA9 not only against the authentic soluble form of Aβ42 but also against the solid type of Aβ42 in the central region. In addition, we demonstrated the cleavage activity using brain slices of AD patients. JAL-TA9 decreased the amount of accumulated Aβ42 in the brain of Alzheimer's patients. Taken together, JAL-TA9 is an attractive seed for the development of peptide drugs with a new strategy for Alzheimer's disease.

100 项与 Ykgsgfrmi 相关的药物交易

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