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.