The present study aimed to examine whether the aged mice with naturally occurring cognitive deficits in learning and memory would benefit from supplementation of choline acetyltransferase (ChAT), the biosynthetic enzyme for neurotransmitter acetylcholine. Delivered by protein transduction domain (PTD), ChAT could pass through the blood-brain barrier, enter the neurons, interact with heat shock protein 70 kDa, and retain enzyme activity. In behavior tests, PTD-ChAT given to the aged and memory-deficient mice almost completely reversed the behavioral changes, such as impairment of memory retention in the step-through test (an index of long-term memory) and prolonged swimming time in water maze test (an index of spatial recognition memory). The results suggest a novel and potential therapeutic use of PTD-ChAT in the age-related cognitive deficits. (c) 2005 Elsevier Inc. All rights reserved.