Intracranial injection of PEG-PEI/ROCK II-siRNA improves cognitive impairment in a mouse model of Alzheimer's disease

Purpose: A plenty of studies have demonstrated that the Rho/ROCK pathway is involved in the neuronal loss and inhibition of axonal regeneration observed in Alzheimer's disease (AD). Therefore, we conducted this study to evaluate whether intracranial injection of PEG-PEI/ROCK II siRNA (PPRS) would improve the cognitive impairments in a senescence-accelerated mouse (SAM) model of AD. Materials and Methods: Five male senescence-resistant inbred strain (SAMR1) mice and 15 male senescence-accelerated mouse prone-8 (SAMP8) strain mice were divided into the following three groups: PPRS group, PEG-PEI/ROCK II-Scramble (PPRScr) siRNA group, and normal group (SAMR1). Total volumes of 2.3 mu l of nanoparticles or saline were intracranially injected under the guidance of a stereotaxic apparatus. The injections were performed every three days and lasted for two weeks. Four weeks after injection, the Morris water maze (MWM) was used to evaluate the spatial learning and memory functions of the mice. Choline acetyltransferase (ChAT) activity was detected by immunohistochemistry. Results: Mice in the PPRS-treated group exhibited decreases in escape latencies over the three successive days of navigating the test and crossing the target quadrant during the spatial probe test more frequently than did the mice in the PPRScr-treated group. Analyses of ChAT activity revealed that greater numbers of ChAT-positive cells were present in the hippocampal regions of the PPRS-treated mice than in the PPRScr group. Conclusions: Intracranial injection of PPRS improved the cognitive impairments of SAM mice, and this improvement may have been mediated by enhancement of ChAT activity in the hippocampus.