Zheng Zhang, Huimin Tan, Fang Shi, Jiajia Dai, Weilong Ding, Junliang Li, Yuke Wang, Rui Yang, Xinke Xu, Cheng Chen, Fei Xiao, Li-An Huang, Xiaoyan Liu, Rui Liao, Li Yan
NAP2 ameliorates multiple AD-related pathological features, an effect accompanied by the inhibition of the Nogo-A/NgR1/ROCK pathway. These findings highlight the therapeutic potential of NAP2 to enhance resilience against Alzheimer's disease pathology.
AIMS: To evaluate the therapeutic effects of NAP2, a novel NgR1 antagonist peptide, on Alzheimer's disease (AD) pathology and to determine whether inhibition of the Nogo-A/NgR1/ROCK signaling axis can ameliorate neurodegenerative alterations in APP/PS1 mice.
METHODS: APP/PS1 transgenic mice received a three-month NAP2 intervention. Cognitive performance was assessed using standard learning and memory tests. Amyloid-β plaque burden, dendritic spine density, tau phosphorylation, and Aβ42 levels were examined by histological and biochemical analyses. Mitochondrial function and downstream ROCK signaling activity were also evaluated.
RESULTS: NAP2 treatment significantly improved cognitive performance in APP/PS1 mice. NAP2 reduced amyloid-β plaque deposition, decreased Aβ42 expression, and increased hippocampal dendritic spine density. Tau hyperphosphorylation was notably attenuated. In addition, NAP2 alleviated Aβ42-induced mitochondrial dysfunction. Mechanistic studies revealed that NAP2 interfered with ROCK signaling downstream of Nogo-A.
CONCLUSION: NAP2 ameliorates multiple AD-related pathological features, an effect accompanied by the inhibition of the Nogo-A/NgR1/ROCK pathway. These findings highlight the therapeutic potential of NAP2 to enhance resilience against Alzheimer's disease pathology.