A Novel Nogo‐A Receptor Antagonist Peptide Impedes Alzheimer's Disease Pathology by Nogo‐A/
NgR
/
ROCK
Signaling Pathway
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 ABSTRACT
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.