Acrolein, an endogenous aldehyde induces synaptic dysfunction in vitro and in vivo: Involvement of RhoA/ROCK2 pathway

• Published in: Aging cell Vol. 21; no. 4; pp. e13587 - n/a
• Main Authors: Zhu, Zeyu, Lu, Junfeng, Wang, Shuyi, Peng, Weijia, Yang, Yang, Chen, Chen, Zhou, Xin, Yang, Xifei, Xin, Wenjun, Chen, Xinyi, Pi, Jiakai, Yin, Wei, Yao, Lin, Pi, Rongbiao
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.04.2022; John Wiley and Sons Inc
• Subjects: Acrolein; Acrolein - adverse effects; Acrolein - metabolism; Aldehydes - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Animals; Apoptosis; Biomarkers; Chen, Lu; Cognitive ability; Cytoskeleton; Dementia; Dementia disorders; Dendritic spines; Disease Models, Animal; Fasudil; Gene expression; Hippocampus - metabolism; Humans; Kinases; Long-term potentiation; Mice; Neurodegenerative diseases; Neurons; Postsynaptic density; Postsynaptic density proteins; Proteins; rho-Associated Kinases - metabolism; rhoA GTP-Binding Protein - metabolism; RhoA protein; ROCK2; Signal transduction; Spatial memory; Synapsin; synaptic dysfunction; synaptic dysfunction; ROCK2; Alzheimer's disease; Fasudil; acrolein
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.13587

Acrolein, an unsaturated aldehyde, is increased in the brain of Alzheimer's disease (AD) patients and identified as a potential inducer of sporadic AD. Synaptic dysfunction, as a typical pathological change occurring in the early stage of AD, is most closely associated with the severity of dementia. However, there remains a lack of clarity on the mechanisms of acrolein inducing AD‐like pathology and synaptic impairment. In this study, acrolein‐treated primary cultured neurons and mice were applied to investigate the effects of acrolein on cognitive impairment and synaptic dysfunction and their signaling mechanisms. In vitro, ROCK inhibitors, Fasudil, and Y27632, could attenuate the axon ruptures and synaptic impairment caused by acrolein. Meanwhile, RNA‐seq distinct differentially expressed genes in acrolein models and initially linked activated RhoA/Rho‐kinase2 (ROCK2) to acrolein‐induced synaptic dysfunction, which could regulate neuronal cytoskeleton and neurite. The Morris water maze test and in vivo field excitatory postsynaptic potential (fEPSP) were performed to evaluate spatial memory and long‐term potential (LTP), respectively. Acrolein induced cognitive impairment and attenuated LTP. Furthermore, the protein level of Synapsin 1 and postsynaptic density 95 (PSD95) and dendritic spines density were also decreased in acrolein‐exposed mice. These changes were improved by ROCK2 inhibitor Fasudil or in ROCK2+/− mice. Together, our findings suggest that RhoA/ROCK2 signaling pathway plays a critical role in acrolein‐induced synaptic damage and cognitive dysfunction, suggesting inhibition of ROCK2 should benefit to the early AD. Acrolein could induce fractures of dendritic spines and synaptic dysfunction both in vitro and in vivo. Synaptic dysfunction induced by acrolein is related to the RhoA/ROCK2 signaling pathway. Synaptic dysfunction induced by acrolein can be attenuated by knocking down ROCK2 or using ROCK inhibitor Fasudil.