Acrolein, an endogenous aldehyde induces Alzheimer's disease-like pathologies in mice: A new sporadic AD animal model

Chen, Chen; Lu, Junfeng; Peng, Weijia; Mak, Marvin; Yang, Yang; Zhu, Zhaowen; Wang, Shuyi; Hou, Jiawei; Zhou, Xin; Xin, Wenjun; Y, Hu; Tsim, Karl Wah Keung; Han, Yifan; Liu, Qinyu

doi:10.1016/j.phrs.2021.106003

Cited by 16 publications

(20 citation statements)

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“…Acrolein could induce cell death in cultured primary hippocampal neurons in a time‐ and concentration‐dependent manner (Lovell et al, 2001 ), and induced axonal rupture and synaptic dysfunction in cultured primary cortical neurons (Chen, Lu, et al, 2021 ). The incubation of high levels of acrolein (10–15 μM) for 24 h did induce the cell death of primary cultured cortical neurons (Figure 1a ), while low concentrations of acrolein (1–5 μM) caused axonal rupture but not cell death (Figure 1a–c ).…”

Section: Resultsmentioning

confidence: 99%

“…Since the concentration of acrolein in the brain of early AD patients is about 4–5 μM (Bradley et al, 2010 ), 5μM acrolein was chosen for the following studies. We previously reported acrolein could induce AD‐like pathologies in mice (Chen, Lu, et al, 2021 ), the expression of typical biomarkers of AD was further tested after the treatment of acrolein in vitro. The levels of Aβ1‐42, p‐Tau 396, and p‐Tau 231 were significantly increased in a concentration‐dependent manner in cultured primary cortical neurons.…”

Section: Resultsmentioning

confidence: 99%

“…Acrolein induce cognitive impairment in mice and rats (Chen, Lu, et al, 2021 ; Huang et al, 2013 ). The firstly marketed ROCK inhibitor Fasudil was evidenced its benefit in mouse models of diverse diseases such as glaucoma, hypertension, and stroke (Chen et al, 2013 ).…”

Section: Resultsmentioning

confidence: 99%

“…The levels of acrolein binding protein in brain tissue, cerebrospinal fluid and plasma of patients with MCI and AD are significantly increased, which suggested that the levels of acrolein and its metabolites could be used to predict the development of AD (Igarashi et al, 2015 ; Mizoi et al, 2014 ). Studies have shown the chronic administration of acrolein (2.5 mg/kg, 8 w) can result in mild cognitive impairment and hippocampal neuronal atrophy in SD rats (Huang et al, 2013 ) and mice (Chen, Chen, et al, 2021 ; Chen, Lu, et al, 2021 ). Here, we for the first time demonstrated that acrolein induces synaptic dysfunction in vitro and in vivo through activating RhoA/ROCK2 pathway.…”

Section: Discussionmentioning

confidence: 99%

“…The chronic administration of acrolein (2.5 mg/kg, 8 w) can result in mild cognitive impairment and hippocampal neuronal atrophy for SD rats (Huang et al, 2013 ). Further, we have demonstrated that acrolein could induce synaptic dysfunction (Chen, Lu, et al, 2021 ). Rho‐associated coiled‐coil‐containing protein kinase (ROCK) can regulate morphogenesis and synaptic plasticity of neuronal dendritic spines in the brain (Magalhaes et al, 2021 ).…”

Section: Introductionmentioning

confidence: 97%

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

Zhu

Wang

et al. 2022

Aging Cell

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

See 3 more Smart Citations

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

Zhu

Wang

et al. 2022

Aging Cell

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Aldehyde dehydrogenase 2 polymorphism is associated with chemotherapy‐related cognitive impairment in patients with breast cancer who receive chemotherapy

Yao

Shao-chun

et al. 2022

Cancer Medicine

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Background Chemotherapy‐related cognitive impairment (CRCI) is a common but easily overlooked condition that markedly affects the quality of life (QOL) of patients with breast cancer. The rs671 is a common gene polymorphism of aldehyde dehydrogenase 2 (ALDH2) in Asia that is involved in aldehyde metabolism and may be closely related to CRCI. However, no study has yet summarised the association between ALDH2 and CRCI. Methods This study enrolled one hundred and twenty‐four patients diagnosed with breast cancer according to the pathology results, genotyped for ALDH2 single‐nucleotide polymorphisms (SNP) to explore these. The mini‐mental state exam (MMSE), verbal fluency test (VFT), and digit span test (DST) results were compared in these patients before and after chemotherapy (CT). Results We found that patients with ALDH2 gene genotypes of rs671_GG, rs886205_GG, rs4648328_CC, and rs4767944_TT polymorphisms were more likely to suffer from cognitive impairment during chemotherapy. A trend toward statistical significance was observed for rs671_GG of DST (z = 2.769, p = 0.006), VFT (t = 4.624, P<0.001); rs886205_GG of DST (z = 3.663, P<0.001); rs4648328_CC of DST (z = 2.850, p = 0.004), VFT (t = 3.477, p = 0.001); and rs4767944_TT of DST (z = 2.967, p = 0.003), VFT (t = 2.776, p = 0.008). The cognitive indicators of these patients significantly decreased after chemotherapy (p < 0.05). The difference in ALDH2 rs671 was most obvious. Conclusion Our results showed what kinds of ALDH2 genotyped patients that are more likely to develop CRCI. In the future, it may be possible to infer the risk of CRCI by detecting the single‐nucleotide locus of ALDH2 that is conducive to strengthening clinical interventions for these patients and improving their QOL. More importantly, this study has important implications for Asian women with breast cancer as ALDH2 rs671 is a common polymorphism in Asians.

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Effects of C-Terminal-Ethyl-Esterification in a Snake-Venom-Based Peptide Against the Neurotoxicity of Acrolein in PC12 Cells

Bernardes

Santos

Costa

et al. 2023

Int J Pept Res Ther

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Acrolein, an endogenous aldehyde induces Alzheimer's disease-like pathologies in mice: A new sporadic AD animal model

Cited by 16 publications

References 62 publications

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

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

Aldehyde dehydrogenase 2 polymorphism is associated with chemotherapy‐related cognitive impairment in patients with breast cancer who receive chemotherapy

Effects of C-Terminal-Ethyl-Esterification in a Snake-Venom-Based Peptide Against the Neurotoxicity of Acrolein in PC12 Cells

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