Impact of mitochondrial aldehyde dehydrogenase 2 on cognitive impairment in the AD model mouse

Abstract

Abstract Alzheimer’s disease (AD) is one of the major life-threatening diseases for the elderly because neither pathogenesis nor effective treatment is available. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) has been shown to reduce the cell-damaging aldehydes in response to reactive oxygen species (ROS). However, whether it plays a role in AD remains elusive. In the present study, we found that ALDH2 overexpression significantly improved the cognitive function of the AD mouse. Behavioral analyses of ALDH2-overexpressing APP/PS1 AD mice showed that the learning and cognitive abilities were significantly higher in these mice than in the control group APP/PS1 mice. Further open-field behavior experiments showed the same results. At the cellular level, ALDH2 protects nerve cells. HT22 cells were challenged with Aβ to establish an AD cell model, in the presence or absence of the ALDH2 activator Alda-1 and ALDH2 inhibitor Daidzin. Incubation with 50 μM Aβ for 24 h significantly reduced HT22 cell survival and cell viability, the effects of which were attenuated by the ALDH2 activator Alda-1 (50 μM). Aβ challenge promoted apoptosis and upregulated caspase3 level but suppressed Bcl-2 level, and the upregulated caspase3 level was reversed by the ALDH-2 agonist Alda-1. Aβ-induced clonal ball abnormal was reversed by Alda-1. Aβ altered the mitochondria geometry evidenced by vacuolar degeneration and membrane rupture, whereas Alda-1 changed the Aβ-induced mitochondria geometry anomalies. Moreover, superoxide anion and toxic 4-hydroxy-nonanal (4-HNE) and ROS increased by Aβ challenge were reversed by Alda-1. Meanwhile, Aβ-induced ATP reduction was reversed by Alda-1. Taken together, ALDH2 overexpression significantly improves the cognitive function of the AD mice. Furthermore, our results suggested that ALDH2 protects against Aβ hippocampal neuronal toxicity possibly through alleviating toxic aldehydes and ROS, as well as increasing ATP production to preserve mitochondrial integrity and reduce neuronal apoptosis.