Cerebral ischemic injury impairs autophagy and exacerbates cognitive impairment in APP/PS1 mice

• Published in: International immunopharmacology 2024-12, Vol.143 (Pt 3), p.113581, Article 113581
• Main Authors: Ning, Zhenqiu, Zhong, Xiaoqin, Wang, Yu, Hu, Dafeng, Tang, Xialin, Deng, Minzhen
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Animals; APP/PS1 mice; Autophagy; Brain Ischemia - metabolism; Brain Ischemia - pathology; Cerebral ischemic injury; Cognitive Dysfunction - etiology; Cognitive Dysfunction - metabolism; Cognitive impairment; Disease Models, Animal; Hippocampus - metabolism; Hippocampus - pathology; Humans; Label-free proteomics; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Oxidative Stress; Presenilin-1 - genetics
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.113581

[Display omitted] •Cerebral ischemia exacerbates learning and memory deficits in APP/PS1 mice.•Autophagy is impaired in APP/PS1 mice compared to WT mice.•The mRNA expression of Abcb8, Sestd1, TPR, and Rab8a was reduced in dementia model mice after cerebral ischemia. Autophagy plays a pivotal role in the pathogenesis and progression of Alzheimer’s disease (AD). Oxidative stress and neuroinflammation involved in autophagy are associated with the cerebral ischemia-induced exacerbation of cognitive deficits in individuals with AD. APP/PS1 mice underwent bilateral common carotid artery clamping for 15 min. The degrees of Aβ deposition, oxidative stress, neuroinflammation, and neuronal and synaptic loss after cerebral ischemia were detected. Autophagy levels were assessed by RT-qPCR, western blotting, immunofluorescence staining, and transmission electron microscopy. DPEs occurring in the hippocampus of APP/PS1 mice after cerebral ischemia were analyzed via label-free proteomics. The present study demonstrated that cerebral ischemia exacerbates learning and memory deficits in APP/PS1 mice. Cerebral ischemia aggravated the cognitive impairment in APP/PS1 mice by worsening neuronal and synaptic loss through damage to intracellular autophagy, increased oxidative stress, and neuroinflammation. Notably, cerebral ischemia interfered with mitochondrial and nuclear transport functions in APP/PS1 transgenic mice, thereby aggravating cognitive deficits. Cellular transport functions may be a target for preventing AD progression. In summary, autophagy is impaired in APP/PS1 mice compared with WT mice, and oxidative stress and neuroinflammation caused by cerebral ischemia exacerbate autophagy-induced damage and are responsible for cognitive decline. Label-free proteomics indicated that cerebral ischemia results in abnormal Abcb8, Sestd1, TPR, and Rab8a protein expression in the hippocampus of APP/PS1 transgenic mice and that an imbalance of mitochondrial transport and nuclear transport functions exacerbates cognitive deficits. Improving autophagy and restoring organelle transport may be targets for the prevention and treatment of dementia.