Mitochondrial dysfunction precedes hippocampal IL-1β transcription and cognitive impairments after low-dose lipopolysaccharide injection in aged mice

Yulim Lee; Xianshu Ju; Jianchen Cui; Tao Zhang; Boohwi Hong; Yoon Hee Kim; Youngkwon Ko; Jiho Park; Chul Hee Choi; Jun Young Heo; Woosuk Chung

doi:10.1016/j.heliyon.2024.e28974

Mitochondrial dysfunction precedes hippocampal IL-1β transcription and cognitive impairments after low-dose lipopolysaccharide injection in aged mice

Heliyon. 2024 Mar 30;10(7):e28974. doi: 10.1016/j.heliyon.2024.e28974. eCollection 2024 Apr 15.

Authors

Yulim Lee^{1

2

3}, Xianshu Ju^{1

4

5}, Jianchen Cui^{1

2

3

6}, Tao Zhang^{1

2

3}, Boohwi Hong^{5

7}, Yoon Hee Kim^{5

7}, Youngkwon Ko^{5

7}, Jiho Park⁸, Chul Hee Choi^{1

3

9}, Jun Young Heo^{1

2

3

4

10}, Woosuk Chung^{1

3

4

5

7}

Affiliations

¹ Department of Medical Science, Chungnam National University School of Medicine, Daejeon, South Korea.
² Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, South Korea.
³ Brain Korea 21 FOUR Project for Medical Science, Chungnam National University, Daejeon, South Korea.
⁴ Brain Research Institute, Chungnam National University School of Medicine, Daejeon, South Korea.
⁵ Department of Anesthesiology and Pain Medicine, Chungnam National University Hospital, Daejeon, South Korea.
⁶ Department of Anesthesiology, The First People's Hospital of Yunnan Province. The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China.
⁷ Department of Anesthesiology and Pain Medicine, Chungnam National University School of Medicine, Daejeon, South Korea.
⁸ Department of Anesthesiology and Pain Medicine, Chungnam National University Hospital, Sejong, South Korea.
⁹ Department of Microbiology, Chungnam National University School of Medicine, Daejeon, South Korea.
¹⁰ Infection Control Convergence Research Center, Chungnam National University School of Medicine, Daejeon, South Korea.

Abstract

Acute cognitive impairments termed delirium often occur after inflammatory insults in elderly patients. While previous preclinical studies suggest mitochondria as a target for reducing neuroinflammation and cognitive impairments after LPS injection, fewer studies have evaluated the effects of a low-grade systemic inflammation in the aged brain. Thus, to identify the significance of mitochondrial dysfunction after a clinically relevant systemic inflammatory stimulus, we injected old-aged mice (18-20 months) with low-dose lipopolysaccharide (LPS, 0.04 mg/kg). LPS injection reduced mitochondrial respiration in the hippocampus 24 h after injection (respiratory control ratio [RCR], state3u/state4o; control = 2.82 ± 0.19, LPS = 2.57 ± 0.08). However, gene expression of the pro-inflammatory cytokine IL-1β was increased (RT-PCR, control = 1.00 ± 0.30; LPS = 2.01 ± 0.67) at a more delayed time point, 48 h after LPS injection. Such changes were associated with cognitive impairments in the Barnes maze and fear chamber tests. Notably, young mice were unaffected by low-dose LPS, suggesting that mitochondrial dysfunction precedes neuroinflammation and cognitive decline in elderly patients following a low-grade systemic insult. Our findings highlight mitochondria as a potential therapeutic target for reducing delirium in elderly patients.

Keywords: Cognition; Inflammation; Lipopolysaccharide; Mitochondria; Neuroinflammation; Old age.