The role of PKC/PKR in aging, Alzheimer's disease, and perioperative neurocognitive disorders

Wenping Lu; Sailan Tang; Ao Li; Qiuyue Huang; Mengyun Dou; Ye Zhang; Xianwen Hu; Raymond Chuen Chung Chang; Gordon Tin Chun Wong; Chunxia Huang

doi:10.3389/fnagi.2022.973068

The role of PKC/PKR in aging, Alzheimer's disease, and perioperative neurocognitive disorders

Front Aging Neurosci. 2022 Sep 12:14:973068. doi: 10.3389/fnagi.2022.973068. eCollection 2022.

Authors

Wenping Lu^{1

2

3}, Sailan Tang^{1

2

3}, Ao Li⁴, Qiuyue Huang⁴, Mengyun Dou¹, Ye Zhang^{1

2}, Xianwen Hu^{1

2}, Raymond Chuen Chung Chang^{5

6}, Gordon Tin Chun Wong⁷, Chunxia Huang^{1

2}

Affiliations

¹ Department of Anesthesiology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
² Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China.
³ Scientific Research and Experiment Center of the Second Affilliated Hospital of Anhui Medical University, Hefei, China.
⁴ The Second Clinical Medical College of Anhui Medical University, Hefei, China.
⁵ Laboratory of Neurodegenerative Diseases, School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
⁶ State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
⁷ Department of Anaesthesiology, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.

Abstract

Background: The incidence of perioperative neurocognitive disorders (PNDs) is reportedly higher in older patients. Mitochondrial and synaptic dysfunctions have consistently been demonstrated in models of aging and neurodegenerative diseases; nonetheless, their role in PND is not well understood.

Methods: The Morris water maze and elevated plus maze tests were used to assess the learning and memory abilities of both C57BL/6 and 3×Tg-AD mice of different ages (8 and 18 months). PND was induced by laparotomy in C57BL/6 mice and 3×Tg-AD mice (8 months old). Markers associated with neuroinflammation, mitochondrial function, synaptic function, and autophagy were assessed postoperatively. The roles of protein kinase C (PKC) and double-stranded RNA-dependent protein kinase (PKR) were further demonstrated by using PKC-sensitive inhibitor bisindolylmaleimide X (BIMX) or PKR^-/- mice.

Results: Significant cognitive impairment was accompanied by mitochondrial dysfunction and autophagy inactivation in both aged C57BL/6 and 3×Tg-AD mice. Laparotomy induced a significant neuroinflammatory response and synaptic protein loss in the hippocampus. Cognitive and neuropathological changes induced by aging or laparotomy were further exacerbated in 3×Tg-AD mice. Deficits in postoperative cognition, hippocampal mitochondria, autophagy, and synapse were significantly attenuated after pharmacological inhibition of PKC or genetic deletion of PKR.

Conclusions: Our findings suggest similar pathogenic features in aging, Alzheimer's disease, and PND, including altered mitochondrial homeostasis and autophagy dysregulation. In addition, laparotomy may exacerbate cognitive deficits associated with distinct neuronal inflammation, mitochondrial dysfunction, and neuronal loss independent of genetic background. The dysregulation of PKC/PKR activity may participate in the pathogenesis of these neurodegenerative diseases.

Keywords: autophagy; double-stranded RNA (dsRNA)-dependent protein kinase; laparotomy; perioperative neurocognitive disorders; protein kinase C.