2. Academic Validation
  3. Pathological convergence of APP and SNCA deficiency in hippocampal degeneration of young rats

Pathological convergence of APP and SNCA deficiency in hippocampal degeneration of young rats

  • Cell Death Dis. 2023 May 13;14(5):325. doi: 10.1038/s41419-023-05846-5.
Yajie Wang # 1,  Zhikang Miao # 1,  Chang Xu 1 2,  Ying Cai 1,  Yuting Yang 1,  Yue Hu 1,  Mengna Zhao 1,  Yue Shao 1,  Zhiqiang Li 1,  Jincao Chen 1,  Shi Chen 3 4,  Lianrong Wang 5 6
Affiliations

Affiliations

  • 1 Brain Center, Department of Neurosurgery, Ministry of Education Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China.
  • 2 The Research and Application Center of Precision Medicine, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450014, China.
  • 3 Brain Center, Department of Neurosurgery, Ministry of Education Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China. [email protected].
  • 4 Department of Burn and Plastic Surgery, Shenzhen Institute of Translational Medicine, Health Science Center, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, 518035, China. [email protected].
  • 5 Brain Center, Department of Neurosurgery, Ministry of Education Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China. [email protected].
  • 6 The Research and Application Center of Precision Medicine, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450014, China. [email protected].
  • # Contributed equally.
PMID: 37179386 DOI: 10.1038/s41419-023-05846-5
Abstract

The common pathogenesis of Alzheimer's disease (AD) and Parkinson's disease (PD) has been supported by biochemical, genetic and molecular evidence. Mitochondrial dysfunction is considered to be the common pathology in early AD and PD. The physiological regulation of APP and α-synuclein on mitochondria remains unclear, let alone whether they share common regulatory mechanisms affecting the development of neurodegenerative diseases. By studying gene knockout rats, the commonality of physiological APP and α-synuclein in maintaining mitochondrial function through calcium homeostasis regulation was revealed, which was critical in inhibiting hippocampal degeneration in young rats. APP and α-synuclein both control hippocampal mitochondrial calcium intake and outflow. In the mitochondrial calcium influx regulation, APP and α-synuclein are located on the mitochondrial-associated endoplasmic reticulum membrane (MAM) and converge to regulate the IP3R1-Grp75-VDAC2 axis. Mitochondrial calcium outflow is redundantly promoted by both α-synuclein and APP. Loss of APP or SNCA leads to mitochondrial calcium overload, thus enhancing aerobic respiration and ER stress, and ultimately causing excessive Apoptosis in the hippocampus and spatial memory impairment in young rats. Based on this study, we believe that the physiological function impairment of APP and SNCA is the early core pathology to induce mitochondrial dysfunction at the early stage of AD and PD, while the IP3R1-Grp75-VDAC2 axis might be the common drug target of these two diseases.

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