2. Academic Validation
  3. β2-Microglobulin coaggregates with Aβ and contributes to amyloid pathology and cognitive deficits in Alzheimer's disease model mice

β2-Microglobulin coaggregates with Aβ and contributes to amyloid pathology and cognitive deficits in Alzheimer's disease model mice

  • Nat Neurosci. 2023 Jun 1. doi: 10.1038/s41593-023-01352-1.
Yini Zhao 1 2,  Qiuyang Zheng 1 2,  Yujuan Hong 1,  Yue Gao 1,  Jiaojiao Hu 3,  Maoju Lang 1,  Hongfeng Zhang 1 2,  Ying Zhou 4,  Hong Luo 1,  Xian Zhang 1,  Hao Sun 1,  Xiao-Xin Yan 5,  Timothy Y Huang 6,  Yan-Jiang Wang 7,  Huaxi Xu 8 9,  Cong Liu 3,  Xin Wang 10 11
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China.
  • 2 Shenzhen Research Institute of Xiamen University, Shenzhen, China.
  • 3 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 4 National Institute for Data Science in Health and Medicine, School of Medicine, Xiamen University, Xiamen, China.
  • 5 Department of Anatomy and Neurobiology, Central South University Xiangya Medical School, Changsha, China.
  • 6 Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 7 Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.
  • 8 Center for Brain Sciences, the First Affiliated Hospital of Xiamen University, Institute of Neuroscience, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Xiamen University, Xiamen, China.
  • 9 Institute for Brain Science and Disease, Chongqing Medical University, Chongqing, China.
  • 10 State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China. wangx@xmu.edu.cn.
  • 11 Shenzhen Research Institute of Xiamen University, Shenzhen, China. wangx@xmu.edu.cn.
PMID: 37264159 DOI: 10.1038/s41593-023-01352-1
Abstract

Extensive studies indicate that β-amyloid (Aβ) aggregation is pivotal for Alzheimer's disease (AD) progression; however, cumulative evidence suggests that Aβ itself is not sufficient to trigger AD-associated degeneration, and whether other additional pathological factors drive AD pathogenesis remains unclear. Here, we characterize pathogenic aggregates composed of β2-microglobulin (β2M) and Aβ that trigger neurodegeneration in AD. β2M, a component of major histocompatibility complex class I (MHC class I), is upregulated in the brains of individuals with AD and constitutes the amyloid plaque core. Elevation of β2M aggravates amyloid pathology independent of MHC class I, and coaggregation with β2M is essential for Aβ neurotoxicity. B2m genetic ablation abrogates amyloid spreading and cognitive deficits in AD mice. Antisense oligonucleotide- or monoclonal antibody-mediated β2M depletion mitigates AD-associated neuropathology, and inhibition of β2M-Aβ coaggregation with a β2M-based blocking peptide ameliorates amyloid pathology and cognitive deficits in AD mice. Our findings identify β2M as an essential factor for Aβ neurotoxicity and a potential target for treating AD.

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