Elevated Levels of Naturally-Occurring Autoantibodies Against the Extracellular Domain of p75NTR Aggravate the Pathology of Alzheimer’s Disease

• DOI: 10.1007/s12264-022-00936-4
• Publication Date: 2022-08-16T16:03:08Z
• Authors: Chen-Yang He; Ding-Yuan Tian; Si-Han Chen; Wang-Sheng Jin; Yuan Cheng; Jia-Yan Xin; Wei-Wei Li; Gui-Hua Zeng; Cheng-Rong Tan; Jie-Ming Jian; Dong-Yu Fan; Jun-Rong Ren; Yu-Hui Liu; Yan-Jiang Wang; Fan Zeng
• Keywords: Neuroimmunology; Neurotoxicity

The extracellular domain (p75ECD) of p75 neurotrophin receptor (p75NTR) antagonizes Aβ neurotoxicity and promotes Aβ clearance in Alzheimer's disease (AD). The impaired shedding of p75ECD is a key pathological process in AD, but its regulatory mechanism is largely unknown. This study was designed to investigate the presence and alterations of naturally-occurring autoantibodies against p75ECD (p75ECD-NAbs) in AD patients and their effects on AD pathology. We found that the cerebrospinal fluid (CSF) level of p75ECD-NAbs was increased in AD, and negatively associated with the CSF levels of p75ECD. Transgenic AD mice actively immunized with p75ECD showed a lower level of p75ECD and more severe AD pathology in the brain, as well as worse cognitive functions than the control groups, which were immunized with Re-p75ECD (the reverse sequence of p75ECD) and phosphate-buffered saline, respectively. These findings demonstrate the impact of p75ECD-NAbs on p75NTR/p75ECD imbalance, providing a novel insight into the role of autoimmunity and p75NTR in AD.