Elevated Levels of Naturally-Occurring Autoantibodies Against the Extracellular Domain of p75NTR Aggravate the Pathology of Alzheimer's Disease
Chen‑Yang He1,8 · Ding‑Yuan Tian1,5 · Si‑Han Chen1,6 · Wang‑Sheng Jin1,3 · Yuan Cheng1 · Jia‑Yan Xin1,7 · Wei‑Wei Li1,8 · Gui‑Hua Zeng1,3 · Cheng‑Rong Tan1,3 · Jie‑Ming Jian1 · Dong‑Yu Fan1,9 · Jun‑Rong Ren1 · Yu‑Hui Liu1,3 · Yan‑Jiang Wang1,2,3,4 · Fan Zeng1,3
1 Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing 400042, China
2 The Institute of Brain and Intelligence, Third Military Medical University, Chongqing 400042, China
3 Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing 400042, China
4 State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Third Military Medical University, Chongqing 400042, China
5 Department of Cardiology, Southwest Hospital, Third Military Medical University, Chongqing 400042, China
6 Department of Neurology, Nanchong Central Hospital, The Second Clinical Medical School, North Sichuan Medical College, Nanchong 637000, China
7 Department of Clinical Medicine, North Sichuan Medical College, Nanchong 637000, China
8 Department of Neurology, The General Hospital of Western Theater Command, Chengdu 610000, China
9 Shigatse Branch, Xinqiao Hospital, Third Military Medical University, Shigatse 857000, China
Abstract
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.
Keywords
Alzheimer’s disease; p75 neurotrophin receptor; Extracellular domain; Autoantibody; Amyloidbeta; Immunity
