Naturally-Occurring Antibodies Against Bim are Decreased in Alzheimer's Disease and Attenuate AD-type Pathology in a Mouse Model

 Jie-Ming Jian1 • Dong-Yu Fan1,2 • Ding-Yuan Tian1 • Yuan Cheng1 • Pu-Yang Sun1 • Cheng-Rong Tan1 • Gui-Hua Zeng1 • Chen-Yang He1 • Ye-Ran Wang1 • Jie Zhu1 • Xiu-Qing Yao3 • Yan-Jiang Wang1,4,5 • Yu-Hui Liu1
1 Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing 400000, China 
2 Shigatse Branch, Xinqiao Hospital, Third Military Medical University, Shigatse 857000, China 
3 Department of Rehabilitation, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400000, China 
4 Key Laboratory of Ageing and Brain Disease, Chongqing 400000, China 
5 Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China

Abstract
Increased neuronal apoptosis is an important pathological feature of Alzheimer’s disease (AD). The Bcl-2-interacting mediator of cell death (Bim) mediates amyloid-beta (Aβ)-induced neuronal apoptosis. Naturally-occurring antibodies against Bim (NAbs-Bim) exist in human blood, with their levels and functions unknown in AD. In this study, we found that circulating NAbs-Bim were decreased in AD patients. Plasma levels of NAbs-Bim were negatively associated with brain amyloid burden and positively associated with cognitive functions. Furthermore, NAbs-Bim purified from intravenous immunoglobulin rescued the behavioral deficits and ameliorated Aβ deposition, tau hyperphosphorylation, microgliosis, and neuronal apoptosis in APP/PS1 mice. In vitro investigations demonstrated that NAbs-Bim were neuroprotective against AD through neutralizing Bim-directed neuronal apoptosis and the amyloidogenic processing of amyloid precursor protein. These findings indicate that the decrease of NAbs-Bim might contribute to the pathogenesis of AD and immunotherapies targeting Bim hold promise for the treatment of AD.

Keywords
Alzheimer's disease; Amyloid-beta; Bim;Naturally-occurring antibodies; Neuronal apoptosis