Dataset Information

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

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.

SUBMITTER: He CY

PROVIDER: S-EPMC9905456 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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

He Chen-Yang CY Tian Ding-Yuan DY Chen Si-Han SH Jin Wang-Sheng WS Cheng Yuan Y Xin Jia-Yan JY Li Wei-Wei WW Zeng Gui-Hua GH Tan Cheng-Rong CR Jian Jie-Ming JM Fan Dong-Yu DY Ren Jun-Rong JR Liu Yu-Hui YH Wang Yan-Jiang YJ Zeng Fan F

Neuroscience bulletin 20220816 2

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 (CS ...[more]

PMID: 35974288

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Project description:BackgroundAbnormal aggregation of proteins induces neuronal cell loss in neurodegenerative disorders such as Alzheimer's Disease, Creutzfeldt-Jakob Disease and Parkinson's Disease. Specific stimuli initialize conformational changes in physiological proteins, causing intra- or extracellular protein aggregation. We and other groups have identified naturally occurring autoantibodies (nAbs) as part of the human antibody pool that are able to prevent peptide fibrillation. These nAbs show a rescue effect following exposure of toxic aggregates on neurons, and they support microglial uptake of aggregated peptides.ObjectiveIdentification of a putative common epitope among the relevant proteins β-Amyloid, α-Synuclein and Prion Protein for the respective nAbs.Material and methodsBinding affinity between the aforementioned proteins and nAbs was tested by Dot Blot, ELISA and SPR-technology. Furthermore, the functionality of the protein-nAbs-complexes was studied in Thioflavin-T assays and microglial uptake experiments to study dependent inhibition of protein aggregation and enhancement of Fcγ mediated uptake by microglial cells.Resultsβ-Amyloid and Prion Protein fragment showed considerable binding affinity and functional efficacy for all applied nAbs. Thereby, no significant difference within the different nAbs was detected. In contrast, α-Synuclein was bound exclusively by nAbs-α-Synuclein, which was reproduced in all binding studies. Surprisingly, functional assays with α-Synuclein revealed no significant effect of nAbs in comparison to IVIg treatment. However, all applied nAbs as well as IVIg show a minimal functionality on the microglial uptake of α-Synuclein.ConclusionnAbs-Aβ, nAbs-PrP possibly display comparable affinity to the same structural epitope within Aβ and PrP106-126 A117V whereas the epitope recognized by nAbs-α-Syn is only present in α-Syn. The structural similarity of Aβ and PrP fragment promotes the outline for an efficient antibody for the treatment of several neurodegenerative disorders and extend the functional characteristics of the investigated nAbs.

Dataset Information

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

Publications

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

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