Repository logo
 

The Role of Antibodies and Their Receptors in Protection Against Ordered Protein Assembly in Neurodegeneration.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Katsinelos, Taxiarchis  ORCID logo  https://orcid.org/0000-0001-6951-3216
Tuck, Benjamin J 
Mukadam, Aamir S 
McEwan, William A 

Abstract

Ordered assemblies of proteins are found in the postmortem brains of sufferers of several neurodegenerative diseases. The cytoplasmic microtubule associated protein tau and alpha-synuclein (αS) are found in an assembled state in Alzheimer's disease and Parkinson's disease, respectively. An accumulating body of evidence suggests a "prion-like" mechanism of spread of these assemblies through the diseased brain. Under this hypothesis, assembled variants of these proteins promote the conversion of native proteins to the assembled state. This likely inflicts pathology on cells of the brain through a toxic gain-of-function mechanism. Experiments in animal models of tau and αS pathology have demonstrated that the passive transfer of anti-tau or anti-αS antibodies induces a reduction in the levels of assembled proteins. This is further accompanied by improvements in neurological function and preservation of brain volume. Immunotherapy is therefore considered one of the brightest hopes as a therapeutic avenue in an area currently without disease-modifying therapy. Following a series of disappointing clinical trials targeting beta-amyloid, a peptide that accumulates in the extracellular spaces of the AD brain, attention is turning to active and passive immunotherapies that target tau and αS. However, there are several remaining uncertainties concerning the mechanism by which antibodies afford protection against self-propagating protein conformations. This review will discuss current understanding of how antibodies and their receptors can be brought to bear on proteins involved in neurodegeneration. Parallels will be made to antibody-mediated protection against classical viral infections. Common mechanisms that may contribute to protection against self-propagating protein conformations include blocking the entry of protein "seeds" to cells, clearance of immune complexes by microglia, and the intracellular protein degradation pathway initiated by cytoplasmic antibodies via the Fc receptor TRIM21. As with anti-viral immunity, protective mechanisms may be accompanied by the activation of immune signaling pathways and we will discuss the suitability of such activation in the neurological setting.

Description

Keywords

Fc receptor, alpha-synuclein, antibody immunity, beta-amyloid, microglia, neurodegeneration, prion-like proteins, tau (MAPT), Animals, Autoantibodies, Brain, Disease Models, Animal, Humans, Immunotherapy, Neurodegenerative Diseases, Vaccines, alpha-Synuclein, tau Proteins

Journal Title

Front Immunol

Conference Name

Journal ISSN

1664-3224
1664-3224

Volume Title

10

Publisher

Frontiers Media SA
Sponsorship
Wellcome Trust (206248/Z/17/Z)