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

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.

Keywords: Fc receptor; alpha-synuclein; antibody immunity; beta-amyloid; microglia; neurodegeneration; prion-like proteins; tau (MAPT).

Figure 1

Protein aggregation and prion-like spread. (A) Native protein undergoes a spontaneous conversion to an assembled state. Assemblies above a critical size are able to extend via the addition of native protein monomers to form a fibril. (B) Assembled protein species are able to transmit between cells via routes that may include (1) free protein release and uptake, (2) tunneling nanotubes and (3) extracellular vesicles. Once taken up to the cytoplasm of a neighbouring cell, seeded aggregation occurs through the templated addition of native protein. By fragmenting, fibrils can exponentially amplify in number.

Figure 2

The maintenance of brain antibody levels. (A) Graphical representation of blood vessels in the brain and the cellular structure of the BBB. Endothelial cells in blood vessels interact via tight junctions, restricting the passage of solutes to the CNS. Pericytes bind to the basal lamina and provide structural support to the barrier. Astrocytic foot processes extend from the interstitial spaces to interact with the basal lamina and surrounding cells. (B) Two models of antibody cycling into the CNS. Under a model of static, low concentration in the CNS, antigen binding is highly restricted. However, a model where antibodies rapidly cycle in and out of the brain permits continuous bathing of brain antigens in dilute antibody solution. Over time, this model allows much higher levels of antigen binding. Evidence in support of such a model includes the observation that antibody half-life in the brain is <1 h, compared to around 3 weeks in serum. AF, astrocyte foot; BL, basal lamina; EC, endothelial cell; PC, pericyte; RBC, red blood cell; TJ, tight junction.

Figure 3

Mechanisms of antibody-mediated protection against prion-like proteins. (A) The process of seeding for tau and αS may be neutralized by antibodies at several stages. Protein seeds attach to cells via interactions with (1) heparan sulfate proteoglycan (HSPGs) or (2) cell surface receptors such as LAG3 for αS. (3) Seeds must escape vesicular compartments in order to induce seeding, a step that by analogy with viral infection could be inhibited by antibodies. (4) Seeds that escape to the cytoplasm with antibodies attached may be prevented from undergoing seeded aggregation or (5) become targets for proteasomal destruction by the cytoplasmic Fc receptor and ubiquitin ligase, TRIM21. (6) Antibodies may be directly taken up into cells in a target-specific manner and mediate degradation of target proteins in the cytoplasm via TRIM21, or in the lysosome/autophagy pathways. (B) Antibody-decorated aggregates can be ligated by cell surface FcγRs on microglia. This induces their uptake and degradation and may play an important role in overall in vivo protection.