Improving immunotherapy for Alzheimer’s Disease - determining the role of effector function in the clearance of plaques and neuro-inflammatory response

Abstract

Alzheimer’s Disease (AD) initially presents as episodic memory loss, followed by severe cognitive deterioration leaving a patient unable to complete daily tasks. Current therapies for AD are ineffective and can only manage the symptoms in the short term, none can modify the progression of disease. The devastating impact of the disease and the world’s ageing population make the development of new therapeutics an urgent unmet clinical need. One of the hallmarks of AD, still used to formally diagnose the disease, is the accumulation of the protein amyloid beta (A?) as extracellular deposits called plaques. Immunotherapy is a promising strategy for the treatment of AD, as antibodies directed against A? are able to successfully clear plaques and reverse cognitive deficits in transgenic mouse models, and now to a certain extent in humans. One issue has been the development of dose limiting side effects in the brain, where clearance of A? is associated with damage to the cerebral vasculature. It is though that these side effects are due to a neuro-inflammatory response, mediated by the activation of Fc gamma receptors (Fc?Rs) by anti-A? antibodies. Therefore engineering of therapeutic antibodies to reduce Fc?R affinity may prevent these side effects from occurring. The role of Fc?Rs in the clearance of A? and the neuro-inflammatory response to immunotherapy has not been thoroughly investigated.

The role of antibody effector function in the clearance of plaques and the associated neuro-inflammatory response was investigated by the generation of murine anti-A? antibodies with different constant regions, IgG1 and IgG2a, which have different Fc?R affinities. These antibodies were administered to transgenic mice via intracerebral and systemic injection, and the neuro-inflammatory response and clearance of A? was measured. The potential for systemic inflammation to affect the response to antibodies was investigated by the infection of transgenic APP mice with the bacterium Salmonella typhimurium, measuring the expression of activating Fc?Rs in the brain and vascular changes following infection.

I found that 3 factors that may impact on the ability of anti-A? antibodies to clear plaques and the strength of the neuro-inflammatory response. The effector function of antibodies is important, as antibodies with the more pro-inflammatory IgG2a constant region, were better at clearing plaques and caused more neuro-inflammation than the same antibody with an IgG1 constant region. The antibody binding specificity was also important; antibodies binding to the N-terminus of A? were better at clearing plaques and caused more inflammation than those binding to different regions. Finally we propose that the inflammatory state of the brain could determine the response to immunotherapy, as I show that peripheral infection is associated with enhanced activating Fc?R expression in the brain.

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Identifiers

ORCID for Jessica Teeling: orcid.org/0000-0003-4004-7391

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