Abstract
There are an estimated 18 million Alzheimer's disease (AD) sufferers worldwide and with no disease modifying treatment currently available, development of new therapies represents an enormous unmet clinical need. AD is characterized by episodic memory loss followed by severe cognitive decline and is associated with many neuropathological changes. AD is characterized by deposits of amyloid beta (Aβ), neurofibrillary tangles, and neuroinflammation. Active immunization or passive immunization against Aβ leads to the clearance of deposits in transgenic mice expressing human Aβ. This clearance is associated with reversal of associated cognitive deficits, but these results have not translated to humans, with both active and passive immunotherapy failing to improve memory loss. One explanation for these observations is that certain anti-Aβ antibodies mediate damage to the cerebral vasculature limiting the top dose and potentially reducing efficacy. Fc gamma receptors (FcγR) are a family of immunoglobulin-like receptors which bind to the Fc portion of IgG, and mediate the response of effector cells to immune complexes. Data from both mouse and human studies suggest that cross-linking FcγR by therapeutic antibodies and the subsequent pro-inflammatory response mediates the vascular side effects seen following immunotherapy. Increasing evidence is emerging that FcγR expression on CNS resident cells, including microglia and neurons, is increased during aging and functionally involved in the pathogenesis of age-related neurodegenerative diseases. Therefore, we propose that increased expression and ligation of FcγR in the CNS, either by endogenous IgG or therapeutic antibodies, has the potential to induce vascular damage and exacerbate neurodegeneration. To produce safe and effective immunotherapies for AD and other neurodegenerative diseases it will be vital to understand the role of FcγR in the healthy and diseased brain. Here we review the literature on FcγR expression, function and proposed roles in multiple age-related neurological diseases. Lessons can be learnt from therapeutic antibodies used for the treatment of cancer where antibodies have been engineered for optimal efficacy.
Highlights
Alzheimer’s disease (AD) is a devastating illness with a hugely detrimental effect on the quality of life of patients and their families
The primary component of plaques was identified as amyloid beta (Aβ), a 39–43 amino acid peptide cleaved from the amyloid precursor protein (APP) (Masters et al, 1985; Allsop et al, 1988)
We showed that type III hypersensitivity in the CNS induces robust expression of: FcγRI, FcγRIIb, FcγRIII, and FcγRIV on microglia followed by a robust neuro-inflammatory response (Teeling et al, 2012; Murinello et al, 2014)
Summary
Alzheimer’s disease (AD) is a devastating illness with a hugely detrimental effect on the quality of life of patients and their families. There are a number of inflammatory changes within the CNS during ageing, which are further affected by AD, including increased expression of all FcγRs on microglial cells and/or perivascular macrophages (Peress et al, 1993; Cribbs et al, 2012) This is functionally relevant as increased expression of activating FcγRs on microglia could drive an exacerbated response to therapeutic antibodies, possibly explaining the side effects observed in the Bapineuzumab clinical trials. Ligation of IgG-immune complexes by activating FcγRs results in the crosslinking of the receptor and the phosphorylation of ITAMs in the cytoplasmic chain This forms a binding site for the Spleen tyrosine kinase (Syk), which activates downstream signaling cascades such as the PI3K pathway. In AD ramified microglia in the parenchyma, but www.frontiersin.org
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