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.