The Promises and Challenges of Erythropoietin for Treatment of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the world, and intracellular neurofibrillary tangles and extracellular amyloid-beta protein deposits represent the major pathological hallmarks of the disease. Currently available treatments provide some symptomatic relief but fail to modify primary pathological processes that underlie the disease. Erythropoietin (EPO), a hematopoietic growth factor, acts primarily to stimulate erythroid cell production, and is clinically used to treat anemia. EPO has evolved as a therapeutic agent for neurodegeneration and has improved neurological outcomes and AD pathology in rodents. However, penetration of the blood-brain barrier (BBB) and negative hematopoietic effects are the two major challenges for the therapeutic development of EPO for chronic neurodegenerative diseases like AD. The transferrin receptors at the BBB, which are responsible for transporting transferrin-bound iron from the blood into the brain parenchyma, can be used to shuttle therapeutic molecules across the BBB. In this review, we discuss the role of EPO as a potential neurotherapeutic for AD, challenges associated with EPO development for AD, and targeting the BBB transferrin receptor for EPO brain delivery.

Keywords: Alzheimer’s disease; Blood–brain barrier; Erythropoietin; Molecular Trojan horse; Transferrin receptor.

Fig 1.. The neuroprotective effect of EPO in AD.

In experimental AD, EPO reduces Aβ toxicity, neuroinflammation and oxidative stress, and enhances neurogenesis and neurotrophic factor expression.

Fig 2.. Schematic of routes of EPO brain delivery.

Penetration of the BBB is a major challenge of EPO administration for CNS diseases including AD. One hypothesis is the existence of EPOR on the luminal side of the brain capillaries that is presumed to provide a route for circulating EPO to enter the brain. This route of EPO entry remains debatable. In the absence of such a receptor, brain delivery of EPO requires compromised BBB permeability. Alternatively, endogenous transferrin receptors (TfR), which are receptor-mediated transcytosis systems, and are highly expressed at the BBB can be harnessed to ferry EPO into the brain. A fusion protein of EPO and a chimeric monoclonal antibody against TfR has been engineered and designated, cTfRMAb-EPO. Upon binding to the BBB TfR, the cTfRMAb-EPO fusion protein is ferried into the brain to enable EPO delivery into the brain across the BBB.