The inflammatory mediator Lactorferrin induces rapid and pronounced amyloidogenic processing of APP
The balance of iron and response to inflammation (e.g. through infection) in the cell are closely linked and has previously been implicated in Alzheimer’s disease. Lactoferrin, an iron transport protein produced in conditions such as increased inflammation was recently discovered by Dr Wong to also bind Amyloid Precursor Protein (APP). The binding of lactoferrin to APP promotes the production of β-amyloid; the main peptide found in senile plaques within the brains of Alzheimer’s disease patients. At first this interaction may be a way of protecting the body by temporarily locking the iron safely within the cell and out of harm’s way, however, more persistent presence of lactoferrin could lead to greater β-amyloid levels which is known to cause neuronal death in Alzheimer’s disease. By investigating the ability of lactoferin binding to APP, Dr Wong hopes to understand the significance of this interaction and identify a potential new drug target.
While a fraction of the Alzheimer’s disease (AD) population carry a familial mutation in the Amyloid Precursor Protein (APP), the more frequent sporadic types of AD are considered to be associated with modifications to proteins such as APP. Brains from AD patients have plaques containing aggregates of b-amyloid (Aβ) peptide derived from increased amyloidogenic processing of APP. Despite strong evidence that toxic oligomers of Aβ play a central role in the pathophysiology of AD, there is still considerable debate regarding the aetiology of the disease and how up-pathway signaling initiates increased levels of Aβ in sporadic AD.
Dr. Bruce Wong has identified a novel interaction between APP and lactoferrin; a member of the transferrin family required for extracellular iron transport with strong immunomodulatory properties. The binding of lactoferrin to APP appears to be important in the location and processing of both proteins and in the case of APP, leads to increase Ab production. This study will attempt to elucidate the significance of this interaction in relation to the underlying iron dyshomeostasis and chronic inflammation that are prevalent in AD. It will also identify whether blocking the interaction between the 2 proteins is a viable drug target for future compound screening.
Dr Wong is a Research Officer based at the Florey Institute for Neuroscience and Mental Health.