Reexamining the Role of Amyloid β Clearance from the Brain: Exporting Labile Iron from the Interstitial Fluid Performs a Protective Function

Advantageous functions have been attributed to amyloid β, which helps explain its expression despite a propensity to aggregate. Besides supporting cognitive processes, it has antimicrobial activity, e.g., amyloid β can entrap pathogens or disrupt their membranes. Since iron is an essential element for invading organisms, limiting its availability is an antimicrobial strategy. This can be achieved by various means, such as reducing circulating iron, as is the case for anemia of inflammation or chronic disease, which may occur in Alzheimer’s disease. The protein lactoferrin, both sequesters iron and generates proteolytic fragments with antimicrobial properties, and amyloid β may have similar traits. Amyloid β, which is derived from proteolytic cleavage of amyloid precursor protein, directly inhibits microorganisms. In addition, it binds redox active metals, such as iron and copper. After being generated, amyloid β can enter the interstitial fluid and undergo clearance by a variety of mechanisms (e.g., glymphatic system, transport across the blood-brain barrier, uptake by microglia or astrocytes). This clearance, together with its small size and iron-binding properties, positions amyloid β to perform a surveillance function to access, capture, and export labile iron. By removing extraneous iron, amyloid β also helps to limit metal-catalyzed reactions that cause tissue damage. In summary, besides preventing the aggregation and neurotoxicity of amyloid β, the clearance of amyloid β from the CNS may serve a surveillance function to remove loosely bound iron to avert injury by redox-reactions and enable amyloid β to function as a mammalian siderophore making iron unavailable to invading microorganisms.