The acute phase protein lactoferrin is a key feature of Alzheimer's disease and predictor of A beta burden through induction of APP amyloidogenic processing

Amyloidogenic processing of the amyloid precursor protein (APP) forms the amyloid-beta peptide (A beta) component of pathognomonic extracellular plaques of AD. Additional early cortical changes in AD include neuroinflammation and elevated iron levels. Activation of the innate immune system in the brain is a neuroprotective response to infection; however, persistent neuroinflammation is linked to AD neuropathology by uncertain mechanisms. Non-parametric machine learning analysis on transcriptomic data from a large neuropathologically characterised patient cohort revealed the acute phase protein lactoferrin (Lf) as the key predictor of amyloid pathology. In vitro studies showed that an interaction between APP and the iron-bound form of Lf secreted from activated microglia diverted neuronal APP endocytosis from the canonical clathrin-dependent pathway to one requiring ADP ribosylation factor 6 trafficking. By rerouting APP recycling to the Rab11-positive compartment for amyloidogenic processing, Lf dramatically increased neuronal A beta production. Lf emerges as a novel pharmacological target for AD that not only modulates APP processing but provides a link between A beta production, neuroinflammation and iron dysregulation.

Automated summary

Amyloidogenic processing of the amyloid precursor protein leads to the formation of amyloid-beta peptide plaques in Alzheimer's disease. Early cortical changes in AD also involve neuroinflammation and elevated iron levels. The activation of the innate immune system in the brain is a neuroprotective response to infection, but persistent neuroinflammation is linked to AD neuropathology through unknown mechanisms.