This paper tells how iron-bound lactoferrin increased amyloid production. The data were collected from human AD populations and machine learning analysis was used. AI Bush was among the authors. Lactoferrin modulation of this increased production is connected with inflammation and iron dysregulation and so they are related to abeta-amyloid production. Interesting paper and I think this gives something totally new about how AD develops.

Mol Psychiatry

. 2021 Aug 16.

doi: 10.1038/s41380-021-01248-1. Online ahead of print.

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

Andrew Tsatsanis ^{# 1 2}, Andrew N McCorkindale ^{# 3}, Bruce X Wong ^{1 2 4}, Ellis Patrick ⁵, Tim M Ryan ⁴, Robert W Evans ⁶, Ashley I Bush ⁴, Greg T Sutherland ⁷, Asipu Sivaprasadarao ², Boris Guennewig ^{# 8}, James A Duce ^{# 9 10 11}

Affiliations expand

• PMID: 34400772

DOI: 10.1038/s41380-021-01248-1

Abstract

Amyloidogenic processing of the amyloid precursor protein (APP) forms the amyloid-β peptide (Aβ) 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 Aβ production. Lf emerges as a novel pharmacological target for AD that not only modulates APP processing but provides a link between Aβ production, neuroinflammation and iron dysregulation.