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

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.

Synapses, Microglia, and Lipids in Alzheimer’s Disease

“…Among the eleven other subclusters was one enriched for genes of proliferation (e.g., TOP2A and MKI67 ), another for markers of cellular stress (e.g., early response genes— FOS and JUNB ; heat-shock genes— HSPA1A and HSPA1B ), and homeostatic subclusters which were inversely correlated with the load of Aβ or tau pathology. The correlation of microglial genes with Aβ pathology was noted recently by us ( Tsatsanis et al, 2021 ) and others beforehand ( Matarin et al, 2015 ). The latter genome-wide expression analysis also demonstrated correlations between genes of synaptic plasticity to tau pathology.…”

“…The small proportion of APP that reaches the plasma membrane is endocytosed within minutes and recycled or degraded in lysosomes. Our recently published results also demonstrate a mechanism of “short-circuited” APP recycling governed by lactoferrin which results in increased Aβ production ( Tsatsanis et al, 2021 ). APP may be proteolytically cleaved by γ-secretase and either α- or β-secretase.…”

Iron Dyshomeostasis and Ferroptosis: A New Alzheimer’s Disease Hypothesis?

“…After activated, they express more ferritin to scavenge the extracellular iron ( Streit et al, 2021 ), resulting in intracellular iron retention ( Kenkhuis et al, 2021 ), increased TNFα expression ( Holland et al, 2018 ), and finally infiltrated with Aβ-plaques ( Peters et al, 2018 ; Kenkhuis et al, 2021 ). Activated microglia also secret Lf, which can interact with APP, promoting the Aβ formation ( Tsatsanis et al, 2021 ). Conversely, formation of Aβ induces more IL-1β expression in microglia in the environment of elevated iron, exacerbating the proinflammatory effects ( Nnah et al, 2020 ).…”

In Vitro Methodologies to Study the Role of Advanced Glycation End Products (AGEs) in Neurodegeneration

“…The application of co-cultures in transwells of neuronal lines with microglial lines is a commonly used model of neuroinflammation in the literature. A suitable model to study AGEs in neuroinflammation is the transwell co-culture system with the HMC3 microglia and the SH-SY5Y neuronal line, presented in a recent study [309]. Especially for the BBB, which by definition describes a physical and functional barrier consisting of multiple types of cells, the co-cultures of brain endothelial cells with other relevant cells such as pericytes in a transwell system could be a good in vitro tool.…”